Gorlin syndrome- MedGen UID:
- 2554
- •Concept ID:
- C0004779
- •
- Neoplastic Process
Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs) usually from the third decade onward. Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals respectively. Approximately 5% of all children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor), generally the desmoplastic subtype. The risk of developing medulloblastoma is substantially higher in individuals with an SUFU pathogenic variant (33%) than in those with a PTCH1 pathogenic variant (<2%). Peak incidence is at age one to two years. Life expectancy in NBCCS is not significantly different from average.
Cleidocranial dysostosis- MedGen UID:
- 3486
- •Concept ID:
- C0008928
- •
- Disease or Syndrome
Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia that represents a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities) to mild CCD to isolated dental anomalies without the skeletal features. Most individuals come to diagnosis because they have classic features. At birth, affected individuals typically have abnormally large, wide-open fontanelles that may remain open throughout life. Clavicular hypoplasia can result in narrow, sloping shoulders that can be opposed at the midline. Moderate short stature may be observed, with most affected individuals being shorter than their unaffected sibs. Dental anomalies may include supernumerary teeth, eruption failure of the permanent teeth, and presence of the second permanent molar with the primary dentition. Individuals with CCD spectrum disorder are at increased risk of developing recurrent sinus infections, recurrent ear infections leading to conductive hearing loss, and upper-airway obstruction. Intelligence is typically normal.
5p partial monosomy syndrome- MedGen UID:
- 41345
- •Concept ID:
- C0010314
- •
- Disease or Syndrome
Cri-du-chat syndrome was first described by Lejeune et al. (1963) as a hereditary congenital syndrome associated with deletion of part of the short arm of chromosome 5. The deletions can vary in size from extremely small and involving only band 5p15.2 to the entire short arm. Although the majority of deletions arise as new mutations, approximately 12% result from unbalanced segregation of translocations or recombination involving a pericentric inversion in one of the parents.
Dejerine-Sottas disease- MedGen UID:
- 3710
- •Concept ID:
- C0011195
- •
- Disease or Syndrome
Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by Baets et al., 2011).
Diaphyseal dysplasia- MedGen UID:
- 4268
- •Concept ID:
- C0011989
- •
- Finding
Camurati-Engelmann disease (CED) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as macrocephaly, frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy are seen in severely affected individuals later in life.
DiGeorge syndrome- MedGen UID:
- 4297
- •Concept ID:
- C0012236
- •
- Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.
Duchenne muscular dystrophy- MedGen UID:
- 3925
- •Concept ID:
- C0013264
- •
- Disease or Syndrome
The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated DCM when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.
Familial dysautonomia- MedGen UID:
- 41678
- •Concept ID:
- C0013364
- •
- Disease or Syndrome
Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.
Progressive myositis ossificans- MedGen UID:
- 4698
- •Concept ID:
- C0016037
- •
- Disease or Syndrome
Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma including intramuscular vaccinations. Painful, recurrent soft-tissue swellings (flare-ups) may precede localized heterotopic ossification. Heterotopic ossification can occur at any location, but typically affects regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification impacting joint mobility. Problems with swallowing and speaking can occur with ossification affecting the jaw, head, and neck, and restriction of the airway and breathing may lead to thoracic insufficiency syndrome.
Focal dermal hypoplasia- MedGen UID:
- 42055
- •Concept ID:
- C0016395
- •
- Disease or Syndrome
Focal dermal hypoplasia is a multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face. Skin manifestations present at birth include atrophic and hypoplastic areas of skin; cutis aplasia; fat nodules in the dermis manifesting as soft, yellow-pink cutaneous nodules; and pigmentary changes. Verrucoid papillomas of the skin and mucous membranes may appear later. The nails can be ridged, dysplastic, or hypoplastic; hair can be sparse or absent. Limb malformations include oligo-/syndactyly and split hand/foot. Developmental abnormalities of the eye can include anophthalmia/microphthalmia, iris and chorioretinal coloboma, and lacrimal duct abnormalities. Craniofacial findings can include facial asymmetry, notched alae nasi, cleft lip and palate, and pointed chin. Occasional findings include dental anomalies, abdominal wall defects, diaphragmatic hernia, and renal anomalies. Psychomotor development is usually normal; some individuals have cognitive impairment.
Fragile X syndrome- MedGen UID:
- 8912
- •Concept ID:
- C0016667
- •
- Disease or Syndrome
FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population.
Fucosidosis- MedGen UID:
- 5288
- •Concept ID:
- C0016788
- •
- Disease or Syndrome
Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex.
Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (Kousseff et al., 1976).
Hallermann-Streiff syndrome- MedGen UID:
- 5414
- •Concept ID:
- C0018522
- •
- Disease or Syndrome
Hallermann-Streiff syndrome is characterized by a typical skull shape (brachycephaly with frontal bossing), hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia, skin atrophy, dental anomalies, and proportionate short stature (Hallermann, 1948; Streiff, 1950; Francois, 1958). Mental retardation is present in a minority of cases (Gorlin et al., 1990).
Ito hypomelanosis- MedGen UID:
- 5920
- •Concept ID:
- C0022283
- •
- Congenital Abnormality
A large brown, blue, or gray hamartoma of dermal melanocytes, usually on the shoulder and upper arm that is most commonly found in Asian populations and in females. It is sometimes associated with sensory changes in the involved skin area, but very rarely becomes cancerous.
Langer-Giedion syndrome- MedGen UID:
- 6009
- •Concept ID:
- C0023003
- •
- Disease or Syndrome
Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.
Marfan syndrome- MedGen UID:
- 44287
- •Concept ID:
- C0024796
- •
- Disease or Syndrome
FBN1-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (>50% of affected individuals); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.
Marinesco-Sjögren syndrome- MedGen UID:
- 6222
- •Concept ID:
- C0024814
- •
- Disease or Syndrome
Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, dysarthria, nystagmus, early-onset (not necessarily congenital) cataracts, myopathy, muscle weakness, and hypotonia. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and various skeletal abnormalities. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. Later, cerebellar findings of truncal ataxia, dysdiadochokinesia, nystagmus, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. Although many adults have severe disabilities, life span in MSS appears to be near normal.
Multiple endocrine neoplasia type 2B- MedGen UID:
- 9959
- •Concept ID:
- C0025269
- •
- Neoplastic Process
Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC.
Mohr syndrome- MedGen UID:
- 10077
- •Concept ID:
- C0026363
- •
- Disease or Syndrome
Orofaciodigital syndrome II (OFD2), also known as Mohr syndrome, is characterized by cleft lip/palate, lobulated tongue with nodules, dental anomalies including tooth agenesis, maxillary hypoplasia, conductive hearing loss, and poly-, syn-, and brachydactyly. Mesomelic shortening of the limbs has also been observed (Mohr, 1941; Gorlin, 1982; Monroe et al., 2016).
Nail-patella syndrome- MedGen UID:
- 10257
- •Concept ID:
- C0027341
- •
- Disease or Syndrome
Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage renal disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population.
Neurofibromatosis, type 1- MedGen UID:
- 18013
- •Concept ID:
- C0027831
- •
- Neoplastic Process
Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.
Lowe syndrome- MedGen UID:
- 18145
- •Concept ID:
- C0028860
- •
- Disease or Syndrome
Lowe syndrome (oculocerebrorenal syndrome) is characterized by involvement of the eyes, central nervous system, and kidneys. Dense congenital cataracts are found in all affected boys and infantile glaucoma in approximately 50%. All boys have impaired vision; corrected acuity is rarely better than 20/100. Generalized hypotonia is noted at birth and is of central (brain) origin. Deep tendon reflexes are usually absent. Hypotonia may slowly improve with age, but normal motor tone and strength are never achieved. Motor milestones are delayed. Almost all affected males have some degree of intellectual disability; 10%-25% function in the low-normal or borderline range, approximately 25% in the mild-to-moderate range, and 50%-65% in the severe-to-profound range of intellectual disability. Affected males have varying degrees of proximal renal tubular dysfunction of the Fanconi type, including low molecular-weight (LMW) proteinuria, aminoaciduria, bicarbonate wasting and renal tubular acidosis, phosphaturia with hypophosphatemia and renal rickets, hypercalciuria, sodium and potassium wasting, and polyuria. The features of symptomatic Fanconi syndrome do not usually become manifest until after the first few months of life, except for LMW proteinuria. Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease between the second and fourth decades of life.
Prader-Willi syndrome- MedGen UID:
- 46057
- •Concept ID:
- C0032897
- •
- Disease or Syndrome
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Pseudo-Hurler polydystrophy- MedGen UID:
- 10988
- •Concept ID:
- C0033788
- •
- Disease or Syndrome
GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.
Rett syndrome- MedGen UID:
- 48441
- •Concept ID:
- C0035372
- •
- Disease or Syndrome
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.
Asphyxiating thoracic dystrophy 3- MedGen UID:
- 19860
- •Concept ID:
- C0036069
- •
- Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013).
There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330).
For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Mucopolysaccharidosis type 7- MedGen UID:
- 43108
- •Concept ID:
- C0085132
- •
- Disease or Syndrome
Mucopolysaccharidosis type VII (MPS7) is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al., 1993). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved.
Mucopolysaccharidosis, MPS-I-H/S- MedGen UID:
- 88566
- •Concept ID:
- C0086431
- •
- Disease or Syndrome
Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.
Mucopolysaccharidosis, MPS-III-A- MedGen UID:
- 39264
- •Concept ID:
- C0086647
- •
- Disease or Syndrome
Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.
Mucopolysaccharidosis, MPS-IV-A- MedGen UID:
- 43375
- •Concept ID:
- C0086651
- •
- Disease or Syndrome
The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA typically have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum (knock-knee), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease.
Mucopolysaccharidosis, MPS-IV-B- MedGen UID:
- 43376
- •Concept ID:
- C0086652
- •
- Disease or Syndrome
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.
Congenital elevation of scapula- MedGen UID:
- 56291
- •Concept ID:
- C0152438
- •
- Congenital Abnormality
A congenital skeletal deformity characterized by the elevation of one scapula (thus, one scapula is located superior to the other).
Angelman syndrome- MedGen UID:
- 58144
- •Concept ID:
- C0162635
- •
- Disease or Syndrome
Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year.
Sotos syndrome- MedGen UID:
- 61232
- •Concept ID:
- C0175695
- •
- Disease or Syndrome
Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference =2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems (most notably autistic spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures.
Aarskog syndrome- MedGen UID:
- 61234
- •Concept ID:
- C0175701
- •
- Disease or Syndrome
Aarskog-Scott syndrome is a genetic disorder that affects the development of many parts of the body, most commonly the head and face, the hands and feet, and the genitals and urinary system (genitourinary tract). This condition mainly affects males, although females may have mild features of the syndrome.\n\nPeople with Aarskog-Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widow's peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Affected individuals can also have wide, flat feet with broad, rounded toes. Other abnormalities in people with Aarskog-Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).\n\nMost males with Aarskog-Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).\n\nThe intellectual development of people with Aarskog-Scott syndrome varies widely. Most individuals with Aarskog-Scott syndrome have normal intelligence; however, some may have mild learning and behavior problems, and in rare cases, severe intellectual disability has been reported.
Aicardi syndrome- MedGen UID:
- 61236
- •Concept ID:
- C0175713
- •
- Disease or Syndrome
Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis.
Larsen syndrome- MedGen UID:
- 104500
- •Concept ID:
- C0175778
- •
- Disease or Syndrome
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Progressive sclerosing poliodystrophy- MedGen UID:
- 60012
- •Concept ID:
- C0205710
- •
- Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Pelizaeus-Merzbacher disease- MedGen UID:
- 61440
- •Concept ID:
- C0205711
- •
- Disease or Syndrome
PLP1 disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease.
Arthrogryposis, distal, type 1A- MedGen UID:
- 113099
- •Concept ID:
- C0220662
- •
- Congenital Abnormality
Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. The term "arthrogryposis" comes from the Greek words for joint (arthro-) and crooked or hooked (gryposis). The characteristic features of this condition include permanently bent fingers and toes (camptodactyly), overlapping fingers, and a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation). Clubfoot, which is an inward- and upward-turning foot, is also commonly seen with distal arthrogryposis type 1. The specific hand and foot abnormalities vary among affected individuals. However, this condition typically does not cause any signs and symptoms affecting other parts of the body.
Gordon syndrome- MedGen UID:
- 66314
- •Concept ID:
- C0220666
- •
- Disease or Syndrome
DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate (summary by Bamshad et al., 2009).
There are 2 syndromes with features overlapping those of DA3 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 5 (DA5; 108145) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of ocular abnormalities and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition.
For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Congenital contractural arachnodactyly- MedGen UID:
- 67391
- •Concept ID:
- C0220668
- •
- Congenital Abnormality
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families.
Amniotic band syndrome- MedGen UID:
- 66322
- •Concept ID:
- C0220724
- •
- Congenital Abnormality
Constriction rings syndrome is a congenital limb malformation disorder with an extremely variable clinical presentation characterized by the presence of partial to complete, congenital, fibrous, circumferential, constriction bands/rings on any part of the body, although a particular predilection for the upper or lower extremities is seen. Phenotypes range from only a mild skin indentation to complete amputation of parts of the fetus (e.g. digits, distal limb). Compression from the rings may lead to edema, skeletal anomalies (e.g. fractures, foot deformities) and, infrequently, neural compromise.
Diastrophic dysplasia- MedGen UID:
- 113103
- •Concept ID:
- C0220726
- •
- Disease or Syndrome
Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized head, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion, the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence.
Metaphyseal chondrodysplasia, McKusick type- MedGen UID:
- 67398
- •Concept ID:
- C0220748
- •
- Congenital Abnormality
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
Craniofrontonasal syndrome- MedGen UID:
- 65095
- •Concept ID:
- C0220767
- •
- Disease or Syndrome
Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).
Pyknodysostosis- MedGen UID:
- 116061
- •Concept ID:
- C0238402
- •
- Disease or Syndrome
Pycnodysostosis is characterized by short-limbed short stature, typical facial appearance (convex nasal ridge and small jaw with obtuse mandibular angle), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge. Additional features include dental and nail anomalies. Intelligence is typically normal with mild psychomotor difficulties reported in some individuals.
Weaver syndrome- MedGen UID:
- 120511
- •Concept ID:
- C0265210
- •
- Disease or Syndrome
EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency.
Marshall-Smith syndrome- MedGen UID:
- 75551
- •Concept ID:
- C0265211
- •
- Disease or Syndrome
The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).
Freeman-Sheldon syndrome- MedGen UID:
- 120516
- •Concept ID:
- C0265224
- •
- Disease or Syndrome
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009).
For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Nager syndrome- MedGen UID:
- 120519
- •Concept ID:
- C0265245
- •
- Disease or Syndrome
Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (263750), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by Bernier et al., 2012).
Ruvalcaba syndrome- MedGen UID:
- 120520
- •Concept ID:
- C0265248
- •
- Disease or Syndrome
Ruvalcaba syndrome is an extremely rare malformation syndrome, described in less than 10 patients to date, characterized by microcephaly with characteristic facies (downslanting parpebral fissures, microstomia, beaked nose, narrow maxilla), very short stature, narrow thoracic cage with pectus carinatum, hypoplastic genitalia and skeletal anomalies (i.e. characteristic brachydactyly and osteochondritis of the spine) as well as intellectual and developmental delay.
Oto-palato-digital syndrome, type I- MedGen UID:
- 78542
- •Concept ID:
- C0265251
- •
- Disease or Syndrome
The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
Coffin-Lowry syndrome- MedGen UID:
- 75556
- •Concept ID:
- C0265252
- •
- Disease or Syndrome
Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Neuropsychiatric concerns can include behavioral problems, loss of strength, progressive spasticity or paraplegia, sleep apnea, or stroke. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Characteristic facial features may be more apparent with age. Upper-extremity differences may be subtle and include short, soft, fleshy hands with tapered fingers as well as fleshy forearms. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Affected females tend to have intellectual disability in the mild-to-moderate range and may also have the typical facial, hand, and skeletal findings noted in males.
Autosomal recessive multiple pterygium syndrome- MedGen UID:
- 82696
- •Concept ID:
- C0265261
- •
- Congenital Abnormality
Multiple pterygium syndromes comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal (253290) and nonlethal (Escobar) types.
Femoral hypoplasia - unusual facies syndrome- MedGen UID:
- 120523
- •Concept ID:
- C0265263
- •
- Disease or Syndrome
Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facies syndrome (FHUFS), is a rare and sporadic multiple congenital anomaly syndrome comprising bilateral femoral hypoplasia and characteristic facial features, such as long philtrum, thin upper lip, micrognathia with or without cleft palate, upward-slanting palpebral fissures, and a short nose with broad tip. Other features, such as renal anomalies, are more variable (summary by Nowaczyk et al., 2010).
Child syndrome- MedGen UID:
- 82697
- •Concept ID:
- C0265267
- •
- Disease or Syndrome
The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males. CHILD syndrome is characterized by unilateral distribution of ichthyosiform (yellow scaly) skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Nail changes are also common. The heart, lung, and kidneys can also be involved. CK syndrome (named for the initials of the original proband) is characterized by mild to severe cognitive impairment and behavior problems (aggression, attention deficit hyperactivity disorder, and irritability). All affected males reported have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported.
Spondylometaphyseal dysplasia, Kozlowski type- MedGen UID:
- 82698
- •Concept ID:
- C0265280
- •
- Congenital Abnormality
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Metatropic dysplasia- MedGen UID:
- 82699
- •Concept ID:
- C0265281
- •
- Congenital Abnormality
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Dyggve-Melchior-Clausen syndrome- MedGen UID:
- 120527
- •Concept ID:
- C0265286
- •
- Disease or Syndrome
Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests (summary by El Ghouzzi et al., 2003).
Metaphyseal chondrodysplasia, Schmid type- MedGen UID:
- 78550
- •Concept ID:
- C0265289
- •
- Disease or Syndrome
Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. Facial features and head size are normal. Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges. Platyspondyly and vertebral end-plate irregularities are less common. Hand and vertebral involvement can resolve with age. Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. Joint pain in the knees and hips is common and may limit physical activity. Adult height is typically more than 3.5 SD below the mean, although a wide spectrum that overlaps normal height has been reported. There are no extraskeletal manifestations.
Pyle metaphyseal dysplasia- MedGen UID:
- 82704
- •Concept ID:
- C0265294
- •
- Disease or Syndrome
Pyle disease is characterized by long bones with wide and expanded trabecular metaphyses, thin cortical bone, and bone fragility. Fractures are common in Pyle disease, and fracture lines usually go through the abnormally wide metaphyses, revealing their fragility (summary by Kiper et al., 2016).
Baller-Gerold syndrome- MedGen UID:
- 120532
- •Concept ID:
- C0265308
- •
- Disease or Syndrome
Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.
Leri-Weill dyschondrosteosis- MedGen UID:
- 75562
- •Concept ID:
- C0265309
- •
- Disease or Syndrome
The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to nonspecific short stature at the mild end of the spectrum. In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shortened in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of short stature caused by SHOX deficiency in the absence of mesomelia and Madelung deformity (called SHOX-deficient short stature in this GeneReview) is highly variable, even within the same family.
Borjeson-Forssman-Lehmann syndrome- MedGen UID:
- 78557
- •Concept ID:
- C0265339
- •
- Disease or Syndrome
Borjeson-Forssman-Lehmann syndrome (BFLS) is an uncommon X-linked intellectual developmental disorder that evolves with age. Clinical manifestations in males are quite variable, with the most consistent features being initial hypotonia, mild to moderate impaired intellectual development, large fleshy ears, underdeveloped genitalia, gynecomastia, truncal obesity, tapering fingers, and shortening of the fourth and fifth toes. Heterozygous females may have a milder similar clinical phenotype, which can include hypothyroidism; however, many carrier females appear unaffected (summary by Crawford et al., 2006).
Cerebro-costo-mandibular syndrome- MedGen UID:
- 120537
- •Concept ID:
- C0265342
- •
- Disease or Syndrome
Cerebrocostomandibular syndrome (CCMS) is a rare autosomal dominant disorder characterized by branchial arch-derivative and thoracic malformations. A key craniofacial characteristic is micrognathia, often associated with cleft palate and feeding and airway difficulties. Patients with CCMS have a narrow chest and striking posterior rib gaps which distinguish this condition (summary by Tooley et al., 2016).
See CDG2G (611209) for a cerebrocostomandibular-like syndrome.
CHARGE syndrome- MedGen UID:
- 75567
- •Concept ID:
- C0265354
- •
- Disease or Syndrome
CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.
Dermatofibrosis lenticularis disseminata- MedGen UID:
- 120545
- •Concept ID:
- C0265514
- •
- Disease or Syndrome
Buschke-Ollendorff syndrome (BOS) is an autosomal dominant connective tissue disorder manifest by multiple subcutaneous nevi or nodules. They may be either elastin-rich (elastoma) or collagen-rich (dermatofibrosis lenticularis disseminata) on histologic examination. The lesions are usually nontender and firm. Affected individuals also have osteopoikilosis (OPK), literally meaning 'spotted bones,' which are osteosclerotic foci that occur in the epiphyses and metaphyses of long bones, wrist, foot, ankle, pelvis, and scapula. Some individuals have both skin and bone manifestations, whereas others may lack skin or bone manifestations. Some individuals may also have melorheostosis (155950), which is characterized by 'flowing' hyperostosis of the cortex of tubular bones. Most reported cases of BOS and OPK are benign, and the bone lesions are found incidentally, although some patients may have joint pain (reviews by Hellemans et al., 2004 and Zhang et al., 2009).
Xeroderma pigmentosum, group F- MedGen UID:
- 120612
- •Concept ID:
- C0268140
- •
- Congenital Abnormality
Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
Aspartylglucosaminuria- MedGen UID:
- 78649
- •Concept ID:
- C0268225
- •
- Disease or Syndrome
Aspartylglucosaminuria (AGU) is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. The disorder is caused by deficient activity of the lysosomal enzyme glycosylasparaginase, which results in body fluid and tissue accumulation of a series of glycoasparagines, i.e., glycoconjugates with an aspartylglucosamine moiety at the reducing end. AGU belongs to the group of disorders commonly referred to as the Finnish disease heritage (summary by Mononen et al., 1993 and Arvio and Arvio, 2002).
Infantile GM1 gangliosidosis- MedGen UID:
- 75665
- •Concept ID:
- C0268271
- •
- Disease or Syndrome
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.
GM1 gangliosidosis type 2- MedGen UID:
- 120625
- •Concept ID:
- C0268272
- •
- Disease or Syndrome
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.
GM1 gangliosidosis type 3- MedGen UID:
- 78655
- •Concept ID:
- C0268273
- •
- Disease or Syndrome
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.
Brittle cornea syndrome 1- MedGen UID:
- 78661
- •Concept ID:
- C0268344
- •
- Disease or Syndrome
Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). It is classified as a form of Ehlers-Danlos syndrome (Malfait et al., 2017).
Genetic Heterogeneity of Brittle Cornea Syndrome
Brittle cornea syndrome-2 (BCS2; 614170) is caused by mutation in the PRDM5 gene (614161) on chromosome 4q27.
Cutis laxa with osteodystrophy- MedGen UID:
- 82795
- •Concept ID:
- C0268355
- •
- Disease or Syndrome
ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression.
Osteogenesis imperfecta type III- MedGen UID:
- 78664
- •Concept ID:
- C0268362
- •
- Disease or Syndrome
COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows: Classic non-deforming OI with blue sclerae (previously OI type I). Perinatally lethal OI (previously OI type II). Progressively deforming OI (previously OI type III). Common variable OI with normal sclerae (previously OI type IV).
Osteogenesis imperfecta with normal sclerae, dominant form- MedGen UID:
- 78665
- •Concept ID:
- C0268363
- •
- Congenital Abnormality
COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows: Classic non-deforming OI with blue sclerae (previously OI type I). Perinatally lethal OI (previously OI type II). Progressively deforming OI (previously OI type III). Common variable OI with normal sclerae (previously OI type IV).
Alstrom syndrome- MedGen UID:
- 78675
- •Concept ID:
- C0268425
- •
- Disease or Syndrome
Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.
Autosomal dominant isolated somatotropin deficiency- MedGen UID:
- 124405
- •Concept ID:
- C0271567
- •
- Disease or Syndrome
Type II IGHD is an autosomal dominant disorder characterized by low but detectable levels of growth hormone (GH), variable height deficit and age at presentation, and good response to rhGH. Patients may show anterior pituitary hypoplasia on MRI (summary by Phillips and Cogan, 1994; Alatzoglou and Dattani, 2012).
Chondrodysplasia punctata 2 X-linked dominant- MedGen UID:
- 79381
- •Concept ID:
- C0282102
- •
- Disease or Syndrome
The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of live-born individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy scaling ichthyosis in the newborn; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; and cataracts.
Deficiency of butyryl-CoA dehydrogenase- MedGen UID:
- 90998
- •Concept ID:
- C0342783
- •
- Disease or Syndrome
Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.
Sialuria- MedGen UID:
- 137980
- •Concept ID:
- C0342853
- •
- Disease or Syndrome
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
Myoclonic-astatic epilepsy- MedGen UID:
- 98284
- •Concept ID:
- C0393702
- •
- Disease or Syndrome
A generalized myoclonic-atonic seizure is a type of generalized motor seizure characterized by a myoclonic jerk followed by an atonic motor component.
Hereditary motor and sensory neuropathy with optic atrophy- MedGen UID:
- 140747
- •Concept ID:
- C0393807
- •
- Disease or Syndrome
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
Neonatal pseudo-hydrocephalic progeroid syndrome- MedGen UID:
- 140806
- •Concept ID:
- C0406586
- •
- Disease or Syndrome
Wiedemann-Rautenstrauch syndrome (WDRTS) is a rare autosomal recessive neonatal progeroid disorder characterized by intrauterine growth retardation, failure to thrive, short stature, a progeroid appearance, hypotonia, and variable mental impairment (summary by Toriello, 1990). Average survival in WDRTS is 7 months, although survival into the third decade of life has been reported (Akawi et al., 2013).
Wrinkly skin syndrome- MedGen UID:
- 98030
- •Concept ID:
- C0406587
- •
- Disease or Syndrome
ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression.
GAPO syndrome- MedGen UID:
- 98034
- •Concept ID:
- C0406723
- •
- Disease or Syndrome
GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) and Bayram et al. (2014) noted that optic atrophy is not a consistent feature of the disorder.
Autosomal recessive limb-girdle muscular dystrophy type 2C- MedGen UID:
- 98045
- •Concept ID:
- C0410173
- •
- Disease or Syndrome
A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a childhood onset of progressive shoulder and pelvic girdle muscle weakness and atrophy frequently associated with calf hypertrophy, diaphragmatic weakness, and/or variable cardiac abnormalities. Mild to moderate elevated serum creatine kinase levels and positive Gowers sign are reported.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4- MedGen UID:
- 140820
- •Concept ID:
- C0410174
- •
- Disease or Syndrome
Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy with poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death.
Ullrich congenital muscular dystrophy 1A- MedGen UID:
- 98046
- •Concept ID:
- C0410179
- •
- Disease or Syndrome
Collagen VI-related dystrophies (COL6-RDs) represent a continuum of overlapping clinical phenotypes with Bethlem muscular dystrophy at the milder end, Ullrich congenital muscular dystrophy (UCMD) at the more severe end, and a phenotype in between UCMD and Bethlem muscular dystrophy, referred to as intermediate COL6-RD. Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures. Hypotonia and delayed motor milestones occur in early childhood; mild hypotonia and weakness may be present congenitally. By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors. The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors. Respiratory involvement is not a consistent feature. UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Decreased fetal movements are frequently reported. Some affected children acquire the ability to walk independently; however, progression of the disease results in a loss of ambulation by age ten to eleven years. Early and severe respiratory insufficiency occurs in all individuals, resulting in the need for nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) by age 11 years. Intermediate COL6-RD is characterized by independent ambulation past age 11 years and respiratory insufficiency that is later in onset than in UCMD and results in the need for NIV in the form of BiPAP by the late teens to early 20s. In contrast to individuals with Bethlem muscular dystrophy, those with intermediate COL6-RD typically do not achieve the ability to run, jump, or climb stairs without use of a railing.
Eichsfeld type congenital muscular dystrophy- MedGen UID:
- 98047
- •Concept ID:
- C0410180
- •
- Disease or Syndrome
Rigid spine muscular dystrophy (RSMD) is a form of congenital muscular dystrophy. Disorders in this group cause muscle weakness and wasting (atrophy) beginning very early in life. In particular, RSMD involves weakness of the muscles of the torso and neck (axial muscles). Other characteristic features include spine stiffness and serious breathing problems.\n\nIn RSMD, muscle weakness is often apparent at birth or within the first few months of life. Affected infants can have poor head control and weak muscle tone (hypotonia), which may delay the development of motor skills such as crawling or walking. Over time, muscles surrounding the spine atrophy, and the joints of the spine develop deformities called contractures that restrict movement. The neck and back become stiff and rigid, and affected children have limited ability to move their heads up and down or side to side. Affected children eventually develop an abnormal curvature of the spine (scoliosis). In some people with RSMD, muscles in the inner thighs also atrophy, although it does not impair the ability to walk.\n\nA characteristic feature of RSMD is breathing difficulty (respiratory insufficiency) due to restricted movement of the torso and weakness of the diaphragm, which is the muscle that separates the abdomen from the chest cavity. The breathing problems, which tend to occur only at night, can be life-threatening. Many affected individuals require a machine to help them breathe (mechanical ventilation) during sleep.\n\nThe combination of features characteristic of RSMD, particularly axial muscle weakness, spine rigidity, and respiratory insufficiency, is sometimes referred to as rigid spine syndrome. While these features occur on their own in RSMD, they can also occur along with additional signs and symptoms in other muscle disorders. The features of rigid spine syndrome typically appear at a younger age in people with RSMD than in those with other muscle disorders.
Myopathy, centronuclear, 2- MedGen UID:
- 98049
- •Concept ID:
- C0410204
- •
- Disease or Syndrome
Any centronuclear myopathy in which the cause of the disease is a mutation in the BIN1 gene.
Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome- MedGen UID:
- 98378
- •Concept ID:
- C0410538
- •
- Congenital Abnormality
Pseudoachondroplasia is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery.
Gillespie syndrome- MedGen UID:
- 96563
- •Concept ID:
- C0431401
- •
- Disease or Syndrome
Gillespie syndrome (GLSP) is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by Gerber et al., 2016 and McEntagart et al., 2016).
Pseudodiastrophic dysplasia- MedGen UID:
- 140924
- •Concept ID:
- C0432206
- •
- Disease or Syndrome
Pseudodiastrophic dysplasia (PDD) is an extremely rare and severe skeletal dysplasia associated with prenatal manifestation and early lethality. Phenotypic features include short-limbed short stature at birth, facial dysmorphism, and distinctive skeletal abnormalities including short ribs, mild to moderate platyspondyly, shortened long bones with metaphyseal flaring, elongation of the proximal and middle phalanges with subluxation of the proximal interphalangeal joints, subluxation of the elbow, and talipes equinovarus (summary by Byrne et al., 2020).
Based on genetic analysis of patients with a clinical diagnosis of PDD, Byrne et al. (2020) proposed that PDD is likely not a separate genetic disorder, but rather the most severe phenotypic manifestation of skeletal dysplasia arising from defects in proteoglycan (PG) biosynthesis (see MOLECULAR GENETICS).
Opsismodysplasia- MedGen UID:
- 140927
- •Concept ID:
- C0432219
- •
- Disease or Syndrome
Opsismodysplasia (OPSMD) is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by Below et al., 2013 and Fradet and Fitzgerald, 2017).
Spondylometaphyseal dysplasia - Sutcliffe type- MedGen UID:
- 98146
- •Concept ID:
- C0432221
- •
- Disease or Syndrome
Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is a skeletal dysplasia characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Radiographic features include enlargement and corner fracture-like lesions of the metaphyses, developmental coxa vara, shortened long bones, scoliosis, and vertebral anomalies. Limited joint mobility and chronic pain are common. Vision impairment and glaucoma have been reported.
Brachyrachia (short spine dysplasia)- MedGen UID:
- 96583
- •Concept ID:
- C0432227
- •
- Congenital Abnormality
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Trichorhinophalangeal dysplasia type I- MedGen UID:
- 140929
- •Concept ID:
- C0432233
- •
- Disease or Syndrome
Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.
Osteoporosis with pseudoglioma- MedGen UID:
- 98480
- •Concept ID:
- C0432252
- •
- Disease or Syndrome
Osteoporosis-pseudoglioma syndrome (OPPG) is an autosomal recessive disorder characterized by severe osteoporosis and visual disturbance from childhood. Juvenile onset of osteoporosis manifests as long-bone fractures, vertebral compression fractures, kyphoscoliosis, deformity of extremities, and short stature. Congenital or early-onset visual disturbances arise from ophthalmologic problems including retinal detachment and microphthalmia (summary by Narumi et al., 2010).
Osteopathia striata with cranial sclerosis- MedGen UID:
- 96590
- •Concept ID:
- C0432268
- •
- Disease or Syndrome
Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. Males can present with a mild or severe phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant. The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.
Deletion of long arm of chromosome 18- MedGen UID:
- 96605
- •Concept ID:
- C0432443
- •
- Disease or Syndrome
Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.
Congenital myopathy with fiber type disproportion- MedGen UID:
- 108177
- •Concept ID:
- C0546264
- •
- Disease or Syndrome
Congenital fiber-type disproportion is a condition that primarily affects skeletal muscles, which are muscles used for movement. People with this condition typically experience muscle weakness (myopathy), particularly in the muscles of the shoulders, upper arms, hips, and thighs. Weakness can also affect the muscles of the face and muscles that control eye movement (ophthalmoplegia), sometimes causing droopy eyelids (ptosis). Individuals with congenital fiber-type disproportion generally have a long face, a high arch in the roof of the mouth (high-arched palate), and crowded teeth.\n\nIndividuals with congenital fiber-type disproportion may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30 percent of people with this disorder experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night (noninvasive mechanical ventilation), and occasionally during the day as well. About 30 percent of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy).\n\nThe severity of congenital fiber-type disproportion varies widely. It is estimated that up to 25 percent of affected individuals experience severe muscle weakness at birth and die in infancy or childhood. Others have only mild muscle weakness that becomes apparent in adulthood. Most often, the signs and symptoms of this condition appear by age 1. The first signs of this condition are usually decreased muscle tone (hypotonia) and muscle weakness. In most cases, muscle weakness does not worsen over time, and in some instances it may improve. Although motor skills such as standing and walking may be delayed, many affected children eventually learn to walk. These individuals often have less stamina than their peers, but they remain active. Rarely, people with this condition have a progressive decline in muscle strength over time. These individuals may lose the ability to walk and require wheelchair assistance.
Spondyloepimetaphyseal dysplasia, Strudwick type- MedGen UID:
- 147134
- •Concept ID:
- C0700635
- •
- Finding
The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (summary by Tiller et al., 1995).
Chiari type I malformation- MedGen UID:
- 196689
- •Concept ID:
- C0750929
- •
- Congenital Abnormality
Arnold-Chiari type I malformation refers to a relatively mild degree of herniation of the posteroinferior region of the cerebellum (the cerebellar tonsils) into the cervical canal with little or no displacement of the fourth ventricle. It is characterized by one or both pointed (not rounded) cerebellar tonsils that project 5 mm below the foramen magnum, measured by a line drawn from the basion to the opisthion (McRae Line)
Classic homocystinuria- MedGen UID:
- 199606
- •Concept ID:
- C0751202
- •
- Disease or Syndrome
Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.
Scapuloperoneal spinal muscular atrophy- MedGen UID:
- 148283
- •Concept ID:
- C0751335
- •
- Disease or Syndrome
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Central core myopathy- MedGen UID:
- 199773
- •Concept ID:
- C0751951
- •
- Disease or Syndrome
Congenital myopathy-1A (CMYO1A) with susceptibility to malignant hyperthermia is an autosomal dominant disorder of skeletal muscle characterized by muscle weakness primarily affecting the proximal muscles of the lower limbs beginning in infancy or early childhood, although later onset of symptoms has been reported. There is significant phenotypic variability, even within families, and the wide clinical diversity most likely depends on the severity of the RYR1 mutation. The disorder is static or slowly progressive; affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Some patients present with orthopedic deformities. Serum creatine kinase is usually not elevated. Respiratory involvement is rare and there is no central nervous system or cardiac involvement. Patients with dominant mutations in the RYR1 gene are at risk for malignant hyperthermia and both disorders may segregate in the same family. Historically, patients with congenital myopathy due to RYR1 mutations were diagnosed based on the finding of pathologic central cores (central core disease; CCD) on muscle biopsy, which represent areas that lack oxidative enzymes and mitochondrial activity in type 1 muscle fibers. However, additional pathologic findings may also be observed, including cores and rods, central nuclei, fiber type disproportion, multiminicores, and uniform type 1 fibers. These histopathologic features are not always specific to RYR1 myopathy and often change over time (Quinlivan et al., 2003; Jungbluth et al., 2007; Klein et al., 2012; Ogasawara and Nishino, 2021). Some patients with RYR1 mutations have pathologic findings on muscle biopsy, but are clinically asymptomatic (Shuaib et al., 1987; Quane et al., 1993).
Rare patients with a more severe phenotype have been found to carry a heterozygous mutation in the RYR1 gene inherited from an unaffected parent. However, in these cases, there is a possibility of recessive inheritance (CMYO1B; 255320) with either a missed second RYR1 mutation in trans or a genomic rearrangement on the other allele that is undetectable on routine genomic sequencing, since the RYR1 gene is very large and genetic analysis may be difficult (Klein et al., 2012).
Genetic Heterogeneity of Congenital Myopathy
See also CMYO1B (255320), caused by mutation in the RYR1 gene (180901) on chromosome 19q13; CMYO2A (161800), CMYO2B (620265), and CMYO2C (620278), caused by mutation in the ACTA1 gene (102610) on chromosome 1q42; CMYO3 (602771), caused by mutation in the SELENON gene (606210) on chromosome 1p36; CMYO4A (255310) and CMYO4B (609284), caused by mutation in the TPM3 gene (191030) on chromosome 1q21; CMYO5 (611705), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMYO6 (605637), caused by mutation in the MYH2 gene (160740) on chromosome 17p13; CMYO7A (608358) and CMYO7B (255160), caused by mutation in the MYH7 gene (160760) on chromosome 14q11; CMYO8 (618654), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMYO9A (618822) and CMYO9B (618823), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYO10A (614399) and CMYO10B (620249), caused by mutation in the MEGF10 gene (612453) on chromosome 5q23; CMYO11 (619967), caused by mutation in the HACD1 gene (610467) on chromosome 10p12; CMYO12 (612540), caused by mutation in the CNTN1 gene (600016) on chromosome 12q12; CMYO13 (255995), caused by mutation in the STAC3 gene (615521) on chromosome 12q13; CMYO14 (618414), caused by mutation in the MYL1 gene (160780) on chromosome 2q34; CMYO15 (620161), caused by mutation in the TNNC2 gene (191039) on chromosome 20q13; CMYO16 (618524), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; CMYO17 (618975), caused by mutation in the MYOD1 gene (159970) on chromosome 11p15; CMYO18 (620246), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; CMYO19 (618578), caused by mutation in the PAX7 gene (167410) on chromosome 1p36; CMYO20 (620310), caused by mutation in the RYR3 gene (180903) on chromosome 15q13; CMYO21 (620326), caused by mutation in the DNAJB4 gene (611327) on chromosome 1p31; CMYO22A (620351) and CMYO22B (620369), both caused by mutation in the SCN4A gene (603967) on chromosome 17q23; CMYO23 (609285), caused by mutation in the TPM2 gene (190990) on chromosome 9p13; and CMYO24 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21.
Recombinant 8 syndrome- MedGen UID:
- 167070
- •Concept ID:
- C0795822
- •
- Disease or Syndrome
Recombinant chromosome 8 syndrome (Rec8 syndrome) is a chromosomal disorder found among individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have impaired intellectual development, congenital heart defects, seizures, a characteristic facial appearance with hypertelorism, thin upper lip, anteverted nares, wide face, and abnormal hair whorl, and other manifestations (Sujansky et al., 1993, summary by Graw et al., 2000).
Chromosome 9p deletion syndrome- MedGen UID:
- 167073
- •Concept ID:
- C0795830
- •
- Disease or Syndrome
A rare chromosomal anomaly with characteristics of psychomotor developmental delay, facial dysmorphism (trigonocephaly, midface hypoplasia, upslanting palpebral fissures, dysplastic small ears, flat nasal bridge with anteverted nostrils and long philtrum, micrognathia, choanal atresia, short neck), single umbilical artery, omphalocele, inguinal or umbilical hernia, genital abnormalities (hypospadia, cryptorchidism), muscular hypotonia and scoliosis.
Kleefstra syndrome 1- MedGen UID:
- 208639
- •Concept ID:
- C0795833
- •
- Disease or Syndrome
Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.
Smith-Magenis syndrome- MedGen UID:
- 162881
- •Concept ID:
- C0795864
- •
- Disease or Syndrome
Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper-body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS.
Allan-Herndon-Dudley syndrome- MedGen UID:
- 208645
- •Concept ID:
- C0795889
- •
- Disease or Syndrome
Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.
Fine-Lubinsky syndrome- MedGen UID:
- 163198
- •Concept ID:
- C0795941
- •
- Disease or Syndrome
Syndrome with characteristics of psychomotor delay, brachycephaly with flat face, small nose, microstomia, cleft palate, cataract, hearing loss, hypoplastic scrotum and digital anomalies. Less than 10 patients have been described in the literature so far. Although the majority of reported cases were sporadic, the syndrome has been reported in one pair of siblings (a brother and sister) with an apparently autosomal recessive inheritance pattern.
Agenesis of the corpus callosum with peripheral neuropathy- MedGen UID:
- 162893
- •Concept ID:
- C0795950
- •
- Disease or Syndrome
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy, and by variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.
Kabuki syndrome- MedGen UID:
- 162897
- •Concept ID:
- C0796004
- •
- Congenital Abnormality
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Kapur-Toriello syndrome- MedGen UID:
- 208654
- •Concept ID:
- C0796005
- •
- Disease or Syndrome
An extremely rare syndrome with characteristics of facial dysmorphism, severe intellectual deficiency, cardiac and intestinal anomalies, and growth retardation. Only four cases have been reported in the literature, in three unrelated families. Dysmorphic features include bilateral cleft lip and palate, bulbous nasal tip and eye anomalies. The condition seems to be inherited as an autosomal recessive trait.
Peters plus syndrome- MedGen UID:
- 163204
- •Concept ID:
- C0796012
- •
- Disease or Syndrome
Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay / intellectual disability. The most common anterior chamber defect is Peters' anomaly, consisting of central corneal clouding, thinning of the posterior cornea, and iridocorneal adhesions. Cataracts and glaucoma are common. Developmental delay is observed in about 80% of children; intellectual disability can range from mild to severe.
Microphthalmia, syndromic 1- MedGen UID:
- 162898
- •Concept ID:
- C0796016
- •
- Congenital Abnormality
Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.
Hereditary spastic paraplegia 23- MedGen UID:
- 167094
- •Concept ID:
- C0796019
- •
- Disease or Syndrome
Spastic paraplegia-23 (SPG23) is an autosomal recessive neurologic disorder characterized by childhood-onset spastic paraplegia resulting in gait difficulties and associated with pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. Some patients may also have a peripheral neuropathy (summary by Lee et al., 2017).
Marden-Walker syndrome- MedGen UID:
- 163206
- •Concept ID:
- C0796033
- •
- Disease or Syndrome
Marden-Walker syndrome (MWKS) is characterized by psychomotor retardation, a mask-like face with blepharophimosis, micrognathia and a high-arched or cleft palate, low-set ears, kyphoscoliosis, and joint contractures. Other features may include Dandy-Walker malformation with hydrocephalus and vertebral abnormalities (summary by Schrander-Stumpel et al., 1993).
There are 2 distal arthrogryposis syndromes with features overlapping those of Marden-Walker syndrome that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and distal arthrogryposis type 5 (DA5; 108145), which are distinguished by the presence of cleft palate and ocular abnormalities, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition.
C syndrome- MedGen UID:
- 167105
- •Concept ID:
- C0796095
- •
- Disease or Syndrome
The C syndrome, also known as Opitz trigonocephaly syndrome, is a malformation syndrome characterized by trigonocephaly, severe mental retardation, hypotonia, variable cardiac defects, redundant skin, and dysmorphic facial features, including upslanted palpebral fissures, epicanthal folds, depressed nasal bridge, and low-set, posteriorly rotated ears (summary by Kaname et al., 2007).
C syndrome shows phenotypic overlap with Bohring-Opitz syndrome, or C-like syndrome (605039), a disorder with more severe features than C syndrome, caused by heterozygous mutation in the ASXL1 gene (612990) on chromosome 20q11.
Corpus callosum agenesis-abnormal genitalia syndrome- MedGen UID:
- 163217
- •Concept ID:
- C0796124
- •
- Disease or Syndrome
Proud syndrome is an X-linked developmental disorder characterized by agenesis of the corpus callosum, severe mental retardation, seizures, and spasticity. Males are severely affected, whereas females may be unaffected or have a milder phenotype (Proud et al., 1992). Proud syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome to infantile spasms without brain malformations (DEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008).
Ramon syndrome- MedGen UID:
- 208669
- •Concept ID:
- C0796133
- •
- Disease or Syndrome
A rare, genetic, primary bone dysplasia syndrome characterized by bilateral, painless swelling of the face extending from the mandible to the inferior orbital margins (cherubism), epilepsy, gingival fibromatosis (possibly obscuring teeth), and intellectual disability. Other associated variable features include hypertrichosis, stunted growth, juvenile rheumatoid arthritis, and development of ocular abnormalities (e.g. pigmentary retinopathy, optic disc pallor, Axenfeld anomaly). Radiological images typically show bilateral multifocal radiolucency involving the body, angle and ramus of the mandible and coronoid process.
Renpenning syndrome- MedGen UID:
- 208670
- •Concept ID:
- C0796135
- •
- Disease or Syndrome
Renpenning syndrome is an X-linked syndromic intellectual developmental disorder with clinically recognizable features. Affected individuals have microcephaly, short stature, small testes, and dysmorphic facies, including tall narrow face, upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. Stevenson et al. (2005) proposed that the various X-linked mental retardation syndromes due to PQBP1 mutations be combined under the name of Renpenning syndrome.
Simpson-Golabi-Behmel syndrome type 1- MedGen UID:
- 162917
- •Concept ID:
- C0796154
- •
- Disease or Syndrome
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.
Syndromic X-linked intellectual disability Snyder type- MedGen UID:
- 162918
- •Concept ID:
- C0796160
- •
- Disease or Syndrome
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.
Wieacker-Wolff syndrome- MedGen UID:
- 163227
- •Concept ID:
- C0796200
- •
- Disease or Syndrome
Wieacker-Wolff syndrome (WRWF) is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia), which results in arthrogryposis multiplex congenita (AMC) apparent at birth. Affected boys are born with severe contractures, show delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and foot deformities. Additional features include global developmental delay with poor or absent speech and impaired intellectual development, feeding difficulties and poor growth, hypotonia, hypogenitalism, and spasticity. Carrier females may be unaffected or have mild features of the disorder (summary by Hirata et al., 2013 and Frints et al., 2019).
Intellectual disability, X-linked 49- MedGen UID:
- 923000
- •Concept ID:
- C0796221
- •
- Disease or Syndrome
CLCN4-related neurodevelopmental disorder (CLCN4-NDD), an X-linked disorder, is characterized in the 36 males reported to date by developmental delay or intellectual disability, behavioral/mental health issues (e.g., autism spectrum disorder, anxiety, hyperactivity, and bipolar disorder), epilepsy, and gastrointestinal dysfunction. The five heterozygous females with a de novo CLCN4 variant reported to date had findings very similar to those of affected males. Twenty-two of 25 heterozygous females identified in family studies following identification of an affected male were unaffected or had only mild specific learning difficulties and/or mental health concerns, whereas three were more severely affected.
X-linked intellectual disability-psychosis-macroorchidism syndrome- MedGen UID:
- 163232
- •Concept ID:
- C0796222
- •
- Disease or Syndrome
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.
Intellectual disability, X-linked 19- MedGen UID:
- 208676
- •Concept ID:
- C0796225
- •
- Disease or Syndrome
X-linked intellectual development disorder-19 (XLID19) is characterized by mildly to moderately impaired intellectual development. Carrier females may be mildly affected. Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS; 303600), a syndrome with impaired intellectual deveopment, dysmorphic facial features, and skeletal anomalies. Some patients with RPS6KA3 mutations have an intermediate phenotype with impaired intellectual development and only mild anomalies reminiscent of CLS. These individuals have mutations resulting in some residual protein function, which likely explains the milder phenotype (summary by Field et al., 2006).
Pettigrew syndrome- MedGen UID:
- 162924
- •Concept ID:
- C0796254
- •
- Disease or Syndrome
X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (XDIBS), or Pettigrew syndrome is a central nervous system malformation characterized by severe intellectual deficit, early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, dysmorphic face (long face with prominent forehead), and brain imaging abnormalities such as Dandy-Walker malformation, and iron deposition. (From Mondo:0010574)
Brown-Vialetto-van Laere syndrome 1- MedGen UID:
- 163239
- •Concept ID:
- C0796274
- •
- Disease or Syndrome
Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010).
Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome
See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q.
Cardio-facio-cutaneous syndrome- MedGen UID:
- 266149
- •Concept ID:
- C1275081
- •
- Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Deficiency of beta-ureidopropionase- MedGen UID:
- 226944
- •Concept ID:
- C1291512
- •
- Disease or Syndrome
Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (Yaplito-Lee et al., 2008).
Nicolaides-Baraitser syndrome- MedGen UID:
- 220983
- •Concept ID:
- C1303073
- •
- Disease or Syndrome
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay / intellectual disability. Seizures are of various types and can be difficult to manage. Developmental delay / intellectual disability (ID) is severe in nearly a half, moderate in a third, and mild in the remainder. Nearly a third never develop speech or language skills.
Shprintzen-Goldberg syndrome- MedGen UID:
- 231160
- •Concept ID:
- C1321551
- •
- Disease or Syndrome
Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings.
Oculootoradial syndrome- MedGen UID:
- 233003
- •Concept ID:
- C1327918
- •
- Disease or Syndrome
IVIC syndrome (IVIC) is an autosomal dominant disorder characterized by upper limb anomalies (radial ray defects, carpal bone fusion), extraocular motor disturbances, and congenital bilateral nonprogressive mixed hearing loss. More variable features include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation, and rectovaginal fistula (summary by Paradisi and Arias, 2007).
Autosomal dominant chondrodysplasia punctata- MedGen UID:
- 303176
- •Concept ID:
- C1442935
- •
- Disease or Syndrome
Autosomal dominant form of chondrodysplasia punctata.
Andersen Tawil syndrome- MedGen UID:
- 327586
- •Concept ID:
- C1563715
- •
- Disease or Syndrome
Andersen-Tawil syndrome (ATS) is characterized by a triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described.
Duane-radial ray syndrome- MedGen UID:
- 301647
- •Concept ID:
- C1623209
- •
- Disease or Syndrome
SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).
Charcot-Marie-Tooth disease type 2D- MedGen UID:
- 316946
- •Concept ID:
- C1832274
- •
- Disease or Syndrome
The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait.
Charcot-Marie-Tooth disease type 4B1- MedGen UID:
- 321947
- •Concept ID:
- C1832399
- •
- Disease or Syndrome
Charcot-Marie-Tooth disease, type 4B1 (CMT4B1) is a severe early-onset demyelinating CMT peripheral sensorimotor polyneuropathy. It was initially described in an Italian family and around 10 additional families have been described so far. Onset occurs during early childhood with distal and proximal muscular weakness starting in the lower extremities, sensory loss and cranial nerve involvement. Foot deformities are frequent and diaphragmatic and facial involvement has been reported. CMT4B1 is caused by mutations in the gene encoding myotubularin-related protein 2 (MTMR2; 11q22), involved in polyphosphoinositide signaling. Transmitted in an autosomal recessive manner.
Amelia cleft lip palate hydrocephalus iris coloboma- MedGen UID:
- 321957
- •Concept ID:
- C1832434
- •
- Disease or Syndrome
Brachial amelia, cleft lip, and holoprosencephaly (ACLH) is a severe multiple congenital anomaly disorder characterized by brachial amelia, cleft lip, and forebrain defects consistent with holoprosencephaly. Although the disorder is rarely reported, the features are consistent enough to constitute a distinct entity (summary by Kariminejad et al., 2009).
Epilepsy-microcephaly-skeletal dysplasia syndrome- MedGen UID:
- 330468
- •Concept ID:
- C1832437
- •
- Disease or Syndrome
A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, seizures, microcephaly, delayed bone maturation, and skeletal abnormalities (such as scoliosis or pectus excavatum, among others). Dysmorphic features include coarse face, hirsutism, thick eyebrows, broad nasal septum, short philtrum, large mouth, and prominent ears. There have been no further descriptions in the literature since 1996.
Brachyolmia-amelogenesis imperfecta syndrome- MedGen UID:
- 318659
- •Concept ID:
- C1832594
- •
- Disease or Syndrome
Dental anomalies and short stature (DASS) is characterized by significant short stature with brachyolmia as well as hypoplastic amelogenesis imperfecta with almost absent enamel (Huckert et al., 2015). Some patients exhibit valvular and/or vascular defects, including mitral valve prolapse, aortic root dilation, and aortic as well as other arterial aneurysms (Dugan et al., 2015; Guo et al., 2018). Inter- and intrafamilial variability has been reported.
Spinal muscular atrophy-progressive myoclonic epilepsy syndrome- MedGen UID:
- 371854
- •Concept ID:
- C1834569
- •
- Disease or Syndrome
The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years.
Bethlem myopathy- MedGen UID:
- 331805
- •Concept ID:
- C1834674
- •
- Disease or Syndrome
Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by distal joint laxity and a combination of distal and proximal joint contractures. The age at onset is highly variable, ranging from infancy to adulthood. Disease progression is slow and ambulation is usually retained into adulthood (summary by Butterfield et al., 2013).
Genetic Heterogeneity of Bethlem Myopathy
See Bethlem myopathy-1B (BTHLM1B; 620725), caused by mutation in the COL6A2 gene (120240) on chromosome 21q22; Bethlem myopathy-1C (620726), caused by mutation the COL6A3 gene (120250) on chromosome 2q37; and Bethlem myopathy-2 (BTHLM2; 616471), caused by mutation in the COL12A1 gene (120320) on chromosome 6q13-q14.
Holoprosencephaly 2- MedGen UID:
- 322517
- •Concept ID:
- C1834877
- •
- Disease or Syndrome
A rare disorder characterized by the partial separation of the cerebral hemispheres. It is associated with mutations in the SIX3 gene.
Spastic paraplegia, optic atropy, and neuropathy- MedGen UID:
- 324411
- •Concept ID:
- C1836010
- •
- Disease or Syndrome
Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by Melo et al., 2015).
Hereditary spastic paraplegia 28- MedGen UID:
- 332174
- •Concept ID:
- C1836295
- •
- Disease or Syndrome
Spastic paraplegia-29 (SPG28) is an autosomal recessive neurodegenerative disorder characterized by early-onset, slowly progressive lower-limb spasticity resulting in walking difficulties. Some patients also have distal sensory impairment (summary by Tesson et al., 2012).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Charcot-Marie-Tooth disease type 4H- MedGen UID:
- 324487
- •Concept ID:
- C1836336
- •
- Disease or Syndrome
Charcot-Marie-Tooth disease, type 4H (CMT4H) is a demyelinating CMT peripheral sensorimotor polyneuropathy. It has been described in 10 individuals from two large consanguineous families from Lebanon and Algeria. Onset occurs within the first two years of life with slowly progressive muscle weakness in the distal extremities. Other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. CMT4H is caused by mutations in the FGD4 gene (12p11.1). Transmitted in an autosomal recessive manner.
Congenital myopathy 23- MedGen UID:
- 324513
- •Concept ID:
- C1836447
- •
- Disease or Syndrome
Nemaline myopathy is divided into six types. In order of decreasing severity, the types are: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. The types are distinguished by the age when symptoms first appear and the severity of symptoms; however, there is overlap among the various types. The severe congenital type is the most life-threatening. Most individuals with this type do not survive past early childhood due to respiratory failure. The Amish type solely affects the Old Order Amish population of Pennsylvania and is typically fatal in early childhood. The most common type of nemaline myopathy is the typical congenital type, which is characterized by muscle weakness and feeding problems beginning in infancy. Most of these individuals do not have severe breathing problems and can walk unassisted. People with the childhood-onset type usually develop muscle weakness in adolescence. The adult-onset type is the mildest of all the various types. People with this type usually develop muscle weakness between ages 20 and 50.\n\nNemaline myopathy is a disorder that primarily affects skeletal muscles, which are muscles that the body uses for movement. People with nemaline myopathy have muscle weakness (myopathy) throughout the body, but it is typically most severe in the muscles of the face; neck; trunk; and other muscles close to the center of the body (proximal muscles), such as those of the upper arms and legs. This weakness can worsen over time. Affected individuals may have feeding and swallowing difficulties, foot deformities, abnormal curvature of the spine (scoliosis), and joint deformities (contractures). Most people with nemaline myopathy are able to walk, although some affected children may begin walking later than usual. As the condition progresses, some people may require wheelchair assistance. In severe cases, the muscles used for breathing are affected and life-threatening breathing difficulties can occur.
Spondyloepiphyseal dysplasia tarda, autosomal recessive, Leroy-Spranger type- MedGen UID:
- 373126
- •Concept ID:
- C1836584
- •
- Disease or Syndrome
Hereditary spastic paraplegia 26- MedGen UID:
- 373138
- •Concept ID:
- C1836632
- •
- Disease or Syndrome
SPG26 is an autosomal recessive form of complicated spastic paraplegia characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive (summary by Boukhris et al., 2013).
For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Spondyloepiphyseal dysplasia with metatarsal shortening- MedGen UID:
- 324580
- •Concept ID:
- C1836683
- •
- Congenital Abnormality
Czech dysplasia is an autosomal dominant skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes (Marik et al., 2004; Kozlowski et al., 2004).
Arthrogryposis-severe scoliosis syndrome- MedGen UID:
- 373169
- •Concept ID:
- C1836756
- •
- Disease or Syndrome
Distal arthrogryposis type 4 (DA4) is distinguished by the presence of scoliosis (summary by Bamshad et al., 2009).
For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Posterior column ataxia-retinitis pigmentosa syndrome- MedGen UID:
- 324636
- •Concept ID:
- C1836916
- •
- Disease or Syndrome
Posterior column ataxia with retinitis pigmentosa (AXPC1) is an autosomal recessive neurologic disorder characterized by childhood-onset retinitis pigmentosa and later onset of gait ataxia due to sensory loss (summary by Ishiura et al., 2011).
Emanuel syndrome- MedGen UID:
- 323030
- •Concept ID:
- C1836929
- •
- Disease or Syndrome
Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males.
Marfanoid habitus with situs inversus- MedGen UID:
- 323046
- •Concept ID:
- C1836994
- •
- Disease or Syndrome
Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome- MedGen UID:
- 324684
- •Concept ID:
- C1837073
- •
- Disease or Syndrome
Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by Hoover-Fong et al., 2014).
Yamamoto et al. (2014) reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence.
Spinocerebellar ataxia type 25- MedGen UID:
- 373347
- •Concept ID:
- C1837518
- •
- Disease or Syndrome
Spinocerebellar ataxia-25 (SCA25) is an autosomal dominant neurologic disorder characterized by the onset of lower limb ataxia resulting in gait difficulties in the first few decades of life, although later onset has been reported. Affected individuals often have upper limb involvement, dysarthria, scoliosis, abnormal eye movements, and sensory neuropathy with decreased reflexes. Some patients have sensorineural hearing loss. Brain imaging shows cerebellar atrophy. There is incomplete penetrance and variable expressivity, even within families (Barbier et al., 2022).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Charcot-Marie-Tooth disease axonal type 2L- MedGen UID:
- 324826
- •Concept ID:
- C1837552
- •
- Disease or Syndrome
A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. In the single family reported to date, CMT2L onset is between 15 and 33 years. Patients present with a symmetric distal weakness of legs and occasionally of the hands, absent or reduced tendon reflexes, distal legs sensory loss and frequently a pes cavus. Progression is slow.
Spondyloepiphyseal dysplasia with congenital joint dislocations- MedGen UID:
- 373381
- •Concept ID:
- C1837657
- •
- Disease or Syndrome
CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.
CODAS syndrome- MedGen UID:
- 333031
- •Concept ID:
- C1838180
- •
- Disease or Syndrome
CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015).
Neuronopathy, distal hereditary motor, autosomal dominant 8- MedGen UID:
- 373984
- •Concept ID:
- C1838492
- •
- Disease or Syndrome
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Leber optic atrophy and dystonia- MedGen UID:
- 333240
- •Concept ID:
- C1839040
- •
- Disease or Syndrome
X-linked myopathy with excessive autophagy- MedGen UID:
- 374264
- •Concept ID:
- C1839615
- •
- Disease or Syndrome
X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive skeletal muscle disorder characterized by childhood onset of progressive muscle weakness and atrophy primarily affecting the proximal muscles. While onset is usually in childhood, it can range from infancy to adulthood. Many patients lose ambulation and become wheelchair-bound. Other organ systems, including the heart, are clinically unaffected. Muscle biopsy shows intracytoplasmic autophagic vacuoles with sarcolemmal features and a multilayered basal membrane (summary by Ramachandran et al., 2013; Kurashige et al., 2013, and Ruggieri et al., 2015).
Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, is a distinct disorder with similar pathologic features.
Skeletal dysplasia-intellectual disability syndrome- MedGen UID:
- 326949
- •Concept ID:
- C1839729
- •
- Disease or Syndrome
This syndrome combines skeletal anomalies (short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia and short middle phalanges) and mild intellectual deficit. It has been described in four male cousins in three sibships. Glucose intolerance was present in three cases, and imperforated anus in one case. Carrier females had minor manifestations (fusion of cervical vertebrae and glucose intolerance). Transmission seems to be X-linked.
King Denborough syndrome- MedGen UID:
- 327082
- •Concept ID:
- C1840365
- •
- Disease or Syndrome
King-Denborough syndrome (KDS) is an autosomal dominant disorder characterized by the triad of congenital myopathy, dysmorphic features, and susceptibility to malignant hyperthermia (summary by Dowling et al., 2011).
Charcot-Marie-Tooth disease recessive intermediate A- MedGen UID:
- 334012
- •Concept ID:
- C1842197
- •
- Disease or Syndrome
GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.
Cataract - congenital heart disease - neural tube defect syndrome- MedGen UID:
- 330832
- •Concept ID:
- C1842363
- •
- Disease or Syndrome
Cataract-congenital heart disease-neural tube defect syndrome is a multiple congenital anomaly syndrome characterized by sacral neural tube defects resulting in tethered cord, atrial and/or ventricular septal heart defects (that are detected in infancy), bilateral, symmetrical hyperopia, rapidly progressive early childhood cataracts, bilateral aphakic glaucoma, and abnormal facial features (low frontal hairline, small ears, short philtrum, prominent, widely spaced central incisors, and micrognathia). Hypotonia, growth and developmental delay, seizures, and joint limitation are also reported.
Spondyloenchondrodysplasia with immune dysregulation- MedGen UID:
- 375009
- •Concept ID:
- C1842763
- •
- Disease or Syndrome
Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family.
Classification of the Enchondromatoses
In their classification of the enchondromatoses, Spranger et al. (1978) called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (156250), type III; and spondyloenchondrodysplasia (SPENCD), also called spondyloenchondromatosis, type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. Halal and Azouz (1991) added 3 tentative categories to the 6 in the classification of Spranger et al. (1978).
Pansuriya et al. (2010) suggested a new classification of enchondromatosis (multiple enchondromas).
Chromosome 1p36 deletion syndrome- MedGen UID:
- 334629
- •Concept ID:
- C1842870
- •
- Disease or Syndrome
The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003).
See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36.
See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features.
Craniolenticulosutural dysplasia- MedGen UID:
- 334671
- •Concept ID:
- C1843042
- •
- Disease or Syndrome
Craniolenticulosutural dysplasia is characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (summary by Boyadjiev et al., 2011).
Acrocapitofemoral dysplasia- MedGen UID:
- 334681
- •Concept ID:
- C1843096
- •
- Disease or Syndrome
Acrocapitofemoral dysplasia (ACFD) is an autosomal recessive skeletal dysplasia characterized by postnatal-onset disproportionate short stature, relatively large head, narrow thorax, lumbar lordosis, short limbs, and brachydactyly with small broad nails (Ozyavuz Cubuk and Duz, 2021).
Charcot-Marie-Tooth disease type 2E- MedGen UID:
- 375127
- •Concept ID:
- C1843225
- •
- Disease or Syndrome
A form of axonal Charcot-Marie-Tooth disease a peripheral sensorimotor neuropathy. Onset is in the first to sixth decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and after years all patients have a pes cavus. Other signs may be present including hearing loss and postural tremor.
Charcot-Marie-Tooth disease X-linked recessive 3- MedGen UID:
- 375530
- •Concept ID:
- C1844865
- •
- Disease or Syndrome
A rare genetic peripheral sensorimotor neuropathy with an X-linked recessive inheritance pattern and the childhood to adolescent-onset of progressive, distal muscle weakness and atrophy (beginning in the lower extremities and then affecting the upper extremities), as well as distal, pan sensory loss in the upper and lower extremities, pes cavus, and absent or reduced distal tendon reflexes. Pain and paraesthesia are frequently the initial sensory symptoms. Spastic paraparesis (manifested by clasp-knife sign, hyperactive deep-tendon reflexes, and Babinski sign) has also been reported.
Catel-Manzke syndrome- MedGen UID:
- 375536
- •Concept ID:
- C1844887
- •
- Disease or Syndrome
Catel-Manzke syndrome is characterized by the Pierre Robin anomaly, which comprises cleft palate, glossoptosis, and micrognathia, and a unique form of bilateral hyperphalangy in which there is an accessory bone inserted between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger (summary by Manzke et al., 2008).
Infantile-onset X-linked spinal muscular atrophy- MedGen UID:
- 337123
- •Concept ID:
- C1844934
- •
- Disease or Syndrome
X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem. Often congenital contractures and/or fractures are present. Intellect is normal. Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement.
Alpha thalassemia-X-linked intellectual disability syndrome- MedGen UID:
- 337145
- •Concept ID:
- C1845055
- •
- Disease or Syndrome
Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.
Intellectual disability, X-linked 82- MedGen UID:
- 337201
- •Concept ID:
- C1845286
- •
- Mental or Behavioral Dysfunction
X-linked intellectual disability, Stocco dos Santos type- MedGen UID:
- 335202
- •Concept ID:
- C1845530
- •
- Disease or Syndrome
X-linked intellectual disability, Stocco Dos Santos type is characterised by severe intellectual deficit with hyperactivity, language delay, congenital hip luxation, short stature, kyphosis and recurrent respiratory infections. Aggressive behaviour and frequent epileptic seizures may also be present. The syndrome has been described in four boys from the same family. Transmission is X-linked and is caused by mutations in the <i>KIAA1202</i> gene, localised to the Xp11.2 region.
FG syndrome 4- MedGen UID:
- 336965
- •Concept ID:
- C1845546
- •
- Disease or Syndrome
CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features.
Uruguay Faciocardiomusculoskeletal syndrome- MedGen UID:
- 335320
- •Concept ID:
- C1846010
- •
- Disease or Syndrome
Uruguay faciocardiomusculoskeletal syndrome (FCMSU) is an X-linked disorder in which affected males have a distinctive facial appearance, muscular hypertrophy, and cardiac ventricular hypertrophy leading to premature death. Additional features include large, broad, and deformed hands and feet, congenital hip dislocation, and scoliosis (summary by Xue et al., 2016).
Oculofaciocardiodental syndrome- MedGen UID:
- 337547
- •Concept ID:
- C1846265
- •
- Disease or Syndrome
Oculofaciocardiodental (OFCD) syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-) and teeth (dental). This condition occurs only in females.\n\nThe eye abnormalities associated with OFCD syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a higher risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.\n\nPeople with OFCD syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes and a broad nasal tip that is divided by a cleft. Some affected people have an opening in the roof of the mouth called a cleft palate.\n\nHeart defects are another common feature of OFCD syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).\n\nTeeth with very large roots (radiculomegaly) are characteristic of OFCD syndrome. Additional dental abnormalities can include delayed loss of primary (baby) teeth, missing or abnormally small teeth, misaligned teeth, and defective tooth enamel.
Hereditary spastic paraplegia 7- MedGen UID:
- 339552
- •Concept ID:
- C1846564
- •
- Disease or Syndrome
Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral leg weakness and spasticity. Most affected individuals have decreased vibration sense and cerebellar signs. Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years. Additional features including ataxia (gait and limbs), spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, ptosis, hearing loss, motor and sensory neuropathy, amyotrophy, scoliosis, pes cavus, and urinary sphincter disturbances may be observed.
Autosomal recessive limb-girdle muscular dystrophy type 2I- MedGen UID:
- 339580
- •Concept ID:
- C1846672
- •
- Disease or Syndrome
MDGDC5 is an autosomal recessive muscular dystrophy characterized by variable age at onset, normal cognition, and no structural brain changes (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006).
For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Multiple epiphyseal dysplasia type 4- MedGen UID:
- 376164
- •Concept ID:
- C1847593
- •
- Disease or Syndrome
Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild.
Muscular dystrophy-dystroglycanopathy type B5- MedGen UID:
- 335764
- •Concept ID:
- C1847759
- •
- Disease or Syndrome
MDDGB5 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006).
For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Spondylocarpotarsal synostosis syndrome- MedGen UID:
- 341339
- •Concept ID:
- C1848934
- •
- Disease or Syndrome
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome- MedGen UID:
- 338595
- •Concept ID:
- C1849011
- •
- Disease or Syndrome
Spondylometaepiphyseal dysplasia, short limb-hand type is an autosomal recessive disorder with clinical and radiologic features of disproportionate short stature, platyspondyly, abnormal epiphyses and metaphyses, shortening of the lower and upper limbs, short and broad fingers, and premature calcifications. The disorder is progressive with respect to the severity of the bowing of the lower limbs and the appearance of calcifications, with some patients being wheelchair-bound from age 11 years (Bargal et al., 2009).
Brachyolmia type 1, Hobaek type- MedGen UID:
- 338605
- •Concept ID:
- C1849055
- •
- Disease or Syndrome
Rock et al. (2008) provided an overview of the brachyolmias, a heterogeneous group of skeletal dysplasias that affect primarily the spine. Type 1 brachyolmia includes the Hobaek and Toledo (BCYM1B; 271630) forms, which are inherited in an autosomal recessive fashion. Both forms of type 1 are characterized by scoliosis, platyspondyly with rectangular and elongated vertebral bodies, overfaced pedicles, and irregular, narrow intervertebral spaces. The Toledo form is distinguished by the presence of corneal opacities and precocious calcification of the costal cartilage. Type 2 brachyolmia (BCYM2; 613678), sometimes referred to as the Maroteaux type, is also an autosomal recessive disorder, primarily distinguished from type 1 by rounded vertebral bodies and less overfaced pedicles. Some cases are associated with precocious calcification of the falx cerebri. Type 3 brachyolmia (BCYM3; 113500) is an autosomal dominant form, caused by mutation in the TRPV4 gene (605427), with severe kyphoscoliosis and flattened, irregular cervical vertebrae. Paradoxically, although the limbs are mildly shortened in all types of brachyolmia, they show minimal epiphyseal and metaphyseal abnormalities on radiographs. Type 4 brachyolmia (BCYM4; 612847) is an autosomal recessive form, caused by mutation in the PAPSS2 gene (603005), with mild epiphyseal and metaphyseal changes.
Spondylocostal dysostosis-anal and genitourinary malformations syndrome- MedGen UID:
- 341373
- •Concept ID:
- C1849069
- •
- Congenital Abnormality
Spondylocostal dysostosis-anal and genitourinary malformations syndrome is characterized by the association of spondylocostal dysostosis with anal and genitourinary malformations (anal atresia and agenesis of external and internal genitalia). To date, only four cases have been described in the literature. Autosomal recessive inheritance has been suggested.
Hereditary spastic paraplegia 5A- MedGen UID:
- 376521
- •Concept ID:
- C1849115
- •
- Disease or Syndrome
Spastic paraplegia-5A (SPG5A) is an autosomal recessive neurologic disorder with a wide phenotypic spectrum. Some patients have pure spastic paraplegia affecting only gait, whereas others may have a complicated phenotype with additional manifestations, including optic atrophy or cerebellar ataxia (summary by Arnoldi et al., 2012).
The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Inheritance is most often autosomal dominant (see 182600), but X-linked (see 303350) and autosomal recessive forms also occur.
Genetic Heterogeneity of Autosomal Recessive Spastic Paraplegia
Autosomal recessive forms of SPG include SPG7 (607259), caused by mutation in the paraplegin gene (602783) on chromosome 16q24; SPG9B (616586), caused by mutation in the ALDH18A1 gene (138250) on 10q24; SPG11 (604360), caused by mutation in the spatacsin gene (610844) on 15q21; SPG15 (270700), caused by mutation in the ZFYVE26 gene (612012) on 14q24; SPG18 (611225), caused by mutation in the ERLIN2 gene (611605) on 8p11; SPG20 (275900), caused by mutation in the spartin gene (607111) on 13q12; SPG21 (248900), caused by mutation in the maspardin gene (608181) on 15q21; SPG26 (609195), caused by mutation in the B4GALNT1 gene (601873) on 12q13; SPG28 (609340), caused by mutation in the DDHD1 gene (614603) on 14q22; SPG30 (610357), caused by mutation in the KIF1A gene (601255) on 2q37; SPG35 (612319), caused by mutation in the FA2H gene (611026) on 16q23; SPG39 (612020), caused by mutation in the PNPLA6 gene (603197) on 19p13; SPG43 (615043), caused by mutation in the C19ORF12 gene (614297) on 19q12; SPG44 (613206), caused by mutation in the GJC2 gene (608803) on 1q42; SPG45 (613162), caused by mutation in the NT5C2 gene (600417) on 10q24; SPG46 (614409), caused by mutation in the GBA2 gene (609471) on 9p13; SPG48 (613647), caused by mutation in the KIAA0415 gene (613653) on 7p22; SPG50 (612936), caused by mutation in the AP4M1 gene (602296) on 7q22; SPG51 (613744), caused by mutation in the AP4E1 gene (607244) on 15q21; SPG52 (614067), caused by mutation in the AP4S1 gene (607243) on 14q12; SPG53 (614898), caused by mutation in the VPS37A gene (609927) on 8p22; SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on 8p11; SPG55 (615035), caused by mutation in the MTRFR gene on 12q24; SPG56 (615030), caused by mutation in the CYP2U1 gene (610670) on 4q25; SPG57 (615658), caused by mutation in the TFG gene (602498) on 3q12; SPG61 (615685), caused by mutation in the ARL6IP1 gene (607669) on 1p12; SPG62 (615681), caused by mutation in the ERLIN1 gene on 10q24; SPG63 (615686), caused by mutation in the AMPD2 gene (102771) on 1p13; SPG64 (615683), caused by mutation in the ENTPD1 gene (601752) on 10q24; SPG72 (615625), caused by mutation in the REEP2 gene (609347) on 5q31; SPG74 (616451), caused by mutation in the IBA57 gene (615316) on 1q42; SPG75 (616680), caused by mutation in the MAG gene (159460) on 19q13; SPG76 (616907), caused by mutation in the CAPN1 gene (114220) on 11q13; SPG77 (617046), caused by mutation in the FARS2 gene (611592) on 6p25; SPG78 (617225), caused by mutation in the ATP13A2 gene (610513) on 1p36; SPG79 (615491), caused by mutation in the UCHL1 gene (191342) on 4p13; SPG81 (618768), caused by mutation in the SELENOI gene (607915) on 2p23; SPG82 (618770), caused by mutation in the PCYT2 gene (602679) on 17q25; SPG83 (619027), caused by mutation in the HPDL gene (618994) on 1p34; SPG84 (619621), caused by mutation in the PI4KA gene (600286) on 22q11; SPG85 (619686), caused by mutation in the RNF170 gene (614649) on 8p11; SPG86 (619735), caused by mutation in the ABHD16A gene (142620) on 6p21; SPG87 (619966), caused by mutation in the TMEM63C gene (619953) on 14q24; SPG89 (620379), caused by mutation in the AMFR gene (603243) on 16q13; SPG90B (620417), caused by mutation in the SPTSSA gene (613540) on 14q13; SPG92 (620911), caused by mutation in the FICD gene (620875) on chromosome 12q23; and SPG93 (620938), caused by mutation in the NFU1 gene (608100) on chromosome 2p13.
Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; 605229), 13q14 (SPG24; 607584), 6q (SPG25; 608220), and 10q22 (SPG27; 609041).
A disorder that was formerly designated SPG49 has been reclassified as hereditary sensory and autonomic neuropathy-9 with developmental delay (HSAN9; 615031).
Charlevoix-Saguenay spastic ataxia- MedGen UID:
- 338620
- •Concept ID:
- C1849140
- •
- Disease or Syndrome
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is clinically characterized by a progressive cerebellar ataxia, peripheral neuropathy, and spasticity. Disease onset of classic ARSACS is often in early childhood, leading to delayed walking because of gait unsteadiness in very young toddlers, while an increasing number of individuals with disease onset in teenage or early-adult years are now being described. Typically the ataxia is followed by lower-limb spasticity and later by peripheral neuropathy – although pronounced peripheral neuropathy has been observed as a first sign of ARSACS. Oculomotor disturbances, dysarthria, and upper-limb ataxia develop with slower progression than the other findings. Brain imaging demonstrates atrophy of the superior vermis and the cerebellar hemisphere with additional findings on MRI, such as linear hypointensities in the pons and hyperintense rims around the thalami. Many affected individuals (though not all) have yellow streaks of hypermyelinated fibers radiating from the edges of the optic disc noted on ophthalmologic exam, and thickened retinal fibers can be demonstrated by optical coherence tomography. Mild intellectual disability, hearing loss, and urinary urgency and incontinence have been reported in some individuals.
Bruck syndrome 1- MedGen UID:
- 342431
- •Concept ID:
- C1850168
- •
- Disease or Syndrome
Bruck syndrome-1 (BRKS1) is characterized by congenital contractures with pterygia, onset of fractures in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis (McPherson and Clemens, 1997).
Genetic Heterogeneity of Bruck Syndrome
Bruck syndrome-2 (BRKS2; 609220) is caused by homozygous mutation in the PLOD2 gene (601865) on chromosome 3q24. Van der Slot et al. (2003) stated that they were unaware of any phenotypic differences between the 2 forms of Bruck syndrome.
Osteogenesis imperfecta type 9- MedGen UID:
- 376720
- •Concept ID:
- C1850169
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized clinically by bone fragility and increased susceptibility to fractures. Osteogenesis imperfecta type IX (OI9) is a severe autosomal recessive form of the disorder (summary by van Dijk et al., 2009).
Giant axonal neuropathy 1- MedGen UID:
- 376775
- •Concept ID:
- C1850386
- •
- Disease or Syndrome
GAN-related neurodegeneration comprises a phenotypic continuum ranging from severe (sometimes called classic giant axonal neuropathy) to milder pure early-onset peripheral motor and sensory neuropathies. The classic giant axonal neuropathy phenotype typically manifests as an infantile-onset neurodegenerative disorder, starting as a severe peripheral motor and sensory neuropathy and evolving into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. At the milder end of the spectrum are predominantly motor and sensory neuropathies (with little to no CNS involvement) that overlap with the axonal form of Charcot-Marie-Tooth neuropathies.
Atelosteogenesis type II- MedGen UID:
- 338072
- •Concept ID:
- C1850554
- •
- Disease or Syndrome
Clinical features of atelosteogenesis type 2 (AO2) include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. AO2 is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. However, it exists in a continuous phenotypic spectrum with diastrophic dysplasia, and long-term survivors have been reported.
Nemaline myopathy 2- MedGen UID:
- 342534
- •Concept ID:
- C1850569
- •
- Disease or Syndrome
Nemaline myopathy-2 (NEM2) is an autosomal recessive skeletal muscle disorder with a wide range of severity. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. Muscle biopsy shows accumulation of Z-disc and thin filament proteins into aggregates named 'nemaline bodies' or 'nemaline rods,' usually accompanied by disorganization of the muscle Z discs. The clinical and histologic spectrum of entities caused by variants in the NEB gene is a continuum, ranging in severity. The distribution of weakness can vary from generalized muscle weakness, more pronounced in proximal limb muscles, to distal-only involvement, although neck flexor weakness appears to be rather consistent. Histologic patterns range from a severe usually nondystrophic disturbance of the myofibrillar pattern to an almost normal pattern, with or without nemaline bodies, sometimes combined with cores (summary by Lehtokari et al., 2014).
Genetic Heterogeneity of Nemaline Myopathy
See also NEM1 (255310), caused by mutation in the tropomyosin-3 gene (TPM3; 191030) on chromosome 1q22; NEM3 (161800), caused by mutation in the alpha-actin-1 gene (ACTA1; 102610) on chromosome 1q42; NEM4 (609285), caused by mutation in the beta-tropomyosin gene (TPM2; 190990) on chromosome 9p13; NEM5A (605355), also known as Amish nemaline myopathy, NEM5B (620386), and NEM5C (620389), all caused by mutation in the troponin T1 gene (TNNT1; 191041) on chromosome 19q13; NEM6 (609273), caused by mutation in the KBTBD13 gene (613727) on chromosome 15q22; NEM7 (610687), caused by mutation in the cofilin-2 gene (CFL2; 601443) on chromosome 14q13; NEM8 (615348), caused by mutation in the KLHL40 gene (615340), on chromosome 3p22; NEM9 (615731), caused by mutation in the KLHL41 gene (607701) on chromosome 2q31; NEM10 (616165), caused by mutation in the LMOD3 gene (616112) on chromosome 3p14; and NEM11 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. Several of the genes encode components of skeletal muscle sarcomeric thin filaments (Sanoudou and Beggs, 2001).
Mutations in the NEB gene are the most common cause of nemaline myopathy (Lehtokari et al., 2006).
Bailey-Bloch congenital myopathy- MedGen UID:
- 340586
- •Concept ID:
- C1850625
- •
- Disease or Syndrome
STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.
Congenital multicore myopathy with external ophthalmoplegia- MedGen UID:
- 340597
- •Concept ID:
- C1850674
- •
- Disease or Syndrome
Congenital myopathy-1B (CMYO1B) is an autosomal recessive disorder of skeletal muscle characterized by severe hypotonia and generalized muscle weakness apparent soon after birth or in early childhood with delayed motor development, generalized muscle weakness and atrophy, and difficulty walking or running. Affected individuals show proximal muscle weakness with axial and shoulder girdle involvement, external ophthalmoplegia, and bulbar weakness, often resulting in feeding difficulties and respiratory insufficiency. Orthopedic complications such as joint laxity, distal contractures, hip dislocation, cleft palate, and scoliosis are commonly observed. Serum creatine kinase is normal. The phenotype is variable in severity (Jungbluth et al., 2005; Bharucha-Goebel et al., 2013). Some patients show symptoms in utero, including reduced fetal movements, polyhydramnios, and intrauterine growth restriction. The most severely affected patients present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (McKie et al., 2014). Skeletal muscle biopsy of patients with recessive RYR1 mutations can show variable features, including multiminicores (Ferreiro and Fardeau, 2002), central cores (Jungbluth et al., 2002), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Myopathy, myosin storage, autosomal recessive- MedGen UID:
- 340603
- •Concept ID:
- C1850709
- •
- Disease or Syndrome
Autosomal recessive myosin storage congenital myopathy-7B (CMYO7B) is a skeletal muscle disorder characterized by the onset of scapuloperoneal muscle weakness in early childhood or young adulthood. Affected individuals have difficulty walking, steppage gait, and scapular winging due to shoulder girdle involvement. The severity and progression of the disorder is highly variable, even within families. Most patients develop respiratory insufficiency, nocturnal hypoventilation, and restrictive lung disease; some develop hypertrophic cardiomyopathy. Additional features include myopathic facies, high-arched palate, scoliosis, and muscle wasting with thin body habitus. Serum creatine kinase may be normal or elevated. Skeletal muscle biopsy shows variable findings, including myosin storage disease, type 1 fiber predominance, centralized nuclei, and multiminicore disease (Onengut et al., 2004; Tajsharghi et al., 2007; Beecroft et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Lateral meningocele syndrome- MedGen UID:
- 342070
- •Concept ID:
- C1851710
- •
- Disease or Syndrome
NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Infants may demonstrate feeding difficulties with poor weight gain.
Ehlers-Danlos syndrome type 7B- MedGen UID:
- 342092
- •Concept ID:
- C1851801
- •
- Disease or Syndrome
Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.\n\nThe various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.\n\nAn unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.\n\nMany people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.\n\nOther types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.\n\nBleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.
Dystonia 5- MedGen UID:
- 342121
- •Concept ID:
- C1851920
- •
- Disease or Syndrome
GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur.
Early-onset generalized limb-onset dystonia- MedGen UID:
- 338823
- •Concept ID:
- C1851945
- •
- Disease or Syndrome
DYT1 early-onset isolated dystonia typically presents in childhood or adolescence and only on occasion in adulthood. Dystonic muscle contractions causing posturing or irregular tremor of a leg or arm are the most common presenting findings. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign.
Calvarial doughnut lesions-bone fragility syndrome- MedGen UID:
- 377572
- •Concept ID:
- C1852022
- •
- Disease or Syndrome
Calvarial doughnut lesions with bone fragility (CDL) is characterized by low bone mineral density, multiple spinal and peripheral fractures beginning in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Some more severely affected individuals exhibit neonatal onset of fractures, severe short stature, marked cranial sclerosis, and spondylometaphyseal dysplasia (CDLSMD) (Pekkinen et al., 2019).
Renal coloboma syndrome- MedGen UID:
- 339002
- •Concept ID:
- C1852759
- •
- Disease or Syndrome
PAX2-related disorder is an autosomal dominant disorder associated with renal and eye abnormalities. The disorder was originally referred to as renal coloboma syndrome and characterized by renal hypodysplasia and abnormalities of the optic nerve; with improved access to molecular testing, a wider range of phenotypes has been recognized in association with pathogenic variants in PAX2. Abnormal renal structure or function is noted in 92% of affected individuals and ophthalmologic abnormalities in 77% of affected individuals. Renal abnormalities can be clinically silent in rare individuals. In most individuals, clinically significant renal insufficiency / renal failure is reported. End-stage renal disease requiring renal transplant is not uncommon. Uric acid nephrolithiasis has been reported. Ophthalmologic abnormalities are typically described as optic nerve coloboma or dysplasia. Iris colobomas have not been reported in any individual with PAX2–related disorder. Ophthalmologic abnormalities may significantly impair vision in some individuals, while others have subtle changes only noted after detailed ophthalmologic examination. Additional clinical findings include high-frequency sensorineural hearing loss, soft skin, and ligamentous laxity. PAX2 pathogenic variants have been identified in multiple sporadic and familial cases of nonsyndromic renal disease including renal hypodysplasia and focal segmental glomerulosclerosis.
Autosomal recessive ataxia, Beauce type- MedGen UID:
- 343973
- •Concept ID:
- C1853116
- •
- Disease or Syndrome
SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia at the mild end to arthrogryposis multiplex congenita (AMC) at the severe end. SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years). While some individuals have a pure cerebellar syndrome (i.e., cerebellar ataxia, dysarthria, dysmetria, abnormalities in ocular saccades and smooth pursuit), many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations). Most individuals develop features of the cerebellar cognitive and affective syndrome (i.e., significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills). The two less common phenotypes are SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability) and SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot).
Noonan syndrome 4- MedGen UID:
- 339908
- •Concept ID:
- C1853120
- •
- Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Osteogenesis imperfecta type 7- MedGen UID:
- 343981
- •Concept ID:
- C1853162
- •
- Disease or Syndrome
Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. OI type VII is an autosomal recessive form of severe or lethal OI (summary by Barnes et al., 2006).
Spondylocostal dysostosis 3, autosomal recessive- MedGen UID:
- 377871
- •Concept ID:
- C1853296
- •
- Disease or Syndrome
Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.
Genitopatellar syndrome- MedGen UID:
- 381208
- •Concept ID:
- C1853566
- •
- Disease or Syndrome
KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype.
Charcot-Marie-Tooth disease axonal type 2C- MedGen UID:
- 342947
- •Concept ID:
- C1853710
- •
- Disease or Syndrome
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2- MedGen UID:
- 340052
- •Concept ID:
- C1853761
- •
- Disease or Syndrome
Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset of ataxia between age three and 30 years after initial normal development, axonal sensorimotor neuropathy, oculomotor apraxia, cerebellar atrophy, and elevated serum concentration of alpha-fetoprotein (AFP).
Myopathy, proximal, and ophthalmoplegia- MedGen UID:
- 381340
- •Concept ID:
- C1854106
- •
- Disease or Syndrome
Congenital myopathy-6 with ophthalmoplegia (CMYO6) is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. CMYO6 can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (summary by Lossos et al., 2005 and Tajsharghi et al., 2014).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Charcot-Marie-Tooth disease type 4G- MedGen UID:
- 343122
- •Concept ID:
- C1854449
- •
- Disease or Syndrome
The Russe type of hereditary motor and sensory neuropathy (HMSNR) is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy (summary by Sevilla et al., 2013).
For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).
Wiedemann-Steiner syndrome- MedGen UID:
- 340266
- •Concept ID:
- C1854630
- •
- Disease or Syndrome
Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. The facial features include thick eyebrows with lateral flare, vertically narrow and downslanted palpebral fissures, widely spaced eyes, long eyelashes, wide nasal bridge, broad nasal tip, thin vermilion of the upper lip, and thick scalp hair. About 60% of affected individuals have hypertrichosis cubiti ("hairy elbows"), which was once thought to be pathognomic for the syndrome, with a majority having hypertrichosis of other body parts. Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies.
GNPTG-mucolipidosis- MedGen UID:
- 340743
- •Concept ID:
- C1854896
- •
- Disease or Syndrome
Mucolipidosis III gamma (ML III?) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood; the progressive course results in severe functional impairment and significant morbidity from chronic pain. Cardiorespiratory complications (restrictive lung disease from thoracic involvement, and thickening and insufficiency of the mitral and aortic valves) are rarely clinically significant. A few (probably <10%) affected individuals display mild cognitive impairment.
Say-Barber-Miller syndrome- MedGen UID:
- 343258
- •Concept ID:
- C1855078
- •
- Disease or Syndrome
Say-Barber-Miller syndrome is characterised by the association of unusual facial features, microcephaly, developmental delay, and severe postnatal growth retardation.
Metaphyseal dysostosis-intellectual disability-conductive deafness syndrome- MedGen UID:
- 344437
- •Concept ID:
- C1855175
- •
- Disease or Syndrome
Metaphyseal dysostosis-intellectual disability-conductive deafness syndrome is characterised by metaphyseal dysplasia, short-limb dwarfism, mild intellectual deficit and conductive hearing loss, associated with repeated episodes of otitis media in childhood. It has been described in three brothers born to consanguineous Sicilian parents. Variable manifestations included hyperopia and strabismus. The mode of inheritance is autosomal recessive.
Absence deformity of leg-cataract syndrome- MedGen UID:
- 343374
- •Concept ID:
- C1855523
- •
- Disease or Syndrome
A very rare congenital limb malformation syndrome characterized by absence deformity of one leg, progressive scoliosis, short stature, and congenital cataract associated with dysplasia of the optic nerve. No intellectual deficit has been reported. There have been no further descriptions in the literature since 1968.
X-linked congenital generalized hypertrichosis- MedGen UID:
- 341002
- •Concept ID:
- C1855900
- •
- Disease or Syndrome
X-linked congenital generalized hypertrichosis is an extremely rare type of hypertrichosis lanuginosa congenita, a congenital skin disease, which is characterized by hair overgrowth on the entire body in males, and mild and asymmetric hair overgrowth in females. It is associated with a mild facial dysmorphism (anterverted nostrils, moderate prognathism), and, in a kindred, it was also associated with dental anomalies and deafness.
Isolated hemihyperplasia- MedGen UID:
- 383853
- •Concept ID:
- C1856184
- •
- Disease or Syndrome
Isolated hemihyperplasia is an abnormality of cell proliferation leading to asymmetric overgrowth of one or more regions of the body. The term 'hemihyperplasia' has replaced the term 'hemihypertrophy' to describe accurately the increase in cell number found in these patients. The incidence of isolated hemihyperplasia is estimated to be 1 in 86,000. Idiopathic hemihypertrophy is associated with increased risk of embryonal cancers in childhood, particularly Wilms tumor (194070) (Shuman et al., 2006).
Hoyme et al. (1998) provided an anatomic classification of hemihyperplasia: complex hemihyperplasia is involvement of half of the body, including at least 1 arm and 1 leg; affected parts may be contralateral or ipsilateral. Simple hemihyperplasia is involvement of a single limb. See also facial hemihyperplasia (133900).
Although isolated hemihyperplasia is a distinct clinical entity, it can also occur as a feature of overgrowth syndromes, including Beckwith-Wiedemann syndrome (BWS; 130650), neurofibromatosis (NF1; 162200), Proteus syndrome (176920), and Klippel-Trenaunay-Weber syndrome (149000) (Shuman et al., 2006).
Hall-Riggs syndrome- MedGen UID:
- 341089
- •Concept ID:
- C1856198
- •
- Disease or Syndrome
A very rare syndrome consisting of microcephaly with facial dysmorphism, spondylometaphyseal dysplasia and severe intellectual deficit. Eight cases have been reported in the literature in two unrelated families. Dysmorphic features include hypertelorism, depressed nasal bridge, and large nose with a large nasal tip, anteverted nostrils and wide mouth with thick lips. Affected patients do not achieve language ability. The condition is probably hereditary, and transmitted as an autosomal recessive trait.
Friedreich ataxia 1- MedGen UID:
- 383962
- •Concept ID:
- C1856689
- •
- Disease or Syndrome
Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years (mean age at onset: 10-15 yrs). FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes.
Rhizomelic chondrodysplasia punctata type 2- MedGen UID:
- 341734
- •Concept ID:
- C1857242
- •
- Disease or Syndrome
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (215100) is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012).
For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
Split hand-foot malformation 1 with sensorineural hearing loss- MedGen UID:
- 347431
- •Concept ID:
- C1857344
- •
- Congenital Abnormality
Split-hand/foot malformation-1 with sensorineural hearing loss (SHFM1D) is an autosomal recessive disorder characterized by severe limb defects and moderate to severe hearing loss. There is nearly complete palmar dorsalization, with circumferential fingernails (Shamseldin et al., 2012).
For a general phenotypic description and a discussion of genetic heterogeneity of split-hand/foot malformation, see SHFM1 (183600).
Becker nevus syndrome- MedGen UID:
- 347608
- •Concept ID:
- C1858042
- •
- Disease or Syndrome
Becker nevus (BN) is a cutaneous hamartoma affecting approximately 1 in 200 individuals that appears in childhood as a unilateral tan patch, and increases in thickness, pigmentation, and hair growth during adolescence. Histologically, epidermal acanthosis is accompanied by irregularly dispersed ectopic smooth muscle bundles and increased terminal hair follicles (summary by Cai et al., 2017). Becker nevus syndrome (BNS) is a phenotype characterized by the presence of a Becker nevus in association with unilateral hypoplasia of breast or other cutaneous, muscular, or skeletal defects (Happle and Koopman, 1997).
MASS syndrome- MedGen UID:
- 346932
- •Concept ID:
- C1858556
- •
- Disease or Syndrome
A genetic disorder of connective tissue caused by mutations in the FBN1 gene. Connective tissue is the material between the cells of the body that gives tissues form and strength. Symptoms include mitral valve prolapse, nearsightedness, borderline and non-progressive aortic enlargement, and skin and skeletal findings that overlap with those seen in Marfan syndrome. Treatment is based on the individuals symptoms.
Hereditary spastic paraplegia 10- MedGen UID:
- 349003
- •Concept ID:
- C1858712
- •
- Disease or Syndrome
Spastic paraplegia-10 (SPG10) is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, 118210). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by Goizet et al., 2009 and Crimella et al., 2012).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Klippel-Feil syndrome 2, autosomal recessive- MedGen UID:
- 395201
- •Concept ID:
- C1859209
- •
- Disease or Syndrome
Klippel-Feil syndrome (KFS) is a congenital anomaly characterized by a defect in the formation or segmentation of the cervical vertebrae, resulting in a fused appearance. The clinical triad consists of short neck, low posterior hairline, and limited neck movement, although less than 50% of patients demonstrate all 3 clinical features (Tracy et al., 2004).
Clarke et al. (1998) proposed a classification system for KFS in which an autosomal recessive form is characterized by the most rostral fusion at C1 and the presence of severe associated anomalies, including short neck, cardiac defects, and craniofacial anomalies.
For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (118100).
Cenani-Lenz syndactyly syndrome- MedGen UID:
- 395226
- •Concept ID:
- C1859309
- •
- Disease or Syndrome
Cenani-Lenz syndactyly syndrome (CLSS) is an autosomal recessive disorder characterized mainly by anomalies of distal limb development, with fusion and disorganization of metacarpal and phalangeal bones, radius and ulnar shortening, radioulnar synostosis, and severe syndactyly of hands and feet. Mild facial dysmorphism is present in most patients. Kidney anomalies, including renal agenesis and hypoplasia, occur in over half of patients (summary by Li et al., 2010).
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia- MedGen UID:
- 395301
- •Concept ID:
- C1859598
- •
- Disease or Syndrome
Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed.
Arterial tortuosity syndrome- MedGen UID:
- 347942
- •Concept ID:
- C1859726
- •
- Disease or Syndrome
Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder, which may include soft or doughy hyperextensible skin, joint hypermobility, inguinal hernia, and diaphragmatic hernia. Skeletal findings include pectus excavatum or carinatum, arachnodactyly, scoliosis, knee/elbow contractures, and camptodactyly. The cardiovascular system is the major source of morbidity and mortality with increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree, and for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs).
Amyotrophic lateral sclerosis type 2, juvenile- MedGen UID:
- 349246
- •Concept ID:
- C1859807
- •
- Disease or Syndrome
ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes: Infantile ascending hereditary spastic paraplegia (IAHSP), characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome caused by progressive cranial nerve involvement. Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years.
Trichorhinophalangeal syndrome, type III- MedGen UID:
- 349899
- •Concept ID:
- C1860823
- •
- Disease or Syndrome
Trichorhinophalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Craniofacial features include sparse, slowly growing scalp hair, laterally sparse eyebrows, a bulbous tip of the nose, protruding ears, long flat philtrum, and thin upper vermillion border. The most typical radiographic findings in TRPS are cone-shaped epiphyses, predominantly at the middle phalanges. Hip malformations such as coxa plana, coxa magna, or coxa vara are present in over 70% of patients. In older patients, the hip abnormalities resemble degenerative arthrosis. TRPS3 differs from TRPS1 by the presence of severe brachydactyly, due to short metacarpals, and severe short stature (summary by Ludecke et al., 2001).
Tibial torsion, bilateral medial- MedGen UID:
- 348785
- •Concept ID:
- C1861097
- •
- Disease or Syndrome
Tibial torsion (twisting of the tibia) can cause toeing in or out, depending on whether it is internal or external torsion. Although some degree of internal tibial torsion is present in almost all infants because of the intrauterine position, it usually corrects spontaneously. Persistence of internal tibial torsion may be inherited as an autosomal dominant trait (summary by Fitch, 1974).
Thoracolaryngopelvic dysplasia- MedGen UID:
- 349978
- •Concept ID:
- C1861197
- •
- Disease or Syndrome
A short-rib dysplasia with characteristics of thoracic dystrophy, laryngeal stenosis and a small pelvis. Less than 10 cases have been reported in the literature so far. Patients present with severe respiratory distress (requiring intubation) during the neonatal period. The rib shortening is less severe than in Jeune syndrome and the thorax is characteristically small, narrow and bell-shaped. The pelvis is reduced in all dimensions and the combination of the thorax anomalies and the small pelvis give the appearance of a protruding abdomen. Subglottic stenosis has also been described but it remains unclear whether this is a congenital anomaly or is secondary to long-term intubation. Transmission is autosomal dominant.
Klippel-Feil syndrome 1, autosomal dominant- MedGen UID:
- 396196
- •Concept ID:
- C1861689
- •
- Disease or Syndrome
Klippel-Feil syndrome is a bone disorder characterized by the abnormal joining (fusion) of two or more spinal bones in the neck (cervical vertebrae). The vertebral fusion is present from birth. Three major features result from this vertebral fusion: a short neck, the resulting appearance of a low hairline at the back of the head, and a limited range of motion in the neck. Most affected people have one or two of these characteristic features. Less than half of all individuals with Klippel-Feil syndrome have all three classic features of this condition.\n\nIn some cases, Klippel-Feil syndrome occurs as a feature of another disorder or syndrome, such as Wildervanck syndrome or hemifacial microsomia. In these instances, affected individuals have the signs and symptoms of both Klippel-Feil syndrome and the additional disorder.\n\nIn people with Klippel-Feil syndrome, the fused vertebrae can limit the range of movement of the neck and back as well as lead to chronic headaches and muscle pain in the neck and back that range in severity. People with minimal bone involvement often have fewer problems compared to individuals with several vertebrae affected. The shortened neck can cause a slight difference in the size and shape of the right and left sides of the face (facial asymmetry). Trauma to the spine, such as a fall or car accident, can aggravate problems in the fused area. Fusion of the vertebrae can lead to nerve damage in the head, neck, or back. Over time, individuals with Klippel-Feil syndrome can develop a narrowing of the spinal canal (spinal stenosis) in the neck, which can compress and damage the spinal cord. Rarely, spinal nerve abnormalities may cause abnormal sensations or involuntary movements in people with Klippel-Feil syndrome. Affected individuals may develop a painful joint disorder called osteoarthritis around the areas of fused bone or experience painful involuntary tensing of the neck muscles (cervical dystonia). In addition to the fused cervical bones, people with this condition may have abnormalities in other vertebrae. Many people with Klippel-Feil syndrome have abnormal side-to-side curvature of the spine (scoliosis) due to malformation of the vertebrae; fusion of additional vertebrae below the neck may also occur.\n\nPeople with Klippel-Feil syndrome may have a wide variety of other features in addition to their spine abnormalities. Some people with this condition have hearing difficulties, eye abnormalities, an opening in the roof of the mouth (cleft palate), genitourinary problems such as abnormal kidneys or reproductive organs, heart abnormalities, or lung defects that can cause breathing problems. Affected individuals may have other skeletal defects including arms or legs of unequal length (limb length discrepancy), which can result in misalignment of the hips or knees. Additionally, the shoulder blades may be underdeveloped so that they sit abnormally high on the back, a condition called Sprengel deformity. Rarely, structural brain abnormalities or a type of birth defect that occurs during the development of the brain and spinal cord (neural tube defect) can occur in people with Klippel-Feil syndrome.
Camptomelic dysplasia- MedGen UID:
- 354620
- •Concept ID:
- C1861922
- •
- Disease or Syndrome
Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional findings identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment.
Weismann-Netter syndrome- MedGen UID:
- 350610
- •Concept ID:
- C1862172
- •
- Disease or Syndrome
The diagnostic hallmarks of Weismann-Netter syndrome (WNS) are anterior bowing of the diaphyses of the tibia and fibula, broadening or 'tibialization' of the fibula, posterior cortical thickening of both bones, and short stature. The diaphyses of other long bones may be similarly affected, but usually to a milder degree. Some WNS patients have also displayed mental retardation (summary by Peippo et al., 2009).
Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome- MedGen UID:
- 350678
- •Concept ID:
- C1862472
- •
- Disease or Syndrome
Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles. Some cases have been reported to have pulmonary hypertension as a result of restrictive lung disease (summary by Bamshad et al., 2009).
There are 2 syndromes with features overlapping those of DA5 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of cleft palate and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders might represent variable expressivity of the same condition.
For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120).
Genetic Heterogeneity of Distal Arthrogryposis 5
A subtype of DA5 due to mutation in the ECEL1 gene (605896) on chromosome 2q36 has been designated DA5D (615065). See NOMENCLATURE.
Amastia, bilateral, with ureteral triplication and dysmorphism- MedGen UID:
- 354882
- •Concept ID:
- C1863015
- •
- Disease or Syndrome
Spondyloepimetaphyseal dysplasia with multiple dislocations- MedGen UID:
- 350960
- •Concept ID:
- C1863732
- •
- Disease or Syndrome
Spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2) is characterized by short stature, distinctive midface retrusion, progressive knee malalignment (genu valgum and/or varum), generalized ligamentous laxity, and mild spinal deformity. Intellectual development is not impaired. Radiographic characteristics include significantly retarded epiphyseal ossification that evolves into epiphyseal dysplasia and precocious osteoarthritis, metaphyseal irregularities and vertical striations, constricted femoral neck, slender metacarpals and metatarsals, and mild thoracolumbar kyphosis or scoliosis with normal or mild platyspondyly (summary by Min et al., 2011).
For a discussion of genetic heterogeneity of SEMD with joint laxity, see SEMDJL1 (271640).
Congenital myasthenic syndrome 5- MedGen UID:
- 400481
- •Concept ID:
- C1864233
- •
- Disease or Syndrome
Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (summary by Engel et al., 2015).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Rubinstein-Taybi syndrome due to 16p13.3 microdeletion- MedGen UID:
- 350477
- •Concept ID:
- C1864648
- •
- Disease or Syndrome
Chromosome 16p13.3deletion syndrome is a chromosome abnormality that can affect many parts of the body. People with this condition are missing a small piece (deletion) of chromosome 16 at a location designated p13.3. Although once thought to be a severe form of Rubinstein-Taybi syndrome, it is now emerging as a unique syndrome. Signs and symptoms may include failure to thrive, hypotonia (reduced muscle tone), short stature, microcephaly (unusually small head), characteristic facial features, mild to moderate intellectual disability, organ anomalies (i.e. heart and/or kidney problems), and vulnerability to infections. Chromosome testing of both parents can provide information about whether the deletion was inherited. In most cases, parents do not have any chromosome abnormalities. However, sometimes one parent has a balanced translocation where a piece of a chromosome has broken off and attached to another one with no gain or loss of genetic material. The balanced translocation normally does not cause signs or symptoms, but it increases the risk for having a child with a chromosome abnormality like a deletion. Treatment is based on the signs and symptoms present in each person.To learn more about chromosome abnormalities in general, view our GARD fact sheet on Chromosome Disorders.
Hypomyelination and Congenital Cataract- MedGen UID:
- 501134
- •Concept ID:
- C1864663
- •
- Congenital Abnormality
Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild-to-moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. Cataracts may be absent in some individuals.
Camptodactyly-tall stature-scoliosis-hearing loss syndrome- MedGen UID:
- 355844
- •Concept ID:
- C1864852
- •
- Disease or Syndrome
This syndrome has characteristics of camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL). It has been described in around 30 individuals from seven generations of the same family. The syndrome is caused by a missense mutation in the FGFR3 gene, leading to a partial loss of function of the encoded protein, which is a negative regulator of bone growth.
Koolen-de Vries syndrome- MedGen UID:
- 355853
- •Concept ID:
- C1864871
- •
- Disease or Syndrome
Koolen-de Vries syndrome (KdVS) is characterized by developmental delay / intellectual disability, neonatal/childhood hypotonia, dysmorphisms, congenital malformations, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism (71% of males). Behavior in most is described as friendly, amiable, and cooperative.
Spondylomegaepiphyseal dysplasia with upper limb mesomelia, punctate calcifications, and deafness- MedGen UID:
- 355893
- •Concept ID:
- C1865022
- •
- Disease or Syndrome
Spondyloepimetaphyseal dysplasia, Shohat type- MedGen UID:
- 400703
- •Concept ID:
- C1865185
- •
- Disease or Syndrome
Shohat-type spondyloepimetaphyseal dysplasia (SEMDSH) is a chondrodysplasia characterized by vertebral, epiphyseal, and metaphyseal abnormalities, including scoliosis with vertebral compression fractures, flattened vertebral bodies, and hypomineralization of long bones. Affected individuals may exhibit a small trunk, short neck, small limbs, joint laxity, bowlegs, and/or abdominal distention with hepatosplenomegaly (summary by Egunsola et al., 2017).
Pelvic dysplasia-arthrogryposis of lower limbs syndrome- MedGen UID:
- 400731
- •Concept ID:
- C1865294
- •
- Disease or Syndrome
Pelvic dysplasia-arthrogryposis of lower limbs syndrome is a rare, genetic, dysostosis syndrome characterized by intrauterine growth restriction, short stature (with short lower segment), lower limb joint contractures and muscular hypotrophy, narrow, small pelvis, lumbar hyperlordosis with scoliosis, and foot deformity (short, overlapping toes). Imaging reveals ovoid/wedge-shaped vertebral bodies, pelvic and skeletal hypoplasia with metatarsal fusion in the lower limbs, and normal skull and upper limbs.
Pierpont syndrome- MedGen UID:
- 356049
- •Concept ID:
- C1865644
- •
- Disease or Syndrome
Pierpont syndrome (PRPTS) is a multiple congenital anomaly syndrome associated with learning disability. Key features include distinctive facial characteristics, especially when smiling, plantar fat pads, and other limb anomalies (summary by Burkitt Wright et al., 2011).
Axial spondylometaphyseal dysplasia- MedGen UID:
- 356065
- •Concept ID:
- C1865695
- •
- Disease or Syndrome
Axial spondylometaphyseal dysplasia (SMDAX) is characterized by postnatal growth failure, including rhizomelic short stature in early childhood that evolves into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection. Impaired visual acuity comes to medical attention in early life and vision rapidly deteriorates. Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on funduscopic examination and as cone-rod dystrophy on electroretinogram. Radiologic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora (summary by Suzuki et al., 2011).
Friedreich ataxia 2- MedGen UID:
- 356134
- •Concept ID:
- C1865981
- •
- Disease or Syndrome
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty (summary by Delatycki et al., 2000).
For a general phenotypic description of Friedreich ataxia (FRDA), see FRDA1 (229300), which is caused by mutation in the FXN gene (606829) on chromosome 9q13.
Acroosteolysis-keloid-like lesions-premature aging syndrome- MedGen UID:
- 400936
- •Concept ID:
- C1866182
- •
- Disease or Syndrome
Penttinen syndrome (PENTT) is characterized by a prematurely aged appearance involving lipoatrophy and epidermal and dermal atrophy, as well as hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acroosteolysis (Johnston et al., 2015).
Ehlers-Danlos syndrome, musculocontractural type- MedGen UID:
- 356497
- •Concept ID:
- C1866294
- •
- Disease or Syndrome
Bleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.\n\nOther types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.\n\nMany people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.\n\nAn unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.\n\nThe various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.\n\nEhlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.
PTEN hamartoma tumor syndrome with granular cell tumor- MedGen UID:
- 400984
- •Concept ID:
- C1866376
- •
- Neoplastic Process
Charcot-Marie-Tooth disease type 4C- MedGen UID:
- 356581
- •Concept ID:
- C1866636
- •
- Disease or Syndrome
SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems.
Omphalocele syndrome, Shprintzen-Goldberg type- MedGen UID:
- 356653
- •Concept ID:
- C1866958
- •
- Disease or Syndrome
A very rare inherited malformation syndrome with characteristics of omphalocele, scoliosis, mild dysmorphic features (downslanted palpebral fissures, s-shaped eyelids and thin upper lip), laryngeal and pharyngeal hypoplasia and learning disabilities.
Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A- MedGen UID:
- 401232
- •Concept ID:
- C1867440
- •
- Disease or Syndrome
Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1A (CPSFS1) is characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported (Carapito et al., 2016; Zieba et al., 2017; Cameron-Christie et al., 2018).
An autosomal recessive form of CPSFS (CPSFS1B; 618469) is caused by compound heterozygous mutation in the MYH3 gene.
Pseudoxanthoma elasticum, forme fruste- MedGen UID:
- 357280
- •Concept ID:
- C1867450
- •
- Disease or Syndrome
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span.
Posterior column ataxia- MedGen UID:
- 357379
- •Concept ID:
- C1867923
- •
- Disease or Syndrome
Orofaciodigital syndrome V- MedGen UID:
- 358131
- •Concept ID:
- C1868118
- •
- Disease or Syndrome
Orofaciodigital syndrome V (OFD5) is an autosomal recessive disorder characterized by cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (summary by Faily et al., 2017).
Parastremmatic dwarfism- MedGen UID:
- 358366
- •Concept ID:
- C1868616
- •
- Congenital Abnormality
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Weill-Marchesani syndrome 2, dominant- MedGen UID:
- 358388
- •Concept ID:
- C1869115
- •
- Disease or Syndrome
Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.
4p partial monosomy syndrome- MedGen UID:
- 408255
- •Concept ID:
- C1956097
- •
- Disease or Syndrome
Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, and micrognathia), and a seizure disorder (Battaglia et al., 2008).
Joubert syndrome 7- MedGen UID:
- 369401
- •Concept ID:
- C1969053
- •
- Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Renal tubular acidosis, distal, with nephrocalcinosis, short stature, intellectual disability, and distinctive facies- MedGen UID:
- 370587
- •Concept ID:
- C1969055
- •
- Disease or Syndrome
Intellectual disability, autosomal dominant 1- MedGen UID:
- 409857
- •Concept ID:
- C1969562
- •
- Mental or Behavioral Dysfunction
MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).
Spastic ataxia 3- MedGen UID:
- 370715
- •Concept ID:
- C1969645
- •
- Disease or Syndrome
A rare genetic autosomal recessive spastic ataxia disease with characteristics of cerebellar ataxia, spasticity, cerebellar (and in some cases cerebral) atrophy, dystonia and leucoencephalopathy. Caused by homozygous or compound heterozygous complex genomic rearrangements involving the MARS2 gene on chromosome 2q33.
COG8-congenital disorder of glycosylation- MedGen UID:
- 409971
- •Concept ID:
- C1970021
- •
- Disease or Syndrome
Syndrome with characteristics of severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products. So far, only two cases have been described. The disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus.
Neuronopathy, distal hereditary motor, autosomal recessive 4- MedGen UID:
- 369682
- •Concept ID:
- C1970211
- •
- Disease or Syndrome
A rare genetic neuromuscular disease characterized by proximal muscle weakness with an early involvement of foot and hand muscles following normal motor development in early childhood, a rapidly progressive disease course leading to generalized areflexic tetraplegia with contractures, severe scoliosis, hyperlordosis, and progressive respiratory insufficiency leading to assisted ventilation. Cranial nerve functions are normal and tongue wasting and fasciculations are absent. Milder phenotype with a moderate generalized weakness and slower disease progress was reported. There is evidence the disease is caused by homozygous mutation in the gene encoding pleckstrin homology domain-containing protein, family G member 5 (PLEKHG5) on chromosome 1p36.
XFE progeroid syndrome- MedGen UID:
- 410064
- •Concept ID:
- C1970416
- •
- Disease or Syndrome
An autosomal recessive condition caused by mutation(s) in the ERCC4 gene, encoding DNA repair endonuclease XPF. it is characterized by characterized by cutaneous photosensitivity and progeroid features in multiple organ systems.
Pitt-Hopkins syndrome- MedGen UID:
- 370910
- •Concept ID:
- C1970431
- •
- Disease or Syndrome
Pitt-Hopkins syndrome (PTHS) is characterized by significant developmental delays with moderate-to-severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.
Osteogenesis imperfecta type 8- MedGen UID:
- 410075
- •Concept ID:
- C1970458
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.
Syndromic X-linked intellectual disability 14- MedGen UID:
- 372646
- •Concept ID:
- C1970822
- •
- Disease or Syndrome
Any X-linked syndromic intellectual disability in which the cause of the disease is a mutation in the UPF3B gene.
Stickler syndrome type 1- MedGen UID:
- 810955
- •Concept ID:
- C2020284
- •
- Disease or Syndrome
Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity.
Early-onset myopathy with fatal cardiomyopathy- MedGen UID:
- 435983
- •Concept ID:
- C2673677
- •
- Disease or Syndrome
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between ages 20 months and four years. In the first decade of life, global motor performance is stable or tends to improve. Moderate joint and neck contractures and spinal rigidity may manifest in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction manifests between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Loeys-Dietz syndrome 2- MedGen UID:
- 382398
- •Concept ID:
- C2674574
- •
- Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Diamond-Blackfan anemia 7- MedGen UID:
- 436451
- •Concept ID:
- C2675512
- •
- Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
Chromosome 1q41-q42 deletion syndrome- MedGen UID:
- 382704
- •Concept ID:
- C2675857
- •
- Disease or Syndrome
1q41q42 microdeletion syndrome is a chromosomal anomaly characterized by a severe developmental delay and/or intellectual disability, typical facial dysmorphic features, brain anomalies, seizures, cleft palate, clubfeet, nail hypoplasia and congenital heart disease.
Chromosome 1q21.1 deletion syndrome- MedGen UID:
- 393913
- •Concept ID:
- C2675897
- •
- Congenital Abnormality
The 1q21.1 recurrent microdeletion itself does not appear to lead to a clinically recognizable syndrome as some persons with the deletion have no obvious clinical findings and others have variable findings that most commonly include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, autistic features, and sleep disturbances.
Bone fragility with contractures, arterial rupture, and deafness- MedGen UID:
- 382811
- •Concept ID:
- C2676285
- •
- Disease or Syndrome
BCARD syndrome is an autosomal recessive connective tissue disorder characterized by bone abnormalities, including low bone mineral density, scoliosis, contractures of the fingers and other joints, prominent knees, and rare pathologic fractures; cataract and other ocular abnormalities, including high myopia, optically empty vitreous, and risk for retinal detachment; risk of arterial rupture due to vascular aneurysm or dissection; and sensorineural deafness. Affected individuals also exhibit recognizable craniofacial dysmorphisms, and variable skin features have been observed, including reduced palmar creases, soft skin with easy bruising, and blistering. Developmental delay, which is present in most patients, may be attributable to sensory deficits or medical complications (Ewans et al., 2019).
Fontaine progeroid syndrome- MedGen UID:
- 394125
- •Concept ID:
- C2676780
- •
- Disease or Syndrome
SLC25A24 Fontaine progeroid syndrome is a multisystem connective tissue disorder characterized by poor growth, abnormal skeletal features, and distinctive craniofacial features with sagging, thin skin, and decreased subcutaneous fat suggesting an aged appearance that is most pronounced in infancy and improves with time. Characteristic radiographic features include turribrachycephaly with widely open anterior fontanelle, craniosynostosis, and anomalies of the terminal phalanges. Cardiovascular, genitourinary, ocular, and gastrointestinal abnormalities may also occur. To date, 13 individuals with a molecularly confirmed diagnosis of SLC25A24 Fontaine progeroid syndrome have been described.
Joubert syndrome 9- MedGen UID:
- 382940
- •Concept ID:
- C2676788
- •
- Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Hunter-Macdonald syndrome- MedGen UID:
- 383181
- •Concept ID:
- C2677745
- •
- Disease or Syndrome
Stevenson-Carey syndrome- MedGen UID:
- 383183
- •Concept ID:
- C2677763
- •
- Disease or Syndrome
Syndromic X-linked intellectual disability Najm type- MedGen UID:
- 437070
- •Concept ID:
- C2677903
- •
- Disease or Syndrome
CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features.
Intellectual disability, X-linked syndromic, Turner type- MedGen UID:
- 394425
- •Concept ID:
- C2678046
- •
- Disease or Syndrome
Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder with a highly variable phenotype. Some affected families show X-linked recessive inheritance, with only males being affected and carrier females having no abnormal findings. In other affected families, males are severely affected, and female mutation carriers show milder cognitive abnormalities or dysmorphic features. In addition, there are female patients with de novo mutations who show the full phenotype, despite skewed X-chromosome inactivation. Affected individuals show global developmental delay from infancy, with variably impaired intellectual development and poor or absent speech, often with delayed walking. Dysmorphic features are common and can include macrocephaly, microcephaly, deep-set eyes, hypotelorism, small palpebral fissures, dysplastic, large, or low-set ears, long face, bitemporal narrowing, high-arched palate, thin upper lip, and scoliosis or mild distal skeletal anomalies, such as brachydactyly or tapered fingers. Males tend to have cryptorchidism. Other features, such as hypotonia, seizures, and delayed bone age, are more variable (summary by Moortgat et al., 2018).
X-linked myopathy with postural muscle atrophy- MedGen UID:
- 395525
- •Concept ID:
- C2678055
- •
- Disease or Syndrome
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals.
Scoliosis, isolated, susceptibility to, 1- MedGen UID:
- 438003
- •Concept ID:
- C2700406
- •
- Finding
Idiopathic scoliosis is a structurally fixed lateral curvature of the spine with a rotatory component. There is at least a 10 degree curvature as demonstrated by upright spine roentgenograms by the Cobb method (Weinstein, 1994).
Scoliosis may occur secondary to other hereditary disorders including Marfan syndrome (154700), dysautonomia (223900), neurofibromatosis (see 162200), Friedreich ataxia (see 229300), and muscular dystrophies.
Genetic Heterogeneity of Susceptibility to Isolated Scoliosis
Loci for isolated scoliosis have been mapped to chromosome 19 (IS1), chromosome 17 (IS2; 607354), chromosome 8 (IS3; 608765), chromosome 9q31-q34 (IS4; 612238), and chromosome 17q25-qter (IS5; 612239).
Spondyloepiphyseal dysplasia congenita- MedGen UID:
- 412530
- •Concept ID:
- C2745959
- •
- Congenital Abnormality
Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990).
Hereditary spastic paraplegia 18- MedGen UID:
- 442343
- •Concept ID:
- C2749936
- •
- Disease or Syndrome
Spastic paraplegia-18B (SPG18B) is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (summary by Alazami et al., 2011 and Yildirim et al., 2011).
Emery-Dreifuss muscular dystrophy 3, autosomal recessive- MedGen UID:
- 413212
- •Concept ID:
- C2750035
- •
- Disease or Syndrome
Emery-Dreifuss muscular dystrophy is characterized classically by the triad of weakness of the shoulder and pelvic girdle muscles, contractures of the elbows, neck, and Achilles tendon, and cardiac involvement, most commonly arrhythmias (summary by Jimenez-Escrig et al., 2012).
For a discussion of genetic heterogeneity of EDMD, see 310300.
Spondylo-megaepiphyseal-metaphyseal dysplasia- MedGen UID:
- 412869
- •Concept ID:
- C2750066
- •
- Disease or Syndrome
Spondylo-megaepiphyseal-metaphyseal dysplasia is a rare autosomal recessive skeletal dysplasia characterized by disproportionate short stature with a short and stiff neck and trunk; relatively long limbs that may show flexion contractures of the distal joints; delayed and impaired ossification of the vertebral bodies and the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones; and numerous pseudoepiphyses of the short tubular bones in hands and feet (summary by Hellemans et al., 2009).
Congenital generalized lipodystrophy type 4- MedGen UID:
- 412871
- •Concept ID:
- C2750069
- •
- Disease or Syndrome
Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009).
For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).
Autosomal dominant omodysplasia- MedGen UID:
- 413823
- •Concept ID:
- C2750355
- •
- Disease or Syndrome
Omodysplasia-2 (OMOD2) is a rare autosomal dominant skeletal dysplasia characterized by shortened humeri, dislocated radial heads, shortened first metacarpals, craniofacial dysmorphism, and variable genitourinary anomalies (Saal et al., 2015).
For a discussion of genetic heterogeneity of OMOD, see 258315.
Hereditary spastic paraplegia 44- MedGen UID:
- 413042
- •Concept ID:
- C2750784
- •
- Disease or Syndrome
A very rare, complex form of hereditary spastic paraplegia characterised by a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement (i.e. loss of finger dexterity, dysmetria), and mild cognitive impairment, without the presence of nystagmus. A hypomyelinating leucodystrophy and thin corpus callosum is observed in all cases and psychomotor development is normal or near normal. Caused by mutations in the GJC2 gene (1q41-q42) encoding the gap junction gamma-2 protein.
Congenital muscular dystrophy due to integrin alpha-7 deficiency- MedGen UID:
- 413044
- •Concept ID:
- C2750786
- •
- Disease or Syndrome
A rare genetic congenital muscular dystrophy due to extracellular matrix protein anomaly. The disease has characteristics of early motor development delay and muscle weakness with mild elevation of serum creatine kinase that may be followed by progressive disease course with predominantly proximal muscle weakness and atrophy, motor development regress, scoliosis and respiratory insufficiency. There is evidence this disease is caused by compound heterozygous mutation in the ITGA7 gene on chromosome 12q13.
Chromosome 5p13 duplication syndrome- MedGen UID:
- 416385
- •Concept ID:
- C2750805
- •
- Disease or Syndrome
A rare partial autosomal trisomy/tetrasomy characterized by global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low set, dysplastic ears, short or shallow philtrum, high arched or narrow palate, micrognathia). Other associated clinical features include sleep disturbances, seizures, aplasia/hypoplasia of the corpus callosum, skeletal abnormalities (large hands and feet, long fingers and toes, talipes).
RIN2 syndrome- MedGen UID:
- 416526
- •Concept ID:
- C2751321
- •
- Disease or Syndrome
A very rare inherited connective tissue disorder with characteristics of macrocephaly, sparse scalp hair, soft redundant and hyperextensible skin, joint hypermobility, and scoliosis. Patients have progressive facial coarsening with downslanted palpebral fissures, upper eyelid fullness/infraorbital folds, thick/everted vermillion, gingival overgrowth and abnormal position of the teeth. Rare manifestations such as abnormal high-pitched voice, bronchiectasis, hypergonadotropic hypergonadism and brachydactyly have also been reported. Caused by homozygous mutation in the RIN2 gene on chromosome 20p11.
Myofibrillar myopathy 6- MedGen UID:
- 414119
- •Concept ID:
- C2751831
- •
- Disease or Syndrome
Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012).
For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).
Autosomal recessive cutis laxa type 2B- MedGen UID:
- 414526
- •Concept ID:
- C2751987
- •
- Disease or Syndrome
The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009).
For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
CLOVES syndrome- MedGen UID:
- 442876
- •Concept ID:
- C2752042
- •
- Disease or Syndrome
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.
Hereditary spastic paraplegia 46- MedGen UID:
- 473687
- •Concept ID:
- C2828721
- •
- Disease or Syndrome
Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging (summary by Boukhris et al., 2010 and Martin et al., 2013).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Potocki-Lupski syndrome- MedGen UID:
- 444010
- •Concept ID:
- C2931246
- •
- Disease or Syndrome
Potocki-Lupski syndrome (PTLS) is characterized by cognitive, behavioral, and medical manifestations. Cognitively, most individuals present with developmental delay, later meeting criteria for moderate intellectual disability. Behaviorally, issues with attention, hyperactivity, withdrawal, and anxiety may be seen. Some individuals meet criteria for autism spectrum disorder. Medically, hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, hypoglycemia associated with growth hormone deficiency, and mildly dysmorphic facial features are observed. Medical manifestations typically lead to identification of PTLS in infancy; however, those with only behavioral and cognitive manifestations may be identified in later childhood.
Hereditary spastic paraplegia 3A- MedGen UID:
- 419393
- •Concept ID:
- C2931355
- •
- Disease or Syndrome
Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a minority of individuals with SPG3A. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. Most persons with early-onset ATL1-HSP have a "pure" ("uncomplicated") HSP; however, complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) has been observed. The rate of progression in ATL1-HSP is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare.
Infantile-onset ascending hereditary spastic paralysis- MedGen UID:
- 419413
- •Concept ID:
- C2931441
- •
- Disease or Syndrome
ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes: Infantile ascending hereditary spastic paraplegia (IAHSP), characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome caused by progressive cranial nerve involvement. Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years.
Cardiospondylocarpofacial syndrome- MedGen UID:
- 444060
- •Concept ID:
- C2931461
- •
- Disease or Syndrome
Cardiospondylocarpofacial syndrome (CSCF) is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion, extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations (summary by Le Goff et al., 2016).
Neurofibromatosis-Noonan syndrome- MedGen UID:
- 419089
- •Concept ID:
- C2931482
- •
- Disease or Syndrome
A variant of neurofibromatosis type 1 characterized by the combination of features of neurofibromatosis type 1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas; and Noonan syndrome, with features such as short stature, typical facial features, congenital heart defects and unusual pectus deformity.
Autosomal recessive limb-girdle muscular dystrophy type 2D- MedGen UID:
- 424706
- •Concept ID:
- C2936332
- •
- Disease or Syndrome
Autosomal recessive limb-girdle muscular dystrophy-3 (LGMDR3) affects mainly the proximal muscles and results in difficulty walking. Most individuals have onset in childhood; the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures. Cardiomyopathy has rarely been reported (summary by Babameto-Laku et al., 2011).
For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Bardet-Biedl syndrome 1- MedGen UID:
- 422452
- •Concept ID:
- C2936862
- •
- Disease or Syndrome
Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014).
Genetic Heterogeneity of Bardet-Biedl Syndrome
BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21.
The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes.
Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001).
Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation.
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis- MedGen UID:
- 461449
- •Concept ID:
- C3150099
- •
- Disease or Syndrome
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2- MedGen UID:
- 461761
- •Concept ID:
- C3150411
- •
- Disease or Syndrome
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (van Reeuwijk et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2- MedGen UID:
- 461766
- •Concept ID:
- C3150416
- •
- Disease or Syndrome
MDDGB2 is an autosomal recessive congenital muscular dystrophy associated with impaired intellectual development and mild structural brain abnormalities (Yanagisawa et al., 2007). It is part of a group of similar disorders, collectively known as 'dystroglycanopathies,' resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) (Godfrey et al., 2007).
For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Chromosome 17q23.1-q23.2 deletion syndrome- MedGen UID:
- 461957
- •Concept ID:
- C3150607
- •
- Disease or Syndrome
17q23.1q23.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, short stature, heart defects and limb abnormalities.
Rett syndrome, congenital variant- MedGen UID:
- 462055
- •Concept ID:
- C3150705
- •
- Disease or Syndrome
The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005).
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency- MedGen UID:
- 462291
- •Concept ID:
- C3150941
- •
- Disease or Syndrome
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.
Spondylocostal dysostosis 4, autosomal recessive- MedGen UID:
- 462292
- •Concept ID:
- C3150942
- •
- Disease or Syndrome
Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.
Noonan syndrome 7- MedGen UID:
- 462320
- •Concept ID:
- C3150970
- •
- Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Chromosome 17p13.1 deletion syndrome- MedGen UID:
- 462419
- •Concept ID:
- C3151069
- •
- Disease or Syndrome
Aneurysm-osteoarthritis syndrome- MedGen UID:
- 462437
- •Concept ID:
- C3151087
- •
- Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Asphyxiating thoracic dystrophy 4- MedGen UID:
- 462535
- •Concept ID:
- C3151185
- •
- Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330).
For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Seckel syndrome 5- MedGen UID:
- 462537
- •Concept ID:
- C3151187
- •
- Disease or Syndrome
Seckel syndrome is an autosomal recessive disorder characterized by proportionate short stature, severe microcephaly, mental retardation, and a typical 'bird-head' facial appearance (summary by Kalay et al., 2011).
For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see 210600.
Osteogenesis imperfecta type 10- MedGen UID:
- 462561
- •Concept ID:
- C3151211
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type X is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera (Christiansen et al., 2010).
Osteogenesis imperfecta type 11- MedGen UID:
- 462568
- •Concept ID:
- C3151218
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XI is an autosomal recessive form of OI (summary by Alanay et al., 2010).
Osteogenesis imperfecta type 12- MedGen UID:
- 462783
- •Concept ID:
- C3151433
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XII is an autosomal recessive form characterized by recurrent fractures, mild bone deformations, generalized osteoporosis, delayed teeth eruption, progressive hearing loss, no dentinogenesis imperfecta, and white sclerae (summary by Lapunzina et al., 2010).
Nestor-Guillermo progeria syndrome- MedGen UID:
- 462796
- •Concept ID:
- C3151446
- •
- Disease or Syndrome
Nestor-Guillermo progeria syndrome (NGPS) is an autosomal recessive disorder characterized by lipoatrophy, osteoporosis, and very severe osteolysis. Patients have no cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia, but suffer profound skeletal abnormalities that affect their quality of life. Onset is after 2 years of age, and lifespan is relatively long (summary by Cabanillas et al., 2011).
Hennekam-Beemer syndrome- MedGen UID:
- 462843
- •Concept ID:
- C3151493
- •
- Disease or Syndrome
A rare multiple congenital anomalies syndrome characterized by cutaneous mastocytosis, microcephaly, microtia and/or hearing loss, hypotonia and skeletal anomalies (e.g. clinodactyly, camptodactyly, scoliosis). Additional common features are short stature, intellectual disability and difficulties. Facial dysmorphism may include upslanted palpebral fissures, highly arched palate and micrognathia. Rarely, seizures and asymmetrically small feet have been reported.
CK syndrome- MedGen UID:
- 463131
- •Concept ID:
- C3151781
- •
- Disease or Syndrome
The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males. CHILD syndrome is characterized by unilateral distribution of ichthyosiform (yellow scaly) skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Nail changes are also common. The heart, lung, and kidneys can also be involved. CK syndrome (named for the initials of the original proband) is characterized by mild to severe cognitive impairment and behavior problems (aggression, attention deficit hyperactivity disorder, and irritability). All affected males reported have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported.
Ogden syndrome- MedGen UID:
- 477078
- •Concept ID:
- C3275447
- •
- Disease or Syndrome
Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015).
Syndromic X-linked intellectual disability Chudley-Schwartz type- MedGen UID:
- 477102
- •Concept ID:
- C3275471
- •
- Mental or Behavioral Dysfunction
A syndromic X-linked intellectual disability characterized by moderate intellectual disability, seizures, dysmorphic facial features and in some older patients slowly progressive unsteady gait and progressive weakness that has material basis in variation in the chromosomal region Xq21.33-q23.
Multiple congenital anomalies-hypotonia-seizures syndrome 2- MedGen UID:
- 477139
- •Concept ID:
- C3275508
- •
- Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.
For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080).
For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350.
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Acrodysostosis 1 with or without hormone resistance- MedGen UID:
- 477858
- •Concept ID:
- C3276228
- •
- Disease or Syndrome
Acrodysostosis-1 (ACRDYS1) is a form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin (summary by Linglart et al., 2011). However, not all patients show endocrine abnormalities (Lee et al., 2012).
Genetic Heterogeneity of Acrodysostosis
See also ACRDYS2 (614613), caused by mutation in the PDE4D gene (600129) on chromosome 5q12.
Larsen-like syndrome, B3GAT3 type- MedGen UID:
- 480034
- •Concept ID:
- C3278404
- •
- Disease or Syndrome
CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.
Keppen-Lubinsky syndrome- MedGen UID:
- 481430
- •Concept ID:
- C3279800
- •
- Disease or Syndrome
Keppen-Lubinsky syndrome (KPLBS) is a rare disorder characterized by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth (summary by Masotti et al., 2015).
Stickler syndrome, type 4- MedGen UID:
- 481571
- •Concept ID:
- C3279941
- •
- Disease or Syndrome
Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity.
Hyperphosphatasia with intellectual disability syndrome 3- MedGen UID:
- 481783
- •Concept ID:
- C3280153
- •
- Disease or Syndrome
Hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3) is an autosomal recessive disorder characterized by severe intellectual disability, hypotonia with poor motor development, poor speech, and increased serum alkaline phosphatase (summary by Hansen et al., 2013). However, the severity of the disorder can also vary to include more mild intellectual impairment (Krawitz et al., 2013). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.
For a discussion of genetic heterogeneity of HPMRS, see HPMRS1 (239300).
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Intellectual disability, autosomal dominant 8- MedGen UID:
- 481912
- •Concept ID:
- C3280282
- •
- Disease or Syndrome
GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems. A subset of individuals show a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. To date, 72 individuals with GRIN1-NDD have been reported.
Pitt-Hopkins-like syndrome 2- MedGen UID:
- 482109
- •Concept ID:
- C3280479
- •
- Disease or Syndrome
Any Pitt-Hopkins-like syndrome in which the cause of the disease is a mutation in the NRXN1 gene.
MEGF10-related myopathy- MedGen UID:
- 482309
- •Concept ID:
- C3280679
- •
- Disease or Syndrome
Congenital myopathy-10A (CMYO10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011).
Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYO10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYO10B) (Croci et al., 2022).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Cutis laxa, autosomal dominant 2- MedGen UID:
- 482424
- •Concept ID:
- C3280794
- •
- Disease or Syndrome
FBLN5-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective disorder such as inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). Occasionally, supravalvar aortic stenosis is observed. Intrafamilial variability in age of onset is observed. Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death.
Chromosome 17q12 deletion syndrome- MedGen UID:
- 482768
- •Concept ID:
- C3281138
- •
- Disease or Syndrome
The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85% to 90% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years).
Coffin-Siris syndrome 1- MedGen UID:
- 482831
- •Concept ID:
- C3281201
- •
- Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Craniofacial microsomia 1- MedGen UID:
- 501171
- •Concept ID:
- C3495417
- •
- Congenital Abnormality
Craniofacial microsomia is a term used to describe a spectrum of abnormalities that primarily affect the development of the skull (cranium) and face before birth. Microsomia means abnormal smallness of body structures. Most people with craniofacial microsomia have differences in the size and shape of facial structures between the right and left sides of the face (facial asymmetry). In about two-thirds of cases, both sides of the face have abnormalities, which usually differ from one side to the other. Other individuals with craniofacial microsomia are affected on only one side of the face. The facial characteristics in craniofacial microsomia typically include underdevelopment of one side of the upper or lower jaw (maxillary or mandibular hypoplasia), which can cause dental problems and difficulties with feeding and speech. In cases of severe mandibular hypoplasia, breathing may also be affected.\n\nPeople with craniofacial microsomia usually have ear abnormalities affecting one or both ears, typically to different degrees. They may have growths of skin (skin tags) in front of the ear (preauricular tags), an underdeveloped or absent external ear (microtia or anotia), or a closed or absent ear canal; these abnormalities may lead to hearing loss. Eye problems are less common in craniofacial microsomia, but some affected individuals have an unusually small eyeball (microphthalmia) or other eye abnormalities that result in vision loss.\n\nAbnormalities in other parts of the body, such as malformed bones of the spine (vertebrae), abnormally shaped kidneys, and heart defects, may also occur in people with craniofacial microsomia.\n\nMany other terms have been used for craniofacial microsomia. These other names generally refer to forms of craniofacial microsomia with specific combinations of signs and symptoms, although sometimes they are used interchangeably. Hemifacial microsomia often refers to craniofacial microsomia with maxillary or mandibular hypoplasia. People with hemifacial microsomia and noncancerous (benign) growths in the eye called epibulbar dermoids may be said to have Goldenhar syndrome or oculoauricular dysplasia.
Charcot-Marie-Tooth disease type 4F- MedGen UID:
- 761704
- •Concept ID:
- C3540453
- •
- Disease or Syndrome
Charcot-Marie-Tooth disease type 4F (CMT4F) is an autosomal recessive demyelinating neuropathy characterized by distal sensory impairment and distal muscle weakness and atrophy affecting the lower more than the upper limbs. Nerve conduction velocities are decreased and sural nerve biopsy shows loss of myelinated fibers. The age at onset is variable and can range from childhood to adult years. When the onset is in infancy, the phenotype is characterized as Dejerine-Sottas syndrome (DSS; 145900).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Pontine tegmental cap dysplasia- MedGen UID:
- 762040
- •Concept ID:
- C3541340
- •
- Disease or Syndrome
Pontine tegmental cap dysplasia (PTCD) refers to a neurologic condition characterized by a distinct pattern of hindbrain malformations apparent on brain imaging. The abnormalities affect the pons, medulla, and cerebellum. In neuroradiologic studies, the ventral side of the pons is flattened, whereas there is vaulting ('capping') of the dorsal pontine border into the fourth ventricle. Affected individuals show a variety of neurologic deficits, most commonly sensorineural deafness, impaired cranial nerve function, and variable psychomotor retardation (summary by Barth et al., 2007).
Spondyloepiphyseal dysplasia tarda, X-linked- MedGen UID:
- 762085
- •Concept ID:
- C3541456
- •
- Congenital Abnormality
X-linked spondyloepiphyseal dysplasia tarda is a condition that impairs bone growth and occurs almost exclusively in males. The name of the condition indicates that it affects the bones of the spine (spondylo-) and the ends of long bones (epiphyses) in the arms and legs. "Tarda" indicates that signs and symptoms of this condition are not present at birth, but appear later in childhood, typically between ages 6 and 10.\n\nMales with X-linked spondyloepiphyseal dysplasia tarda have skeletal abnormalities and short stature. Affected boys grow steadily until late childhood, when their growth slows. Their adult height ranges from 4 feet 6 inches (137 cm) to 5 feet 4 inches (163 cm). Impaired growth of the spinal bones (vertebrae) primarily causes the short stature. Spinal abnormalities include flattened vertebrae (platyspondyly) with hump-shaped bulges, progressive thinning of the discs between vertebrae, and an abnormal curvature of the spine (scoliosis or kyphosis). These spinal problems also cause back pain in people with this condition. Individuals with X-linked spondyloepiphyseal dysplasia tarda have a short torso and neck, and their arms are disproportionately long compared to their height.\n\nOther skeletal features of X-linked spondyloepiphyseal dysplasia tarda include an abnormality of the hip joint that causes the upper leg bones to turn inward (coxa vara); multiple abnormalities of the epiphyses, including a short upper end of the thigh bone (femoral neck); and a broad, barrel-shaped chest. A painful joint condition called osteoarthritis that typically occurs in older adults often develops in early adulthood in people with X-linked spondyloepiphyseal dysplasia tarda and worsens over time, most often affecting the hips, knees, and shoulders.
Congenital myopathy 10b, mild variant- MedGen UID:
- 762102
- •Concept ID:
- C3541476
- •
- Disease or Syndrome
Congenital myopathy-10B (CMYO10B) is an autosomal recessive skeletal muscle disorder characterized by infantile- or childhood-onset myopathy, areflexia, dysphagia, and respiratory distress that usually requires nocturnal ventilation. Other common features include facial and neck muscle weakness, feeding difficulties, contractures, scoliosis, high-arched palate, hyporeflexia, and difficulties walking. The disorder is slowly progressive and most patients follow a chronic course. Muscle biopsy shows variable findings, including type 1 fiber predominance, minicore lesions, and myofibrillar disorganization (Boyden et al., 2012; Harris et al., 2018).
Patients with missense mutations affecting conserved cysteine residues in the EGF-like domain show the mild variant phenotype (CMYO10B) with later onset of respiratory failure and minicores on muscle biopsy, whereas patients with more damaging mutations, including nonsense or frameshift null mutations, show the severe variant phenotype (CMYO10A) (Croci et al., 2022).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Ectopia lentis 1, isolated, autosomal dominant- MedGen UID:
- 762106
- •Concept ID:
- C3541518
- •
- Disease or Syndrome
Ectopia lentis is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010).
Citing the revised Ghent criteria for Marfan syndrome, Loeys et al. (2010) proposed the designation 'ectopia lentis syndrome' (ELS) for patients with ectopia lentis and a mutation in the FBN1 gene who lack aortic involvement, to highlight the systemic nature of the condition and to emphasize the need for assessment of features outside the ocular system (see DIAGNOSIS).
Genetic Heterogeneity of Isolated Ectopia Lentis
An autosomal recessive form of isolated ectopia lentis (ECTOL2; 225100) is caused by mutation in the ADAMTSL4 gene (610113).
Intellectual disability, autosomal dominant 15- MedGen UID:
- 766162
- •Concept ID:
- C3553248
- •
- Disease or Syndrome
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with SMARCB1 mutations may have more severe neurodevelopmental deficits including severe intellectual disability, brain structural abnormalities, and no expressive words, as well as scoliosis (summary by Kosho et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Intellectual disability, autosomal dominant 16- MedGen UID:
- 766163
- •Concept ID:
- C3553249
- •
- Disease or Syndrome
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with SMARCA4 mutations may have less coarse craniofacial appearances and fewer behavioral abnormalities than Coffin-Siris patients with mutations in other genes (summary by Kosho et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Brown-Vialetto-van Laere syndrome 2- MedGen UID:
- 766452
- •Concept ID:
- C3553538
- •
- Disease or Syndrome
Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (summary by Johnson et al., 2012; Foley et al., 2014).
For discussion of genetic heterogeneity of Brown-Vialetto-Van Laere syndrome, see BVVLS1 (211530).
Congenital myasthenic syndrome 13- MedGen UID:
- 766559
- •Concept ID:
- C3553645
- •
- Disease or Syndrome
Congenital myasthenic syndrome-13 (CMS13) is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Belaya et al., 2012).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Malan overgrowth syndrome- MedGen UID:
- 766574
- •Concept ID:
- C3553660
- •
- Disease or Syndrome
Malan syndrome (MALNS) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present (summary by Martinez et al., 2015).
Cerebellar dysfunction with variable cognitive and behavioral abnormalities- MedGen UID:
- 766575
- •Concept ID:
- C3553661
- •
- Disease or Syndrome
Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) is an autosomal dominant neurologic disorder with significant phenotypic heterogeneity, even within families. The disorder is most often diagnosed through genetic analysis with retrospective clinical phenotyping. Symptom onset is usually in early childhood, although later onset, even in adulthood, has been reported. Most affected individuals show global developmental delay from early childhood, particularly of motor and language skills. Many have mild intellectual disability; behavioral and psychiatric abnormalities such as autism and obsessive-compulsive disorder are also often observed. The movement disorder is prominent and may include cerebellar signs such as ataxia, tremor, dysmetria, poor coordination, and dysarthria. Other abnormal movements including spasticity, myoclonus, and dystonia have been reported, thus widening the phenotypic spectrum. Brain imaging is usually normal, but may show cerebellar atrophy or nonspecific white matter lesions. Variable dysmorphic facial features may also be present (summary by Thevenon et al., 2012; Jacobs et al., 2021; Wijnen et al., 2020).
Loeys-Dietz syndrome 4- MedGen UID:
- 766676
- •Concept ID:
- C3553762
- •
- Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Osteogenesis imperfecta type 13- MedGen UID:
- 766801
- •Concept ID:
- C3553887
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Martinez-Glez et al. (2012) described osteogenesis imperfecta type XIII, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity.
Pontocerebellar hypoplasia type 8- MedGen UID:
- 767123
- •Concept ID:
- C3554209
- •
- Disease or Syndrome
Pontocerebellar hypoplasia type 8 is an autosomal recessive neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum (summary by Mochida et al., 2012).
For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Distal arthrogryposis type 5D- MedGen UID:
- 767329
- •Concept ID:
- C3554415
- •
- Disease or Syndrome
This autosomal recessive form of distal arthrogryposis, designated DA5D by McMillin et al. (2013), is characterized by severe camptodactyly of the hands, including adducted thumbs and wrists; mild camptodactyly of the toes; clubfoot and/or a calcaneovalgus deformity; extension contractures of the knee; unilateral ptosis or ptosis that is more severe on one side; a round-shaped face; arched eyebrows; a bulbous, upturned nose; and micrognathia. Notably, these patients do not have ophthalmoplegia.
For a general phenotypic description and discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120).
For discussion of genetic heterogeneity of distal arthrogryposis type 5, see DA5 (108145).
Osteogenesis imperfecta type 14- MedGen UID:
- 767342
- •Concept ID:
- C3554428
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160).
Shaheen et al. (2012) described osteogenesis imperfecta type XIV (OI14), an autosomal recessive form of the disorder characterized by variable degrees of severity of multiple fractures and osteopenia, with normal teeth, sclerae, and hearing. Fractures first occur prenatally or by age 6 years.
Microcephalic primordial dwarfism, Alazami type- MedGen UID:
- 767353
- •Concept ID:
- C3554439
- •
- Disease or Syndrome
Alazami syndrome is an autosomal recessive disorder characterized by severe growth restriction present at birth, severely impaired intellectual development, and distinctive facial features. Some patients have been reported with skeletal and behavioral features (summary by Imbert-Bouteille et al., 2019).
Severe intellectual disability-progressive spastic diplegia syndrome- MedGen UID:
- 767363
- •Concept ID:
- C3554449
- •
- Disease or Syndrome
CTNNB1 neurodevelopmental disorder (CTNNB1-NDD) is characterized in all individuals by mild-to-profound cognitive impairment and in up to 39% of reported individuals by exudative vitreoretinopathy, an ophthalmologic finding consistent with familial exudative vitreoretinopathy (FEVR). Other common findings include truncal hypotonia, peripheral spasticity, dystonia, behavior problems, microcephaly, and refractive errors and strabismus. Less common features include intrauterine growth restriction, feeding difficulties, and scoliosis.
Cowden syndrome 5- MedGen UID:
- 767432
- •Concept ID:
- C3554518
- •
- Disease or Syndrome
PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.
Cowden syndrome 6- MedGen UID:
- 767433
- •Concept ID:
- C3554519
- •
- Disease or Syndrome
\n\nThe features of Cowden syndrome overlap with those of another disorder called Bannayan-Riley-Ruvalcaba syndrome. People with Bannayan-Riley-Ruvalcaba syndrome also develop hamartomas and other noncancerous tumors. Some people with Cowden syndrome have relatives diagnosed with Bannayan-Riley-Ruvalcaba syndrome, and other affected individuals have the characteristic features of both conditions. Based on these similarities, researchers have proposed that Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome (named for the genetic cause of the conditions) instead of two distinct conditions.\n\nSome people do not meet the strict criteria for a clinical diagnosis of Cowden syndrome, but they have some of the characteristic features of the condition, particularly the cancers. These individuals are often described as having Cowden-like syndrome. Both Cowden syndrome and Cowden-like syndrome are caused by mutations in the same genes.\n\nCowden syndrome is associated with an increased risk of developing several types of cancer, particularly cancers of the breast, a gland in the lower neck called the thyroid, and the lining of the uterus (the endometrium). Other cancers that have been identified in people with Cowden syndrome include kidney cancer, colorectal cancer, and an agressive form of skin cancer called melanoma. Compared with the general population, people with Cowden syndrome develop these cancers at younger ages, often beginning in their thirties or forties. People with Cowden syndrome are also more likely to develop more than one cancer during their lifetimes compared to the general population. Other diseases of the breast, thyroid, and endometrium are also common in Cowden syndrome. Additional signs and symptoms can include an enlarged head (macrocephaly) and a rare, noncancerous brain tumor called Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development, intellectual disability, or autism spectrum disorder, which can affect communication and social interaction.\n\nAlmost everyone with Cowden syndrome develops hamartomas. These growths are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but they can also occur in the intestine and other parts of the body. The growth of hamartomas on the skin and mucous membranes typically becomes apparent by a person's late twenties.\n\nCowden syndrome is a genetic disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers.
Steel syndrome- MedGen UID:
- 767508
- •Concept ID:
- C3554594
- •
- Disease or Syndrome
Steel syndrome is characterized by characteristic facies, dislocated hips and radial heads, carpal coalition (fusion of carpal bones), short stature, scoliosis, and cervical spine anomalies. The dislocated hips are resistant to surgical intervention (summary by Flynn et al., 2010).
Mitochondrial complex III deficiency nuclear type 2- MedGen UID:
- 767519
- •Concept ID:
- C3554605
- •
- Disease or Syndrome
Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life (summary by Ghezzi et al., 2011). The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances (Morino et al., 2014; Atwal, 2014; Nogueira et al., 2013).
For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Atelosteogenesis type III- MedGen UID:
- 777149
- •Concept ID:
- C3668942
- •
- Congenital Abnormality
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Charcot-Marie-Tooth disease type 4B3- MedGen UID:
- 811329
- •Concept ID:
- C3695063
- •
- Disease or Syndrome
A subtype of Charcot-Marie-Tooth type 4 with characteristics of childhood onset of slowly progressing, demyelinating sensorimotor neuropathy, focally folded myelin sheaths in nerve biopsy, reduced nerve conduction velocities and the typical Charcot-Marie-Tooth phenotype (i.e. distal muscle weakness and atrophy, and sensory loss). There is evidence this disease is caused by homozygous or compound heterozygous mutation in the SBF1 gene on chromosome 22q.
Blepharophimosis - intellectual disability syndrome, MKB type- MedGen UID:
- 785805
- •Concept ID:
- C3698541
- •
- Disease or Syndrome
MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.
Actin accumulation myopathy- MedGen UID:
- 777997
- •Concept ID:
- C3711389
- •
- Disease or Syndrome
Congenital myopathy-2A (CMYO2A) is an autosomal dominant disorder of the skeletal muscle characterized by infantile- or childhood-onset myopathy with delayed motor milestones and nonprogressive muscle weakness. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype (CMYO2C; 620278). Some patients with de novo mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation. Less frequently, autosomal dominant transmission of the disorder within a family may occur when the ACTA1 mutation produces a phenotype compatible with adult life. Of note, intrafamilial variability has also been reported: a severely affected proband may be identified and then mildly affected or even asymptomatic relatives are found to carry the same mutation. The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021).
The most common histologic finding on muscle biopsy in patients with ACTA1 mutations is the presence of 'nemaline rods,' which represent abnormal thread- or rod-like structures ('nema' is Greek for 'thread'). However, skeletal muscle biopsy from patients with mutations in the ACTA1 gene can show a range of pathologic phenotypes. These include classic rods, intranuclear rods, clumped filaments, cores, or fiber-type disproportion, all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. Most patients have clinically severe disease, regardless of the histopathologic phenotype (Nowak et al., 2007; Sewry et al., 2019). ACTA1 mutations are the second most common cause of congenital myopathies classified histologically as 'nemaline myopathy' after mutations in the NEB gene (161650). ACTA1 mutations are overrepresented in the severe phenotype with early death (Laing et al., 2009).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).
Mandibular hypoplasia-deafness-progeroid syndrome- MedGen UID:
- 811623
- •Concept ID:
- C3715192
- •
- Disease or Syndrome
Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance, and metabolic abnormalities including insulin resistance and diabetes mellitus. Sensorineural deafness occurs late in the first or second decades of life (summary by Weedon et al., 2013).
Osteogenesis imperfecta type 15- MedGen UID:
- 815174
- •Concept ID:
- C3808844
- •
- Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Keupp et al. (2013) and Pyott et al. (2013) described osteogenesis imperfecta type XV, an autosomal recessive form of the disorder characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclera. Tooth development and hearing are normal. Learning and developmental delays and brain anomalies have been observed in some patients.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12- MedGen UID:
- 815294
- •Concept ID:
- C3808964
- •
- Disease or Syndrome
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as dystroglycanopathies (summary by Stevens et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Cardiofaciocutaneous syndrome 3- MedGen UID:
- 815336
- •Concept ID:
- C3809006
- •
- Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Cardiofaciocutaneous syndrome 4- MedGen UID:
- 815337
- •Concept ID:
- C3809007
- •
- Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Charcot-Marie-Tooth disease recessive intermediate C- MedGen UID:
- 815639
- •Concept ID:
- C3809309
- •
- Disease or Syndrome
CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by Azzedine et al., 2013).
For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (608340).
Multiple congenital anomalies-hypotonia-seizures syndrome 3- MedGen UID:
- 815686
- •Concept ID:
- C3809356
- •
- Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.
For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080).
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Hypotonia, infantile, with psychomotor retardation and characteristic facies 1- MedGen UID:
- 815784
- •Concept ID:
- C3809454
- •
- Disease or Syndrome
Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. Affected individuals show very poor, if any, normal cognitive development. Some patients are never learn to sit or walk independently (summary by Al-Sayed et al., 2013).
Genetic Heterogeneity of Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies
See also IHPRF2 (616801), caused by mutation in the UNC80 gene (612636) on chromosome 2q34; and IHPRF3 (616900), caused by mutation in the TBCK gene (616899) on chromosome 4q24.
Mitochondrial DNA depletion syndrome 13- MedGen UID:
- 815922
- •Concept ID:
- C3809592
- •
- Disease or Syndrome
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome- MedGen UID:
- 816016
- •Concept ID:
- C3809686
- •
- Mental or Behavioral Dysfunction
A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, feeding difficulties, behavioral anomalies, vision anomalies and mild facial dysmorphism. Other associated features may include microcephaly, short stature, urogenital or palatal anomalies (e.g. cleft palate), minor cardiac defects, recurrent infections or hearing loss.
Van Maldergem syndrome 2- MedGen UID:
- 816205
- •Concept ID:
- C3809875
- •
- Disease or Syndrome
Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013).
For a discussion of genetic heterogeneity of Van Maldergem syndrome, see 601390.
Autism spectrum disorder - epilepsy - arthrogryposis syndrome- MedGen UID:
- 816240
- •Concept ID:
- C3809910
- •
- Disease or Syndrome
Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies (Edmondson et al., 2017; Marini et al., 2017).
8q24.3 microdeletion syndrome- MedGen UID:
- 816353
- •Concept ID:
- C3810023
- •
- Disease or Syndrome
Verheij syndrome is characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal, mainly vertebral, abnormalities. Additional variable features may include coloboma, renal defects, and cardiac defects (summary by Verheij et al., 2009 and Dauber et al., 2013).
Hereditary sclerosing poikiloderma with tendon and pulmonary involvement- MedGen UID:
- 816655
- •Concept ID:
- C3810325
- •
- Disease or Syndrome
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is characterized by the skin findings of poikiloderma (typically beginning in the first six months and mainly localized to the face), hypohidrosis with heat intolerance, mild lymphedema of the extremities, chronic erythematous and scaly skin lesions on the extremities, sclerosis of the digits, and mild palmoplantar keratoderma. Scalp hair, eyelashes, and/or eyebrows are typically sparse. Muscle contractures are usually seen in childhood and can be present as early as age two years. The majority of affected individuals develop progressive weakness of the proximal and distal muscles of all four limbs. Some adults develop progressive interstitial pulmonary fibrosis, which can be life threatening within three to four years after respiratory symptoms appear. Other features are exocrine pancreatic insufficiency, liver impairment, hematologic abnormalities, relative short stature, and cataract.
Nemaline myopathy 9- MedGen UID:
- 816714
- •Concept ID:
- C3810384
- •
- Disease or Syndrome
Nemaline myopathy-9 is an autosomal recessive muscle disorder characterized by onset of muscle weakness in early infancy. The phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. Muscle biopsy shows typical rod-like structure in myofibers (summary by Gupta et al., 2013).
For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.
Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency- MedGen UID:
- 816736
- •Concept ID:
- C3810406
- •
- Mental or Behavioral Dysfunction
Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency is a rare, syndromic intellectual disability characterized by intellectual disability of various severity, hypotonia, feeding difficulties, dysmorphic features, autism and behavioral issues. Growth retardation, congenital heart anomalies, gastrointestinal and genitourinary defects have been rarely associated.
Smith-McCort dysplasia 1- MedGen UID:
- 854757
- •Concept ID:
- C3888088
- •
- Disease or Syndrome
Any Smith-McCort dysplasia in which the cause of the disease is a mutation in the DYM gene.
Hennekam lymphangiectasia-lymphedema syndrome 1- MedGen UID:
- 860487
- •Concept ID:
- C4012050
- •
- Disease or Syndrome
Hennekam lymphangiectasia-lymphedema syndrome (HKLLS1) is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (summary by Alders et al., 2014).
Genetic Heterogeneity of Hennekam Lymphangiectasia-Lymphedema Syndrome
See also HKLLS2 (616006), caused by mutation in the FAT4 gene (612411) on chromosome 4q28, and HKLLS3 (618154), caused by mutation in the ADAMTS3 gene (605011) on chromosome 4q13.
Desbuquois dysplasia 1- MedGen UID:
- 860583
- •Concept ID:
- C4012146
- •
- Disease or Syndrome
Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (summary by Huber et al., 2009).
Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011).
Genetic Heterogeneity of Desbuquois Dysplasia
DBQD2 (615777) is caused by mutation in the XYLT1 gene (608124) on chromosome 16p12.
Two unrelated patients with immunodeficiency-23 (IMD23; 615816), due to mutation in the PGM3 gene (172100), were reported to have skeletal features reminiscent of DBQD.
SSR4-congenital disorder of glycosylation- MedGen UID:
- 860832
- •Concept ID:
- C4012395
- •
- Disease or Syndrome
Congenital disorder of glycosylation type Iy (CDG1Y) is an X-linked disorder characterized by developmental delay, speech delay, impaired intellectual development, muscular hypotonia, microcephaly, and distinctive facial features (summary by Johnsen et al., 2024).
Immunodeficiency 23- MedGen UID:
- 862808
- •Concept ID:
- C4014371
- •
- Disease or Syndrome
IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity (summary by Bjorksten and Lundmark, 1976 and Zhang et al., 2014).
Autism spectrum disorder due to AUTS2 deficiency- MedGen UID:
- 862872
- •Concept ID:
- C4014435
- •
- Mental or Behavioral Dysfunction
A rare genetic syndromic intellectual disability characterized by global developmental delay and borderline to severe intellectual disability, autism spectrum disorder with obsessive behavior, stereotypies, hyperactivity but frequently friendly and affable personality, feeding difficulties, short stature, muscular hypotonia, microcephaly, characteristic dysmorphic features (hypertelorism, high arched eyebrows, ptosis, deep and/or broad nasal bridge, broad/prominent nasal tip, short and/or upturned philtrum, narrow mouth, and micrognathia), and skeletal anomalies (kyphosis and/or scoliosis, arthrogryposis, slender habitus and extremities). Other clinical features may include hernias, congenital heart defects, cryptorchidism and seizures.
Pontocerebellar hypoplasia type 2E- MedGen UID:
- 862925
- •Concept ID:
- C4014488
- •
- Disease or Syndrome
Pontocerebellar hypoplasia type 2E is an autosomal recessive neurodegenerative disorder characterized by profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy (summary by Feinstein et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470).
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder- MedGen UID:
- 862975
- •Concept ID:
- C4014538
- •
- Disease or Syndrome
ADNP-related disorder is characterized by hypotonia, severe speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip) based on a cohort of 78 individuals. Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, brain abnormalities, seizures, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, endocrine issues including short stature and hormonal deficiencies, cardiac and urinary tract anomalies, and hearing loss.
Tatton-Brown-Rahman overgrowth syndrome- MedGen UID:
- 862982
- •Concept ID:
- C4014545
- •
- Disease or Syndrome
Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference =2 SD above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors.
Polyglucosan body myopathy type 1- MedGen UID:
- 863042
- •Concept ID:
- C4014605
- •
- Disease or Syndrome
Polyglucosan body myopathy-1 (PGBM1) is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation. Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood (summary by Boisson et al., 2012 and Nilsson et al., 2013).
Genetic Heterogeneity of Polyglucosan Body Myopathy
See also PGBM2 (616199), caused by mutation in the GYG1 gene (603942) on chromosome 3q24.
Tall stature-scoliosis-macrodactyly of the great toes syndrome- MedGen UID:
- 863127
- •Concept ID:
- C4014690
- •
- Disease or Syndrome
Miura-type epiphyseal chondrodysplasia (ECDM) is an overgrowth syndrome characterized by tall stature, arachnodactyly of the hands, macrodactyly of the great toes, scoliosis, coxa valga, and slipped capital femoral epiphysis (Miura et al., 2014). Multiple extra epiphyses are present in the hands (Boudin et al., 2018).
Mutation in the NPR3 gene (108962) results in Boudin-Mortier syndrome (BOMOS; 619543), a similar phenotype of tall stature, arachnodactyly, elongated great toes, and multiple extra epiphyses.
Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome- MedGen UID:
- 863379
- •Concept ID:
- C4014942
- •
- Disease or Syndrome
CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is an autosomal recessive multisystemic disorder with a highly variable phenotypic spectrum. Not all of these features are always present, and almost all the features may present at different times and/or become more apparent with age. The skeletal features are consistent with spondyloepimetaphyseal dysplasia (SEMD) (summary by Vona et al., 2018).
One family had a distinctive presentation with infantile-onset intractable seizures and cortical abnormalities reminiscent of Leigh syndrome (see 256000). The correlation between genotype and phenotype remains unclear, but since the IARS2 gene is involved in mitochondrial function, heterogeneous manifestations can be expected (Takezawa et al., 2018).
Microcephaly, short stature, and impaired glucose metabolism 1- MedGen UID:
- 863434
- •Concept ID:
- C4014997
- •
- Disease or Syndrome
Microcephaly, short stature, and impaired glucose metabolism-1 (MSSGM1) is an autosomal recessive syndrome characterized by microcephaly associated with impaired intellectual development, short stature, and early-onset diabetes or abnormalities of glucose homeostasis (Igoillo-Esteve et al., 2013; Gillis et al., 2014).
Genetic Heterogeneity of Microcephaly, Short Stature, and Impaired Glucose Metabolism
MSSGM2 (616817) is caused by mutation in the PPP1R15B gene (613257) on chromosome 1q32.
Also see Wolcott-Rallison syndrome (226980), which is characterized by multiple epiphyseal dysplasia, microcephaly, short stature, and early-onset diabetes mellitus and is caused by mutation in the EIF2AK3 gene (604032) on chromosome 2p11.
Neu-Laxova syndrome 2- MedGen UID:
- 863456
- •Concept ID:
- C4015019
- •
- Disease or Syndrome
Neu-Laxova syndrome-2 (NLS2) is a rare autosomal recessive disorder characterized by a recognizable pattern of severe congenital malformations leading to prenatal or early postnatal lethality. Affected individuals have abnormal craniofacial features, microcephaly, intrauterine growth retardation, ichthyosis, flexion deformities, limb malformations, and edema of the hands and feet. Some patients have malformations of the central nervous system, such as abnormal gyration (summary by Acuna-Hidalgo et al., 2014).
For a discussion of genetic heterogeneity of Neu-Laxova syndrome, see NLS1 (256520).
Charcot-Marie-Tooth disease axonal type 2S- MedGen UID:
- 863786
- •Concept ID:
- C4015349
- •
- Disease or Syndrome
Charcot-Marie-Tooth disease type 2S is a relatively pure form of autosomal recessive axonal neuropathy characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy affecting the lower and upper limbs. Patients have decreased reflexes and variable distal sensory impairment (summary by Cottenie et al., 2014).
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Cerebellar-facial-dental syndrome- MedGen UID:
- 863932
- •Concept ID:
- C4015495
- •
- Disease or Syndrome
Cerebellofaciodental syndrome is an autosomal recessive neurodevelopmental disorder characterized by delayed development, intellectual disability, abnormal facial and dental findings, and cerebellar hypoplasia (summary by Borck et al., 2015).
Motor developmental delay due to 14q32.2 paternally expressed gene defect- MedGen UID:
- 863995
- •Concept ID:
- C4015558
- •
- Disease or Syndrome
Temple syndrome is a short stature disorder of imprinting. The cardinal features are low birth weight, hypotonia and motor delay, feeding problems early in life, early puberty, and significantly reduced final height. Facial features include a broad forehead and short nose with a wide nasal tip, and the majority of patients have small hands and feet. However, many of the clinical features are nonspecific, making diagnosis difficult. In addition, isodisomy may uncover recessive disorders, which may influence the phenotype in maternal uniparental disomy of chromosome 14 (UPD14mat) cases (summary by Ioannides et al., 2014).
Congenital myasthenic syndrome 14- MedGen UID:
- 864034
- •Concept ID:
- C4015597
- •
- Disease or Syndrome
Congenital myasthenic syndrome-14 is an autosomal recessive neuromuscular disorder characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. There is no respiratory or cardiac involvement. Treatment with anticholinesterase medication may be beneficial (summary by Cossins et al., 2013).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Tenorio syndrome- MedGen UID:
- 864147
- •Concept ID:
- C4015710
- •
- Disease or Syndrome
Tenorio syndrome (TNORS) is characterized by overgrowth, macrocephaly, and impaired intellectual development. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (270150) (summary by Tenorio et al., 2014).
Spondylocostal dysostosis 5- MedGen UID:
- 901825
- •Concept ID:
- C4083048
- •
- Disease or Syndrome
Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1- MedGen UID:
- 897191
- •Concept ID:
- C4225153
- •
- Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Myopathy, reducing body, X-linked, childhood-onset- MedGen UID:
- 904593
- •Concept ID:
- C4225159
- •
- Disease or Syndrome
Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death (RBMX1A; 300717), and a less severe form has onset in late childhood or adulthood (RBMX1B) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).
Autosomal dominant Robinow syndrome 3- MedGen UID:
- 907878
- •Concept ID:
- C4225164
- •
- Disease or Syndrome
Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above.
Cerebellar atrophy, visual impairment, and psychomotor retardation;- MedGen UID:
- 905041
- •Concept ID:
- C4225172
- •
- Disease or Syndrome
Progressive scapulohumeroperoneal distal myopathy- MedGen UID:
- 905125
- •Concept ID:
- C4225181
- •
- Disease or Syndrome
Scapulohumeroperoneal myopathy is an autosomal dominant muscle disorder characterized by slowly progressive muscle weakness and atrophy affecting both proximal and distal muscles of the upper and lower limbs. Onset is usually in the first decade and can be as early as infancy, although some patients do not notice symptoms until young adulthood. There is marked variability in severity (summary by Zukosky et al., 2015).
Lymphatic malformation 6- MedGen UID:
- 908120
- •Concept ID:
- C4225184
- •
- Disease or Syndrome
Lymphatic malformation-6 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPHM6, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema, but childhood onset of lymphedema with or without systemic involvement also occurs. Mild facial edema is often present. Patients have normal intelligence and no seizures (summary by Fotiou et al., 2015).
For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.
Lamb-Shaffer syndrome- MedGen UID:
- 903542
- •Concept ID:
- C4225202
- •
- Disease or Syndrome
Lamb-Shaffer syndrome is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, and mild dysmorphic facial features. Additional variable skeletal abnormalities may also be present (summary by Nesbitt et al., 2015).
Hypotonia, infantile, with psychomotor retardation and characteristic facies 2- MedGen UID:
- 907651
- •Concept ID:
- C4225203
- •
- Disease or Syndrome
UNC80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. The majority of individuals do not learn to walk. All individuals lack expressive language; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional features can include nystagmus, extremity hypertonia, a high-pitched cry, repetitive and self-stimulatory behaviors, constipation, clubfeet, joint contractures, and scoliosis. For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have a loss of skills suggestive of neurodegeneration.
Spastic paraplegia-severe developmental delay-epilepsy syndrome- MedGen UID:
- 897828
- •Concept ID:
- C4225215
- •
- Disease or Syndrome
Spastic paraplegia and psychomotor retardation with or without seizures is an autosomal recessive complex neurodevelopmental disorder with onset in infancy. Affected children show hypotonia followed by severely impaired global development and significant motor disability. Most develop seizures in childhood and have speech delay. Other features, such as ocular abnormalities, foot deformities, hypoplasia of the corpus callosum, and decreased white matter, are more variable (summary by Hollstein et al., 2015).
Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome- MedGen UID:
- 906646
- •Concept ID:
- C4225222
- •
- Disease or Syndrome
Takenouchi-Kosaki syndrome is a highly heterogeneous autosomal dominant complex congenital developmental disorder affecting multiple organ systems. The core phenotype includes delayed psychomotor development with variable intellectual disability, dysmorphic facial features, and cardiac, genitourinary, and hematologic or lymphatic defects, including thrombocytopenia and lymphedema. Additional features may include abnormalities on brain imaging, skeletal anomalies, and recurrent infections. Some patients have a milder disease course reminiscent of Noonan syndrome (see, e.g., NS1, 163950) (summary by Martinelli et al., 2018).
Seizures-scoliosis-macrocephaly syndrome- MedGen UID:
- 909039
- •Concept ID:
- C4225248
- •
- Disease or Syndrome
Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by Gentile et al., 2019).
Craniosynostosis 6- MedGen UID:
- 904675
- •Concept ID:
- C4225269
- •
- Disease or Syndrome
Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). Craniosynostosis-6 (CRS6) is a bicoronal form associated with bony defects in the sagittal, metopic, or lambdoid sutures (Twigg et al., 2015).
For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).
Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome- MedGen UID:
- 896409
- •Concept ID:
- C4225270
- •
- Disease or Syndrome
Kosaki overgrowth syndrome (KOGS) is characterized by a facial gestalt involving prominent forehead, proptosis, downslanting palpebral fissures, broad nasal bridge, thin upper lip, and pointed chin. Affected individuals are tall, with an elongated lower segment, and have large hands and feet. Skin is hyperelastic and fragile. Patients exhibit progressive dilatory and vascular changes in basilar/vertebral and coronary arteries starting in the teenage years (Takenouchi et al., 2015; Takenouchi et al., 2021).
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome- MedGen UID:
- 895574
- •Concept ID:
- C4225276
- •
- Disease or Syndrome
Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB) is an autosomal recessive disorder characterized by severe neurologic impairment including impaired intellectual development, epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. Most affected individuals are nonambulatory, cannot sit unassisted, and have no speech development. More variable features include feeding difficulties, poor growth, cortical visual impairment, spasticity, scoliosis, immunodeficiency, and thrombocytopenia (Tanaka et al., 2015).
Spondylocostal dysostosis 6, autosomal recessive- MedGen UID:
- 899713
- •Concept ID:
- C4225279
- •
- Disease or Syndrome
Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.
Noonan syndrome 10- MedGen UID:
- 902892
- •Concept ID:
- C4225280
- •
- Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Progressive myoclonic epilepsy type 9- MedGen UID:
- 901242
- •Concept ID:
- C4225289
- •
- Disease or Syndrome
A rare genetic neurological disorder with characteristics of childhood-onset severe myoclonic and tonic-clonic seizures and early-onset ataxia leading to severe gait disturbances associated with normal to slightly diminished cognition. Scoliosis, diffuse muscle atrophy and subcutaneous fat loss, as well as developmental delay, may be associated. Brain MRI may reveal complete agenesis of the corpus callosum, ventriculomegaly, interhemispheric cysts and simplified gyration (frontally).
Neuropathy, hereditary motor and sensory, type 6B- MedGen UID:
- 895482
- •Concept ID:
- C4225302
- •
- Disease or Syndrome
Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals may also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements such as ataxia, dysmetria, and myoclonus (summary by Abrams et al., 2015).
For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152).
Bethlem myopathy 2- MedGen UID:
- 907426
- •Concept ID:
- C4225313
- •
- Disease or Syndrome
Bethlem myopathy-2 (BTHLM2) is characterized by congenital hypotonia and myopathy. Motor development is delayed, but muscle strength improves with age, and patients are able to achieve ambulation. Proximal joint contractures that improve over time, as well as joint hyperlaxity, are also present. Muscle biopsy shows mild variability in fiber diameter, without degeneration or regeneration (Zou et al., 2014; Hicks et al., 2014).
For a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1 (158810).
Acrofacial dysostosis Cincinnati type- MedGen UID:
- 903483
- •Concept ID:
- C4225317
- •
- Disease or Syndrome
The Cincinnati type of acrofacial dysostosis is a ribosomopathy characterized by a spectrum of mandibulofacial dysostosis phenotypes, with or without extrafacial skeletal defects (Weaver et al., 2015). In addition, a significant number of neurologic abnormalities have been reported, ranging from mild delays to refractory epilepsy, as well as an increased incidence of congenital heart defects, primarily septal in nature (Smallwood et al., 2023).
Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome- MedGen UID:
- 897292
- •Concept ID:
- C4225323
- •
- Disease or Syndrome
Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities (summary by Basel-Vanagaite et al., 2015).
Retinitis pigmentosa 71- MedGen UID:
- 897209
- •Concept ID:
- C4225342
- •
- Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the IFT172 gene.
Houge-Janssens syndrome 2- MedGen UID:
- 899880
- •Concept ID:
- C4225352
- •
- Disease or Syndrome
PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp).
Congenital myasthenic syndrome 9- MedGen UID:
- 895641
- •Concept ID:
- C4225368
- •
- Disease or Syndrome
Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients may show a favorable response to amifampridine (summary by Engel et al., 2015).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Intellectual disability, autosomal dominant 33- MedGen UID:
- 899389
- •Concept ID:
- C4225375
- •
- Mental or Behavioral Dysfunction
Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the DPP6 gene.
Singleton-Merten syndrome 2- MedGen UID:
- 907372
- •Concept ID:
- C4225380
- •
- Disease or Syndrome
Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies (summary by Jang et al., 2015).
For a general phenotypic description and discussion of genetic heterogeneity of Singleton-Merten syndrome, see SGMRT1 (182250).
Congenital contractures of the limbs and face, hypotonia, and developmental delay- MedGen UID:
- 907234
- •Concept ID:
- C4225398
- •
- Disease or Syndrome
CLIFAHDD is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo (summary by Chong et al., 2015).
Myasthenic syndrome, congenital, 1B, fast-channel- MedGen UID:
- 909200
- •Concept ID:
- C4225405
- •
- Disease or Syndrome
Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor (AChR) channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (summary by Sine et al., 2003 and Engel et al., 2015).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Intellectual disability, X-linked 99, syndromic, female-restricted- MedGen UID:
- 899839
- •Concept ID:
- C4225416
- •
- Disease or Syndrome
Female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F) is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development and mild to moderate intellectual disability. Affected females can have a wide range of additional congenital anomalies, including scoliosis, postaxial polydactyly, mild cardiac or urogenital anomalies, dysmorphic facial features, and mild structural brain abnormalities (summary by Reijnders et al., 2016).
Syndromic X-linked intellectual disability 34- MedGen UID:
- 902184
- •Concept ID:
- C4225417
- •
- Mental or Behavioral Dysfunction
X-linked syndromic intellectual developmental disorder-34 (MRXS34) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by Mircsof et al., 2015).
Intellectual disability, X-linked, syndromic 33- MedGen UID:
- 895979
- •Concept ID:
- C4225418
- •
- Disease or Syndrome
X-linked syndromic intellectual developmental disorder-33 (MRXS33) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by O'Rawe et al., 2015).
Ritscher-Schinzel syndrome 2- MedGen UID:
- 897005
- •Concept ID:
- C4225419
- •
- Disease or Syndrome
Ritscher-Schinzel syndrome (RSS) is a clinically recognizable condition that includes the cardinal findings of craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome. Dysmorphic facial features may include brachycephaly, hypotonic face with protruding tongue, flat appearance of the face on profile view, short midface, widely spaced eyes, downslanted palpebral fissures, low-set ears with overfolding of the upper helix, smooth or short philtrum, and high or cleft palate. Affected individuals also typically have a characteristic metacarpal phalangeal profile showing a consistent wavy pattern on hand radiographs. RSS is associated with variable degrees of developmental delay and intellectual disability. Eye anomalies and hypercholesterolemia may be variably present.
Myopathy, reducing body, X-linked, early-onset, severe- MedGen UID:
- 906731
- •Concept ID:
- C4225423
- •
- Disease or Syndrome
Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death, and a less severe form has onset in late childhood or adulthood (RBMX1B; 300718) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).
Singleton-Merten syndrome 1- MedGen UID:
- 899946
- •Concept ID:
- C4225427
- •
- Disease or Syndrome
Singleton-Merten syndrome (SGMRT) is an uncommon autosomal dominant disorder characterized by abnormalities of blood vessels, teeth, and bone. Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty and can lead to early death. Dental findings include delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization, leading to tooth loss. Osseous features consist of osteoporosis, either generalized or limited to distal extremities, distal limb osteolysis, widened medullary cavities, and easy tearing of tendons from bone. Less common features are mild facial dysmorphism (high anterior hair line, broad forehead, smooth philtrum, thin upper vermilion border), generalized muscle weakness, psoriasis, early-onset glaucoma, and recurrent infections. The disorder manifests with variable inter- and intrafamilial phenotypes (summary by Rutsch et al., 2015).
Genetic Heterogeneity of Singleton-Merten Syndrome
An atypical form of Singleton-Merten syndrome (SGMRT2; 616298) is caused by mutation in the DDX58 gene (609631) on chromosome 9p21.
VATER association- MedGen UID:
- 902479
- •Concept ID:
- C4225671
- •
- Disease or Syndrome
VATER is a mnemonically useful acronym for the nonrandom association of vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R). This combination of associated defects was pointed out by Quan and Smith (1972). Nearly all cases have been sporadic.
VACTERL is an acronym for an expanded definition of the association that includes cardiac malformations (C) and limb anomalies (L). The VACTERL association is a spectrum of various combinations of its 6 components, which can be a manifestation of several recognized disorders rather than a distinct anatomic or etiologic entity (Khoury et al., 1983).
Also see VATER/VACTERL association with hydrocephalus (VACTERL-H; 276950) and VACTERL with or without hydrocephalus (VACTERLX; 314390).
Maternal uniparental disomy of chromosome 20- MedGen UID:
- 909388
- •Concept ID:
- C4275029
- •
- Congenital Abnormality
The Mulchandani-Bhoj-Conlin syndrome (MBCS) is characterized by prenatal growth restriction, severe short stature with proportional head circumference, and profound feeding difficulty (Mulchandani et al., 2016).
Frontometaphyseal dysplasia 1- MedGen UID:
- 923943
- •Concept ID:
- C4281559
- •
- Congenital Abnormality
The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
MIRAGE syndrome- MedGen UID:
- 924576
- •Concept ID:
- C4284088
- •
- Disease or Syndrome
MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported.
Fanconi anemia complementation group R- MedGen UID:
- 924579
- •Concept ID:
- C4284093
- •
- Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Aortic aneurysm, familial thoracic 10- MedGen UID:
- 924785
- •Concept ID:
- C4284414
- •
- Disease or Syndrome
Any familial thoracic aortic aneurysm and aortic dissection in which the cause of the disease is a mutation in the LOX gene.
X-linked intellectual disability, van Esch type- MedGen UID:
- 930741
- •Concept ID:
- C4305072
- •
- Disease or Syndrome
Van Esch-O'Driscoll syndrome (VEODS) is characterized by varying degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations (Van Esch et al., 2019).
Nephronophthisis 20- MedGen UID:
- 934607
- •Concept ID:
- C4310640
- •
- Disease or Syndrome
Nephronophthisis-20 (NPHP20) is an autosomal recessive tubulointerstitial nephritis characterized by progressive renal fibrosis resulting in end-stage renal failure. The age at onset is relatively late compared to other forms of NPHP, and patients develop end-stage renal disease in the second or third decades. Unlike most other forms of NPHP, NPHP20 does not have features of a ciliopathy and patients do not appear to have extrarenal manifestations (summary by Macia et al., 2017).
For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).
Myofibrillar myopathy 8- MedGen UID:
- 934612
- •Concept ID:
- C4310645
- •
- Disease or Syndrome
Myofibrillar myopathy-8 (MFM8) is an autosomal recessive myopathy characterized by slowly progressive proximal muscle weakness and atrophy affecting the upper and lower limbs, resulting in increased falls, gait problems, difficulty running or climbing stairs, and upper limb weakness or scapular winging. Some patients develop distal muscle weakness and atrophy. The phenotype may also be consistent with a clinical diagnosis of limb-girdle muscular dystrophy (LGMD). Age at symptom onset ranges from infancy to adulthood. Ambulation is generally preserved and cardiac involvement is rare, but respiratory compromise with decreased forced vital capacity often occurs. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization; some patients have been reported to have dystrophic changes on muscle biopsy (O'Grady et al., 2016; Daimaguler et al., 2021). There is significant phenotypic variation, even in patients with the same mutation, which must be taken into account when counseling affecting individuals (Woods et al., 2020).
For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Encephalopathy, progressive, with amyotrophy and optic atrophy- MedGen UID:
- 934634
- •Concept ID:
- C4310667
- •
- Disease or Syndrome
Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) is a severe autosomal recessive neurodegenerative disorder characterized by delayed development with hypotonia apparent in infancy and subsequent motor regression. Most affected individuals are unable to or lose the ability to sit and show distal amyotrophy and weakness of all 4 limbs. The patients are cognitively impaired and unable to speak or have severe dysarthria. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy (Sferra et al., 2016).
Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome- MedGen UID:
- 934638
- •Concept ID:
- C4310671
- •
- Disease or Syndrome
PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by Miyake et al., 2016; Flex et al., 2016).
Shashi-Pena syndrome- MedGen UID:
- 934639
- •Concept ID:
- C4310672
- •
- Disease or Syndrome
Shashi-Pena syndrome is a neurodevelopmental syndrome characterized by delayed psychomotor development, variable intellectual disability, hypotonia, facial dysmorphism, and some unusual features, including enlarged head circumference, glabellar nevus flammeus, and deep palmar creases. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures (summary by Shashi et al., 2016).
Harel-Yoon syndrome- MedGen UID:
- 934644
- •Concept ID:
- C4310677
- •
- Disease or Syndrome
Harel-Yoon syndrome is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, truncal hypotonia, spasticity, and peripheral neuropathy. Other more variable features such as optic atrophy may also occur. Laboratory studies in some patients show evidence of mitochondrial dysfunction (summary by Harel et al., 2016).
Ehlers-Danlos syndrome, periodontal type 2- MedGen UID:
- 934648
- •Concept ID:
- C4310681
- •
- Disease or Syndrome
Periodontal Ehlers-Danlos syndrome (pEDS) is characterized by distinct oral manifestations. Periodontal tissue breakdown beginning in the teens results in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. Since the first descriptions of pEDS in the 1970s, 148 individuals have been reported in the literature; however, future in-depth descriptions of non-oral manifestations in newly diagnosed individuals with a molecularly confirmed diagnosis of pEDS will be important to further define the clinical features.
Arthrogryposis, distal, with impaired proprioception and touch- MedGen UID:
- 934659
- •Concept ID:
- C4310692
- •
- Disease or Syndrome
Distal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (summary by Chesler et al., 2016 and Delle Vedove et al., 2016).
Congenital myasthenic syndrome 20- MedGen UID:
- 934661
- •Concept ID:
- C4310694
- •
- Disease or Syndrome
Congenital myasthenic syndrome-20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (summary by Bauche et al., 2016).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
ZTTK syndrome- MedGen UID:
- 934663
- •Concept ID:
- C4310696
- •
- Disease or Syndrome
ZTTK syndrome (ZTTKS) is a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability. Affected individuals have characteristic dysmorphic facial features, hypotonia, poor feeding, poor overall growth, and eye or visual abnormalities. Most patients also have musculoskeletal abnormalities, and some have congenital defects of the heart and urogenital system. Brain imaging usually shows developmental abnormalities such as gyral changes, cortical and/or cerebellar atrophy, and thin corpus callosum (summary by Kim et al., 2016).
Frontometaphyseal dysplasia 2- MedGen UID:
- 934664
- •Concept ID:
- C4310697
- •
- Disease or Syndrome
Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia characterized by supraorbital hyperostosis, undermodeling of the small bones, and small and large joint contractures, as well as extraskeletal developmental abnormalities, primarily of the cardiorespiratory system and genitourinary tract. Patients with FMD2 appear to have a propensity for keloid formation (summary by Wade et al., 2016).
For a discussion of genetic heterogeneity of frontometaphyseal dysplasia, see FMD1 (305620).
Myofibrillar myopathy 7- MedGen UID:
- 934678
- •Concept ID:
- C4310711
- •
- Disease or Syndrome
Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures (summary by Straussberg et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;- MedGen UID:
- 934692
- •Concept ID:
- C4310725
- •
- Disease or Syndrome
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
Congenital disorder of glycosylation, type IAA- MedGen UID:
- 934694
- •Concept ID:
- C4310727
- •
- Disease or Syndrome
Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome- MedGen UID:
- 934703
- •Concept ID:
- C4310736
- •
- Disease or Syndrome
A rare congenital muscular dystrophy characterised by neonatal hypotonia, life-threatening respiratory failure and feeding difficulties, furthermore by delayed motor development, severe muscle weakness predominantly affecting axial muscles (leading to poor head control, rigid cervical spine, and severe scoliosis), generalised joint laxity with no or mild contractures, as well as dry skin with follicular hyperkeratosis. Serum creatine kinase is normal or slightly elevated. Muscle biopsy shows fibre size variability, rounded fibres with mild increase of endomysial connective tissue and adipose replacement, abundant minicore lesions, increase of centrally located nuclei, angular fibres and cap lesions.
Meier-Gorlin syndrome 7- MedGen UID:
- 934705
- •Concept ID:
- C4310738
- •
- Disease or Syndrome
Any Meier-Gorlin syndrome in which the cause of the disease is a mutation in the CDC45 gene.
Okur-Chung neurodevelopmental syndrome- MedGen UID:
- 934706
- •Concept ID:
- C4310739
- •
- Disease or Syndrome
Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability (typically in the mild-to-moderate range), generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. Developmental delay affects all areas of development, but language is more impaired than gross motor skills in most individuals. Intellectual disability has been reported in about three quarters of individuals. Less common findings may include kyphoscoliosis, postnatal short stature, disrupted circadian rhythm leading to sleep disturbance, seizures, and poor coordination.
Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome- MedGen UID:
- 934707
- •Concept ID:
- C4310740
- •
- Disease or Syndrome
TRIO-related intellectual disability (ID) is characterized by delay in acquisition of motor and language skills, mild to borderline intellectual disability, and neurobehavioral problems (including autistic traits or autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or aggression). Neonatal or infantile feeding difficulties including poor suck, impaired bottle feeding, and failure to thrive are common and are often the presenting finding. Other findings can include microcephaly, variable hand and dental abnormalities, and suggestive facial features. Only ten of the 20 individuals with a TRIO pathogenic variant reported to date had sufficient information to make preliminary generalizations about clinical manifestations; it is anticipated that the phenotype of this newly described disorder will continue to evolve.
PERCHING syndrome- MedGen UID:
- 934709
- •Concept ID:
- C4310742
- •
- Disease or Syndrome
PERCHING syndrome is an autosomal recessive multisystem disorder characterized by global developmental delay, dysmorphic facial features, feeding and respiratory difficulties with poor overall growth, axial hypotonia, and joint contractures. The features are variable, even within families, and may also include retinitis pigmentosa, cardiac or genitourinary anomalies, and abnormal sweating. Each letter of the PERCHING acronym represents 2 important phenotypic elements: Postural and Palatal abnormalities; Exophthalmos and Enteral-tube dependency/feeding issues; Respiratory distress and Retinitis pigmentosa; Contractures and Camptodactyly; Hypertelorism and Hirsutism; Intrauterine growth retardation (IUGR)/growth failure and Intellectual disability/developmental delay; Nevus flammeus and Neurologic malformations; and facial Gestalt/grimacing and Genitourinary abnormalities (Jeffries et al., 2019). Death in infancy or early childhood often occurs, although survival to the third decade has been reported. Some of the features, such as contractures, dysmorphic craniofacial features, and severe feeding difficulties, are reminiscent of Bohring-Opitz syndrome (605039) (summary by Kanthi et al., 2019 and Buers et al., 2020).
Hypermanganesemia with dystonia 2- MedGen UID:
- 934732
- •Concept ID:
- C4310765
- •
- Disease or Syndrome
SLC39A14 deficiency is characterized by evidence between ages six months and three years of delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance). Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor. By the end of the first decade they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, and scoliosis, and lose independent ambulation. Cognitive impairment appears to be less prominent than motor disability. Some affected children have succumbed in their first decade due to secondary complications such as respiratory infections.
Macrocephaly, dysmorphic facies, and psychomotor retardation- MedGen UID:
- 934733
- •Concept ID:
- C4310766
- •
- Disease or Syndrome
Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) is an autosomal recessive neurodevelopmental disorder characterized by large head and somatic overgrowth apparent at birth followed by global developmental delay. Affected individuals have characteristic dysmorphic facial features and persistently large head, but increased birth weight normalizes with age. Additional neurologic features, including seizures, hypotonia, and gait ataxia, may also occur. Patients show severe intellectual impairment (summary by Ortega-Recalde et al., 2015).
Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart- MedGen UID:
- 934739
- •Concept ID:
- C4310772
- •
- Disease or Syndrome
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.
SIN3A-related intellectual disability syndrome due to a point mutation- MedGen UID:
- 934771
- •Concept ID:
- C4310804
- •
- Disease or Syndrome
Witteveen-Kolk syndrome (WITKOS) is an autosomal dominant disorder with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging (summary by Balasubramanian et al., 2021).
Intellectual disability, X-linked, syndromic, Bain type- MedGen UID:
- 934781
- •Concept ID:
- C4310814
- •
- Disease or Syndrome
Most individuals with HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) have symptoms early in life, before age 12 months. The major features of HNRNPH2-NDD are developmental delay / intellectual disability, motor and language delays, behavioral and psychiatric disorders, and growth and musculoskeletal abnormalities. Minor features include dysmorphic facies, gastrointestinal disturbances, epilepsy, and visual defects. Although HNRNPH2-NDD is an X-linked condition, there is not enough information on affected females versus affected males to make any generalizations about phenotypic differences between the two sexes.
Myopathy with abnormal lipid metabolism- MedGen UID:
- 934789
- •Concept ID:
- C4310822
- •
- Disease or Syndrome
Lipid storage myopathy due to FLAD1 deficiency is an autosomal recessive inborn error of metabolism that includes variable mitochondrial dysfunction. The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment (summary by Olsen et al., 2016).
Cole-Carpenter syndrome 1- MedGen UID:
- 1374755
- •Concept ID:
- C4317154
- •
- Disease or Syndrome
Cole-Carpenter syndrome is characterized by bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features (Cole and Carpenter, 1987).
Genetic Heterogeneity of Cole-Carpenter Syndrome
Cole-Carpenter syndrome-2 (CLCRP2; 616294) is caused by mutation in the SEC24D gene (607186).
Developmental and epileptic encephalopathy, 36- MedGen UID:
- 1382656
- •Concept ID:
- C4317295
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-36 (DEE36) is an X-linked neurodevelopmental disorder characterized by the onset of seizures at a mean age of 6.5 months. Most patients present with infantile spasms associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. The seizures tend to be refractory to treatment, although some patients may respond to benzodiazepines or a ketogenic diet. Affected individuals have severely delayed psychomotor development with poor motor function, severe intellectual disability, poor or absent speech, and limited eye contact. More variable features include feeding difficulties sometimes requiring tube feeding, ocular defects including cortical visual impairment, dysmorphic facial features, and scoliosis or osteopenia. The vast majority of patients reported have been females, although rare affected males with a similar phenotype have been described. Most patients show normal N-glycosylation on transferrin isoelectric focusing, but some show abnormal N-glycosylation consistent with CDG type I (summary by Ng et al., 2020).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
For a discussion of the classification of CDGs, see CDG1A (212065).
Intellectual disability, X-linked, syndromic, 35- MedGen UID:
- 1392054
- •Concept ID:
- C4478383
- •
- Disease or Syndrome
Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder- MedGen UID:
- 1385307
- •Concept ID:
- C4479246
- •
- Disease or Syndrome
CDK13-related disorder, reported in 43 individuals to date, is characterized in all individuals by developmental delay / intellectual disability (DD/ID); nearly all individuals older than age one year display impaired verbal language skills (either absent or restricted speech). Other common findings are recognizable facial features in some individuals, behavioral problems (autism spectrum disorder or autistic traits/stereotypies, attention-deficit/hyperactivity disorder), feeding difficulties in infancy, structural cardiac defects, and seizures.
Congenital heart defects and ectodermal dysplasia- MedGen UID:
- 1387409
- •Concept ID:
- C4479250
- •
- Disease or Syndrome
Congenital heart defects and ectodermal dysplasia (CHDED) is a rare disorder characterized by these cardinal features, with additional variable features of microcephaly, craniofacial or skeletal dysmorphism, feeding difficulties, or hypotonia (Sifrim et al., 2016).
Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination- MedGen UID:
- 1377894
- •Concept ID:
- C4479333
- •
- Disease or Syndrome
Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination is a syndromic form of severe to profound intellectual disability with onset of delayed psychomotor development and seizures in infancy. Affected children have hypotonia, feeding difficulties resulting in failure to thrive, and inability to speak or walk, and they tend to show repetitive stereotypic behaviors. Brain imaging shows cerebral atrophy and delayed myelination (summary by Schoch et al., 2017).
Congenital muscular dystrophy with cataracts and intellectual disability- MedGen UID:
- 1382291
- •Concept ID:
- C4479410
- •
- Disease or Syndrome
MDCCAID is an autosomal recessive form of muscular dystrophy with onset of progressive muscle weakness in early childhood. Almost all patients also have early-onset cataracts, most have impaired intellectual development of varying severity, and some have seizures (summary by Wiessner et al., 2017 and Osborn et al., 2017).
Lopes-Maciel-Rodan syndrome- MedGen UID:
- 1379711
- •Concept ID:
- C4479491
- •
- Disease or Syndrome
Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies- MedGen UID:
- 1375601
- •Concept ID:
- C4479520
- •
- Disease or Syndrome
IDDFSDA is an autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early-onset seizures, intellectual disability, and dysmorphic features. There is phenotypic variability. The most severely affected patients have a neurodevelopmental disorder with microcephaly, absent speech, and inability to walk, and they require feeding tubes. Some patients have congenital heart defects or nonspecific abnormalities on brain imaging. Less severely affected individuals have mild to moderate intellectual disability with normal speech and motor development (summary by Santiago-Sim et al., 2017).
Townes-Brocks syndrome 2- MedGen UID:
- 1381939
- •Concept ID:
- C4479534
- •
- Disease or Syndrome
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies- MedGen UID:
- 1380860
- •Concept ID:
- C4479566
- •
- Disease or Syndrome
NMIHBA is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay apparent from infancy and profoundly impaired intellectual development. Affected individuals have microcephaly with accompanying dysmorphic features, truncal hypotonia, peripheral spasticity, and lack of independent ambulation or speech acquisition. Brain imaging shows variable abnormalities, including cortical atrophy, thin corpus callosum, cerebellar hypoplasia, and delayed myelination (summary by Zollo et al., 2017).
Noonan syndrome-like disorder with loose anagen hair 2- MedGen UID:
- 1376945
- •Concept ID:
- C4479577
- •
- Disease or Syndrome
An inherited condition caused by autosomal dominant mutation(s) in the PPP1CB gene, encoding serine/threonine-protein phosphatase PP1-beta catalytic subunit. The condition is characterized by facial features similar to those seen in Noonan syndrome but may also include short stature, cognitive deficits, relative macrocephaly, small posterior fossa resulting in Chiari I malformation, hypernasal voice, cardiac defects, and ectodermal abnormalities, which typically presents as slow-growing, sparse, and/or unruly hair.
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness- MedGen UID:
- 1382171
- •Concept ID:
- C4479603
- •
- Disease or Syndrome
SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported.
Gaze palsy, familial horizontal, with progressive scoliosis, 2- MedGen UID:
- 1393733
- •Concept ID:
- C4479640
- •
- Disease or Syndrome
Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy- MedGen UID:
- 1382553
- •Concept ID:
- C4479653
- •
- Disease or Syndrome
NKX6-2-related disorder is characterized by a spectrum of progressive neurologic manifestations resulting from diffuse central nervous system hypomyelination. At the severe end of the spectrum is neonatal-onset nystagmus, severe spastic tetraplegia with joint contractures and scoliosis, and visual and hearing impairment, all of which rapidly progress resulting in death in early childhood. At the milder end of the spectrum is normal achievement of early motor milestones in the first year of life followed by slowly progressive complex spastic ataxia with pyramidal findings (spasticity with increased muscle tone and difficulty with gait and fine motor coordination) and cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia) with loss of developmental milestones. To date NKX6-2-related disorder has been reported in 25 individuals from 13 families.
Cohen-Gibson syndrome- MedGen UID:
- 1386939
- •Concept ID:
- C4479654
- •
- Disease or Syndrome
EED-related overgrowth is characterized by fetal or early childhood overgrowth (tall stature, macrocephaly, large hands and feet, and advanced bone age) and intellectual disability that ranges from mild to severe. To date, EED-related overgrowth has been reported in eight individuals.
Craniometadiaphyseal dysplasia wormian bone type- MedGen UID:
- 1382152
- •Concept ID:
- C4510809
- •
- Disease or Syndrome
Craniometadiaphyseal dysplasia (CRMDD) is characterized clinically by macrocephaly with frontal prominence, dental hypoplasia, and increased bone fragility. Diagnostic radiologic features include thin bones in the superior part of calvaria with prominent wormian bones, diaphyseal widening of the long tubular bones in early childhood with wide undermineralized metaphyses in older individuals, widened ribs and clavicles, and broadening of short tubular bones with increased transparency and thin cortices (summary by Dhar et al., 2010).
Autosomal recessive limb-girdle muscular dystrophy type R18- MedGen UID:
- 1385598
- •Concept ID:
- C4517996
- •
- Disease or Syndrome
Autosomal recessive limb-girdle muscular dystrophy-18 (LGMDR18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (Liang et al., 2015; Koehler et al., 2017).
For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Syringomyelia, isolated- MedGen UID:
- 1622554
- •Concept ID:
- C4538540
- •
- Disease or Syndrome
Syringomyelia (Greek: 'syrinx,' pipe, and 'myelos,' marrow) is a tubular cavity in the spinal cord. It can occur sporadically in association with spinal cord tumors, inflammatory arachnoiditis, or posttraumatically. It is rarely idiopathic (less than 1% of cases). The vast majority of cases of syringomyelia are cervical, noncommunicating, and associated with an abnormality at the foramen magnum, particularly the Chiari malformation type I (CM1; 118420), as well as basilar impression (109500) and Dandy-Walker malformation (220200) (Speer et al., 2003; Levine, 2004); these cases have shown familial segregation.
The form of syringomyelia discussed here is 'noncommunicating' with the fourth ventricle, but may communicate with the subarachnoid space. In contrast, 'communicating' syringomyelia, or 'hydromelia,' opens rostrally into the fourth ventricle and almost always occurs in children with hydrocephalus, Chiari malformation type II (CM2; 207950), and spina bifida (see 182940) (Levine, 2004).
Galloway-Mowat syndrome 2, X-linked- MedGen UID:
- 1625619
- •Concept ID:
- C4538784
- •
- Disease or Syndrome
Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Most patients die in the first years of life (summary by Braun et al., 2017).
For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).
Intellectual disability, autosomal dominant 45- MedGen UID:
- 1616472
- •Concept ID:
- C4539848
- •
- Mental or Behavioral Dysfunction
Congenital heart defects and skeletal malformations syndrome- MedGen UID:
- 1618340
- •Concept ID:
- C4539857
- •
- Disease or Syndrome
Congenital heart defects and skeletal malformations syndrome (CHDSKM) is characterized by atrial and ventricular septal defects, with aortic root dilation in adulthood. Skeletal defects are variable and include pectus excavatum, scoliosis, and finger contractures, and some patients exhibit joint laxity. Failure to thrive is observed during infancy and early childhood (Wang et al., 2017).
Intellectual disability, autosomal dominant 47- MedGen UID:
- 1622196
- •Concept ID:
- C4539951
- •
- Mental or Behavioral Dysfunction
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, variable degrees of intellectual disability, and facial dysmorphism (including high nasal bridge, deep-set eyes, and wide mouth), often associated with feeding difficulties and/or gastroesophageal reflux. Additional reported manifestations are seizures, hypotonia, autistic features, and joint laxity. Brain imaging may show non-specific features (such as cerebral atrophy).
Developmental and epileptic encephalopathy, 56- MedGen UID:
- 1621755
- •Concept ID:
- C4540034
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-56 (DEE56) is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by impaired intellectual development, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia (summary by Guella et al., 2017).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome- MedGen UID:
- 1620960
- •Concept ID:
- C4540096
- •
- Disease or Syndrome
Mitochondrial myopathy and ataxia (MMYAT) is an autosomal recessive mtDNA depletion disorder characterized by cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic, and pigmentary retinopathy (summary by Donkervoort et al., 2019).
Intellectual disability, autosomal dominant 48- MedGen UID:
- 1619532
- •Concept ID:
- C4540321
- •
- Mental or Behavioral Dysfunction
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities.
Myopathy, centronuclear, 6, with fiber-type disproportion- MedGen UID:
- 1627492
- •Concept ID:
- C4540345
- •
- Disease or Syndrome
Centronuclear myopathy-6 with fiber-type disproportion (CNM6) is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy (summary by Vasli et al., 2017).
For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).
Kleefstra syndrome 2- MedGen UID:
- 1623903
- •Concept ID:
- C4540395
- •
- Disease or Syndrome
Kleefstra syndrome-2 (KLEFS2) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variably impaired intellectual development, and mild dysmorphic features (summary by Koemans et al., 2017).
For a discussion of genetic heterogeneity of Kleefstra syndrome, see KLEFS1 (610253).
Intellectual disability, autosomal recessive 61- MedGen UID:
- 1622296
- •Concept ID:
- C4540424
- •
- Mental or Behavioral Dysfunction
MRT61 is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, moderate to severe intellectual disability, and variable dysmorphic facial features. More severely affected patients may develop refractory seizures and have brain abnormalities, including hypoplasia of the corpus callosum (summary by Alwadei et al., 2016).
Neurodevelopmental disorder with severe motor impairment and absent language- MedGen UID:
- 1622162
- •Concept ID:
- C4540496
- •
- Mental or Behavioral Dysfunction
NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017 and Mannucci et al., 2021).
Seckel syndrome 1- MedGen UID:
- 1637056
- •Concept ID:
- C4551474
- •
- Disease or Syndrome
Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance (Shanske et al., 1997).
Genetic Heterogeneity of Seckel Syndrome
Other forms of Seckel syndrome include SCKL2 (606744), caused by mutation in the RBBP8 gene (604124) on chromosome 18q11; SCKL4 (613676), caused by mutation in the CENPJ gene (609279) on chromosome 13q12; SCKL5 (613823), caused by mutation in the CEP152 gene (613529) on chromosome 15q21; SCKL6 (614728), caused by mutation in the CEP63 gene (614724) on chromosome 3q22; SCKL7 (614851), caused by mutation in the NIN gene (608684) on chromosome 14q22; SCKL8 (615807), caused by mutation in the DNA2 gene (601810) on chromosome 10q21; SCKL9 (616777), caused by mutation in the TRAIP gene (605958) on chromosome 3p21; SCKL10 (617253), caused by mutation in the NSMCE2 gene (617246) on chromosome 8q24; and SCKL11 (620767), caused by mutation in the CEP295 gene (617728) on chromosome 11q21.
The report of a Seckel syndrome locus on chromosome 14q, designated SCKL3, by Kilinc et al. (2003) was found to be in error; see History section.
Schwartz-Jampel syndrome type 1- MedGen UID:
- 1647990
- •Concept ID:
- C4551479
- •
- Disease or Syndrome
Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive disorder characterized by muscle stiffness (myotonia) and chondrodysplasia. Affected individuals usually present in childhood with permanent muscle stiffness or bone deformities. Common clinical features include mask-like facies (narrow palpebral fissures, blepharospasm, and pursed lips); permanent muscle stiffness with continuous skeletal muscle activity recorded on electromyography; dwarfism; pectus carinatum; kyphoscoliosis; bowing of long bones; and epiphyseal, metaphyseal, and hip dysplasia. The disorder is slowly progressive but does not appear to alter life span (summary by Stum et al., 2006).
Ehlers-Danlos syndrome, periodontal type 1- MedGen UID:
- 1642148
- •Concept ID:
- C4551499
- •
- Disease or Syndrome
Periodontal Ehlers-Danlos syndrome (pEDS) is characterized by distinct oral manifestations. Periodontal tissue breakdown beginning in the teens results in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. Since the first descriptions of pEDS in the 1970s, 148 individuals have been reported in the literature; however, future in-depth descriptions of non-oral manifestations in newly diagnosed individuals with a molecularly confirmed diagnosis of pEDS will be important to further define the clinical features.
RAB23-related Carpenter syndrome- MedGen UID:
- 1644017
- •Concept ID:
- C4551510
- •
- Disease or Syndrome
Carpenter syndrome is a rare autosomal recessive disorder with the cardinal features of acrocephaly with variable synostosis of the sagittal, lambdoid, and coronal sutures; peculiar facies; brachydactyly of the hands with syndactyly; preaxial polydactyly and syndactyly of the feet; congenital heart defects; growth retardation; mental retardation; hypogenitalism; and obesity. In addition, cerebral malformations, oral and dental abnormalities, coxa valga, genu valgum, hydronephrosis, precocious puberty, and hearing loss may be observed (summary by Altunhan et al., 2011).
Genetic Heterogeneity of Carpenter Syndrome
Carpenter syndrome-2 (CRPT2; 614976), in which the features of Carpenter syndrome are sometimes associated with defective lateralization, is caused by mutation in the MEGF8 gene (604267).
Ehlers-Danlos syndrome, arthrochalasia type- MedGen UID:
- 1645042
- •Concept ID:
- C4551623
- •
- Disease or Syndrome
Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (Byers et al., 1997; Giunta et al., 2008).
Genetic Heterogeneity of Arthrochalasia-type Ehlers-Danlos Syndrome
See EDSARTH2 (617821), caused by mutation in the COL1A2 gene (120160).
Perrault syndrome 1- MedGen UID:
- 1640257
- •Concept ID:
- C4551721
- •
- Disease or Syndrome
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Zimmermann-Laband syndrome 1- MedGen UID:
- 1639277
- •Concept ID:
- C4551773
- •
- Disease or Syndrome
Zimmermann-Laband syndrome is a rare disorder characterized by gingival fibromatosis, dysplastic or absent nails, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, hirsutism, and abnormalities of the cartilage of the nose and/or ears (summary by Balasubramanian and Parker, 2010).
Genetic Heterogeneity of Zimmermann-Laband Syndrome
ZLS2 (616455) is caused by mutation in the ATP6V1B2 gene (606939) on chromosome 8p21. ZLS3 (618658) is caused by mutation in the KCNN3 gene (602983) on chromosome 1q21.
Rubinstein-Taybi syndrome due to CREBBP mutations- MedGen UID:
- 1639327
- •Concept ID:
- C4551859
- •
- Disease or Syndrome
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.
Van Maldergem syndrome 1- MedGen UID:
- 1644627
- •Concept ID:
- C4551950
- •
- Disease or Syndrome
Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013).
Genetic Heterogeneity of Van Maldergem Syndrome
See also VMLDS2 (615546), caused by mutation in the FAT4 gene (612411) on chromosome 4q28.
Loeys-Dietz syndrome 1- MedGen UID:
- 1646567
- •Concept ID:
- C4551955
- •
- Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Weill-Marchesani syndrome 1- MedGen UID:
- 1637058
- •Concept ID:
- C4552002
- •
- Disease or Syndrome
Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.
Ehlers-Danlos syndrome, spondylodysplastic type, 1- MedGen UID:
- 1646889
- •Concept ID:
- C4552003
- •
- Disease or Syndrome
Ehlers-Danlos syndrome spondylodysplastic type 1 (EDSSPD1) is characterized by short stature, developmental anomalies of the forearm bones and elbow, and bowing of extremities, in addition to the classic stigmata of Ehlers-Danlos syndrome, including joint laxity, skin hyperextensibility, and poor wound healing. Significant developmental delay is not a consistent feature (Guo et al., 2013).
Genetic Heterogeneity of Ehlers-Danlos Syndrome, Spondylodysplastic Type
See EDSSPD2 (615349), caused by mutation in the B3GALT6 gene (615291), and EDSSPD3 (612350), caused by mutation in the SLC39A13 gene (608735).
MYH7-related skeletal myopathy- MedGen UID:
- 1647391
- •Concept ID:
- C4552004
- •
- Disease or Syndrome
Laing distal myopathy is characterized by early-onset weakness (usually before age 5 years) that initially involves the dorsiflexors of the ankles and great toes and then the finger extensors, especially those of the third and fourth fingers. Weakness of the neck flexors is seen in most affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness may be observed. Life expectancy is normal.
Cerebroretinal microangiopathy with calcifications and cysts 1- MedGen UID:
- 1636142
- •Concept ID:
- C4552029
- •
- Disease or Syndrome
Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Developmental and epileptic encephalopathy, 59- MedGen UID:
- 1633749
- •Concept ID:
- C4693550
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-59 (DEE59) is characterized by severe global developmental delay apparent in infancy with onset of various types of seizures in the first months of life (range 3 to 11 months). The seizures are usually refractory and are often associated with hypsarrhythmia on EEG, although brain imaging is usually normal. More severely affected individuals may be unable to speak or walk, have poor interaction, and require a feeding tube (summary by the EuroEPINOMICS-RES Consortium et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Ververi-Brady syndrome- MedGen UID:
- 1647785
- •Concept ID:
- C4693824
- •
- Disease or Syndrome
Ververi-Brady syndrome (VEBRAS) is characterized by mild developmental delay, mildly impaired intellectual development and speech delay, and mild dysmorphic facial features. Affected individuals can usually attend mainstream schools with support, and may also show autistic features (summary by Ververi et al., 2018).
Jaberi-Elahi syndrome- MedGen UID:
- 1647359
- •Concept ID:
- C4693848
- •
- Disease or Syndrome
Jaberi-Elahi syndrome (JABELS) is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and impaired intellectual development with additional variable features. Patients have onset of symptoms in infancy, but the severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, such as tremor or dystonia, whereas others do not achieve any motor control and are unable to speak. Additional features may include retinal anomalies, visual impairment, microcephaly, abnormal foot or hand posturing, and kyphoscoliosis; some patients have dysmorphic facial features or seizures. Brain imaging typically shows cerebellar atrophy and hypoplasia of the corpus callosum (summary by et al., 2016 and Bertoli-Avella et al., 2018).
Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis-1 (NEDFET1; 620888) is a similar disorder caused by mutation in the GTPBP1 gene (602245) on chromosome 22q13.
Charcot-Marie-Tooth disease type 2A2- MedGen UID:
- 1648317
- •Concept ID:
- C4721887
- •
- Disease or Syndrome
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
Neuropathy, congenital hypomyelinating, 2- MedGen UID:
- 1648446
- •Concept ID:
- C4722277
- •
- Disease or Syndrome
Congenital hypomyelinating neuropathy-2 is an autosomal dominant neurologic disorder characterized by early-onset hypotonia, severely delayed motor development, muscle weakness with areflexia, and severely decreased nerve conduction velocities (NCV) resulting from improper myelination of axons. The severity is variable: some patients may present at birth with contractures and respiratory insufficiency, whereas others may achieve walking (summary by Warner et al., 1996).
CHN shows significant phenotypic overlap with Dejerine-Sottas syndrome (DSS; 145900), which is also a neuropathy with early onset. Some classify the disorders differently, noting that CHN is characterized by hypo- or amyelination resulting from a congenital defect in myelin formation, whereas DSS has features of continuous myelin breakdown, with demyelination and remyelination (summary by Smit et al., 2008).
For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).
Osteogenesis imperfecta, type 19- MedGen UID:
- 1648353
- •Concept ID:
- C4746956
- •
- Disease or Syndrome
Osteogenesis imperfecta type XIX (OI19) is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia (Lindert et al., 2016).
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures- MedGen UID:
- 1669929
- •Concept ID:
- C4747715
- •
- Disease or Syndrome
SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013).
For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).
Intellectual disability, autosomal dominant 57- MedGen UID:
- 1648280
- •Concept ID:
- C4748003
- •
- Mental or Behavioral Dysfunction
MRD57 is an autosomal dominant neurodevelopmental disorder with a highly variable phenotype. Most affected individuals have delayed psychomotor development apparent in infancy or early childhood, language delay, and behavioral abnormalities. Additional features may include hypotonia, feeding problems, gastrointestinal issues, and dysmorphic facial features (summary by Reijnders et al., 2018).
Neurodevelopmental disorder with spasticity and poor growth- MedGen UID:
- 1648309
- •Concept ID:
- C4748081
- •
- Disease or Syndrome
Neurodevelopmental disorder with spasticity and poor growth (NEDSG) is an autosomal recessive disorder characterized by severe early-onset encephalopathy with progressive microcephaly (Nahorski et al., 2018).
Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development- MedGen UID:
- 1648480
- •Concept ID:
- C4748283
- •
- Disease or Syndrome
Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by Ylikallio et al., 2017).
Glycosylphosphatidylinositol biosynthesis defect 18- MedGen UID:
- 1648478
- •Concept ID:
- C4748357
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-95 (DEE95) is a severe autosomal recessive disorder characterized by severely impaired global development, hypotonia, weakness, ataxia, coarse facial features, and intractable seizures. More variable features may include abnormalities of the hands and feet, inguinal hernia, and feeding difficulties. The disorder is part of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by Nguyen et al., 2018).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Ophthalmoplegia, external, with rib and vertebral anomalies- MedGen UID:
- 1648445
- •Concept ID:
- C4748418
- •
- Disease or Syndrome
External ophthalmoplegia with rib and vertebral anomalies (EORVA) is characterized by congenital nonprogressive external ophthalmoplegia and ptosis, with torticollis and scoliosis developing during childhood. In addition, patients exhibit hypoplastic or missing ribs with fusion anomalies (Di Gioia et al., 2018).
Cardiac, facial, and digital anomalies with developmental delay- MedGen UID:
- 1648330
- •Concept ID:
- C4748484
- •
- Disease or Syndrome
CAFDADD is a multisystemic developmental disorder with variable cardiac and digital anomalies and facial dysmorphism. Some patients may have seizures and ocular/aural abnormalities (Tokita et al., 2018).
Osteochondrodysplasia, brachydactyly, and overlapping malformed digits- MedGen UID:
- 1648332
- •Concept ID:
- C4748496
- •
- Disease or Syndrome
Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum (Shabbir et al., 2018).
Snijders Blok-Campeau syndrome- MedGen UID:
- 1648495
- •Concept ID:
- C4748701
- •
- Disease or Syndrome
Snijders Blok-Campeau syndrome (SNIBCPS) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and delayed speech acquisition. Affected individuals tend to have expressive language deficits, with speech apraxia and dysarthria. Other features include macrocephaly and characteristic facial features, such as prominent forehead and hypertelorism, hypotonia, and joint laxity. The severity of the neurologic deficits and presence of nonneurologic features is variable (summary by Snijders Blok et al., 2018).
Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome- MedGen UID:
- 1648431
- •Concept ID:
- C4748715
- •
- Disease or Syndrome
Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder characterized by infantile hypotonia, ophthalmic abnormalities, moderate to profound global developmental delay, poor or absent speech, behavioral abnormalities, hyperkinetic movements, and EEG abnormalities in the absence of overt seizures (summary by Baker et al., 2018).
Vertebral anomalies and variable endocrine and T-cell dysfunction- MedGen UID:
- 1648299
- •Concept ID:
- C4748741
- •
- Disease or Syndrome
Vertebral anomalies and variable endocrine and T-cell dysfunction is a syndrome characterized by an overlapping spectrum of features. Skeletal malformations primarily involve the vertebrae, and endocrine abnormalities involving parathyroid hormone (PTH; 168450), growth hormone (GH1; 139250), and the thyroid gland have been reported. T-cell abnormalities have been observed, with some patients showing thymus gland aplasia or hypoplasia. Patients have mild craniofacial dysmorphism, and some show developmental delay or behavioral problems. Cardiac defects may be present (Liu et al., 2018).
Mitochondrial complex 1 deficiency, nuclear type 11- MedGen UID:
- 1648356
- •Concept ID:
- C4748769
- •
- Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 16- MedGen UID:
- 1648351
- •Concept ID:
- C4748785
- •
- Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 17- MedGen UID:
- 1648418
- •Concept ID:
- C4748786
- •
- Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 19- MedGen UID:
- 1648450
- •Concept ID:
- C4748791
- •
- Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 23- MedGen UID:
- 1648408
- •Concept ID:
- C4748799
- •
- Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 23 (MC1DN23) is an autosomal recessive nuclear-encoded mitochondrial disease with clinical presentations ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI findings may include basal ganglia abnormalities or optic atrophy (summary by Magrinelli et al., 2022).
Trichohepatoneurodevelopmental syndrome- MedGen UID:
- 1648322
- •Concept ID:
- C4748898
- •
- Disease or Syndrome
Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).
Spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant- MedGen UID:
- 1648362
- •Concept ID:
- C4749003
- •
- Disease or Syndrome
SMALED2B is a severe neuromuscular disorder with onset in utero. Affected individuals show decreased fetal movements and are usually born with congenital contractures consistent with arthrogryposis multiplex congenita (AMC). After birth, they have severe hypotonia and muscle atrophy as well as respiratory insufficiency due to muscle weakness. Some patients may have dysmorphic facial features and/or abnormalities on brain imaging. Many patients die in early childhood (summary by Storbeck et al., 2017)
For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).
Developmental and epileptic encephalopathy, 70- MedGen UID:
- 1648407
- •Concept ID:
- C4749023
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-70 (DEE70) is neurologic disorder characterized by the onset of epileptic spasms or seizures in the first months of life. EEG may show hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals show severely delayed psychomotor development with impaired or absent walking and language skills; intellectual impairment ranges from moderate to severe (summary by Hamada et al., 2018).
For a discussion of genetic heterogeneity of DEE, see 308350.
Autosomal recessive spastic paraplegia type 70- MedGen UID:
- 1655287
- •Concept ID:
- C4749431
- •
- Disease or Syndrome
A very rare complex subtype of hereditary spastic paraplegia that presents in infancy with delayed motor development (crawling, walking) and has characteristics of lower limb spasticity, increased deep tendon reflexes, extensor plantar responses, impaired vibratory sensation at ankles, amyotrophy and borderline intellectual disability. Additional signs may include gait disturbances, Achilles tendon contractures, and scoliosis and cerebellar abnormalities.
Developmental and epileptic encephalopathy, 2- MedGen UID:
- 1663579
- •Concept ID:
- C4750718
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but DEE2 is considered to be a distinct entity (summary by Fehr et al., 2013).
For a discussion of genetic heterogeneity of DEE, see 308350.
Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome- MedGen UID:
- 1656239
- •Concept ID:
- C4750837
- •
- Disease or Syndrome
ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies.
Ferro-cerebro-cutaneous syndrome- MedGen UID:
- 1658844
- •Concept ID:
- C4751570
- •
- Disease or Syndrome
A rare genetic metabolic liver disease with characteristics of progressive neurodegeneration, cutaneous abnormalities including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations including microdontia, widely spaced and pointed teeth with delayed eruption and gingival overgrowth.
Autosomal recessive spinocerebellar ataxia 20- MedGen UID:
- 1684324
- •Concept ID:
- C5190595
- •
- Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by Thomas et al., 2014).
Congenital muscular dystrophy with intellectual disability and severe epilepsy- MedGen UID:
- 1682844
- •Concept ID:
- C5190603
- •
- Disease or Syndrome
A rare fatal inborn error of metabolism disorder with characteristics of respiratory distress and severe hypotonia at birth, severe global developmental delay, early-onset intractable seizures, myopathic facies with craniofacial dysmorphism (trigonocephaly/progressive microcephaly, low anterior hairline, arched eyebrows, hypotelorism, strabismus, small nose, prominent philtrum, thin upper lip, high-arched palate, micrognathia, malocclusion), severe, congenital flexion joint contractures and elevated serum creatine kinase levels. Scoliosis, optic atrophy, mild hepatomegaly, and hypoplastic genitalia may also be associated. There is evidence the disease is caused by homozygous or compound heterozygous mutation in the DPM2 gene on chromosome 9q34.
Progressive myoclonic epilepsy type 6- MedGen UID:
- 1681379
- •Concept ID:
- C5190805
- •
- Disease or Syndrome
Progressive myoclonic epilepsy-6 (EPM6) is an autosomal recessive neurologic disorder characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected, although mild memory difficulties may occur in the third decade (summary by Corbett et al., 2011).
For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800).
Mullegama-Klein-Martinez syndrome- MedGen UID:
- 1683985
- •Concept ID:
- C5193008
- •
- Disease or Syndrome
Mullegama-Klein-Martinez syndrome (MKMS) is an X-linked recessive disorder with features of microcephaly, microtia, hearing loss, developmental delay, dysmorphic features, congenital heart defect, and digit abnormalities. Females are generally affected more severely than males (Mullegama et al., 2019).
Distal arthrogryposis type 2B1- MedGen UID:
- 1676961
- •Concept ID:
- C5193014
- •
- Disease or Syndrome
Distal arthrogryposis is a clinically and genetically heterogeneous disorder characterized by clenched fist, overlapping fingers, camptodactyly, ulnar deviation, and positional foot deformities from birth. It is a disorder of primary limb malformation without primary neurologic or muscle disease. DA1 is not associated with other abnormalities, whereas other forms of DA have additional phenotypic features (Bamshad et al., 1996). The congenital contractures in DA2B (Sheldon-Hall syndrome, SHS) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by Bamshad et al., 2009).
For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Lethal arthrogryposis-anterior horn cell disease syndrome- MedGen UID:
- 1677784
- •Concept ID:
- C5193016
- •
- Disease or Syndrome
Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by Smith et al., 2017 and Tan et al., 2017).
Distinction from Lethal Congenital Contracture Syndrome 1
Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. Smith et al. (2017) suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, Said et al. (2017) concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements.
Vuopala et al. (1995) differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1.
Intellectual developmental disorder with cardiac defects and dysmorphic facies- MedGen UID:
- 1675627
- •Concept ID:
- C5193024
- •
- Disease or Syndrome
IDDCDF is an autosomal recessive syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Additional features, such as distal skeletal anomalies, may also be observed (Stephen et al., 2018).
Myasthenic syndrome, congenital, 25, presynaptic- MedGen UID:
- 1683288
- •Concept ID:
- C5193027
- •
- Disease or Syndrome
Congenital myasthenic syndrome-25 (CMS25) is an autosomal recessive neuromuscular disorder characterized by hypotonia and generalized muscle weakness apparent from birth. Affected individuals have feeding difficulties and delayed motor development, usually never achieving independent ambulation. Additional variable features include eye movement abnormalities, joint contractures, and rigid spine. Pyridostigmine treatment may be partially effective (summary by Shen et al., 2017).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Menke-Hennekam syndrome 1- MedGen UID:
- 1675629
- •Concept ID:
- C5193034
- •
- Disease or Syndrome
Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-1 (RSTS1; 180849), patients with MKHK1 do not resemble the striking phenotype of RSTS1.
Genetic Heterogeneity of Menke-Hennekam Syndrome
Menke-Hennekam syndrome-2 (MKHK2; 618333) is caused by heterozygous mutation in exons 30 or 31 of the EP300 gene (602700). Mutation elsewhere in that gene results in RSTS2 (613684).
Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency- MedGen UID:
- 1684464
- •Concept ID:
- C5193036
- •
- Disease or Syndrome
IMAGEI is an autosomal recessive disorder characterized by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency. Patients exhibit distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency (Logan et al., 2018).
An autosomal dominant form of the disorder, without immunodeficiency (IMAGE; 614732), is caused by mutation in the CDKN1C gene (600856) on chromosome 11p15.
Coffin-Siris syndrome 8- MedGen UID:
- 1679527
- •Concept ID:
- C5193054
- •
- Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis- MedGen UID:
- 1676818
- •Concept ID:
- C5193055
- •
- Disease or Syndrome
Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS)is characterized by disproportionate short stature, defective tooth enamel formation, and skeletal dysplasia with severe scoliosis in some patients. Variable features include facial dysmorphism, moderate hearing impairment, and mildly impaired intellectual development (Ashikov et al., 2018).
Developmental and epileptic encephalopathy, 73- MedGen UID:
- 1681654
- •Concept ID:
- C5193065
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-73 (DEE73) is a neurologic disorder characterized by the onset of refractory seizures in the first months of life. Affected individuals meet almost no developmental milestones: they have hypotonia and are unable to walk, speak, or feed properly. They have poor overall growth with small head circumference and dysmorphic facial features. Additional manifestations include cortical visual impairment with roving eye movements and variable hearing loss (summary by Edvardson et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Spondyloepimetaphyseal dysplasia with joint laxity, type 3- MedGen UID:
- 1677378
- •Concept ID:
- C5193073
- •
- Disease or Syndrome
Spondyloepimetaphyseal dysplasia with joint laxity-3 (SEMDJL3) is characterized by multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age, and poorly ossified carpal and tarsal bones (Girisha et al., 2016).
For a discussion of genetic heterogeneity of SEMD with joint laxity, see SEMDJL1 (271640).
Combined oxidative phosphorylation deficiency 39- MedGen UID:
- 1683958
- •Concept ID:
- C5193075
- •
- Disease or Syndrome
Combined oxidative phosphorylation deficiency-39 (COXPD39) is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. Affected individuals show global developmental delay, sometimes with regression after normal early development, axial hypotonia with limb spasticity or abnormal involuntary movements, and impaired intellectual development with poor speech. More variable features may include hypotonia, seizures, and features of Leigh syndrome (256000) on brain imaging. There are variable deficiencies of the mitochondrial respiratory chain enzyme complexes in patient tissues (summary by Glasgow et al., 2017).
For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Leukodystrophy, hypomyelinating, 18- MedGen UID:
- 1680067
- •Concept ID:
- C5193078
- •
- Disease or Syndrome
Hypomyelinating leukodystrophy-18 (HLD18) is an autosomal recessive neurologic disorder characterized by onset of global developmental delay usually in early infancy. Affected individuals have very poor psychomotor development, including inability to sit or walk independently in the more severe cases, as well as poor or absent speech, dystonia, and spasticity. A subset of patients may develop seizures. Brain imaging shows hypomyelinating leukodystrophy affecting various brain regions; some patients may also have progressive atrophy of the corpus callosum, thalami, and cerebellum (summary by Pant et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.
Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression- MedGen UID:
- 1681269
- •Concept ID:
- C5193083
- •
- Disease or Syndrome
Recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN) is an autosomal recessive metabolic disorder with a highly variable phenotype. Most affected individuals present in the first years of life with episodic lactic acidosis associated with illness or stress, resulting in transient or permanent neurologic dysfunction. Some patients may recover, whereas others show subsequent variable developmental regression of motor and cognitive skills. Other features may include dystonia, hypotonia with inability to sit or walk, seizures, and abnormal signals in the basal ganglia. There is significant phenotypic heterogeneity, even among patients with the same mutation (summary by Almannai et al., 2018).
Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy- MedGen UID:
- 1679397
- •Concept ID:
- C5193085
- •
- Disease or Syndrome
Myoectodermal gonadal dysgenesis syndrome (MEGD) is characterized by 46,XY complete or partial gonadal dysgenesis, or 46,XX gonadal dysgenesis, in association with extragonadal anomalies, including low birth weight, typical facies, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. Dysmorphic facial features along with muscular habitus are the hallmarks of the syndrome. Abnormal hair patterning with frontal upsweep and additional whorls, eyebrow abnormalities comprising broad, arched, and sparse or thick eyebrows, underdeveloped alae nasi, smooth philtrum, and low-set ears with overfolded helices facilitate a gestalt diagnosis. (Guran et al., 2019; Altunoglu et al., 2022).
Developmental delay with variable intellectual impairment and behavioral abnormalities- MedGen UID:
- 1676192
- •Concept ID:
- C5193092
- •
- Disease or Syndrome
Developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA) is an autosomal dominant neurodevelopmental disorder. Most patients have impaired intellectual development with speech difficulties, and many have behavioral abnormalities, most commonly autism spectrum disorder (ASD), defects in attention, and/or hyperactivity. Many patients have dysmorphic features, although there is not a consistent gestalt. Additional more variable features may include hypotonia, somatic overgrowth with macrocephaly, mild distal skeletal anomalies, sleep disturbances, movement disorders, and gastrointestinal issues, such as constipation. The phenotype is highly variable (summary by Vetrini et al., 2019 and Torti et al., 2019).
Arthrogryposis, distal, type 2B3- MedGen UID:
- 1676839
- •Concept ID:
- C5193098
- •
- Disease or Syndrome
Distal arthrogryposis type 2B3 (DA2B3) is characterized by facial dysmorphism and congenital joint contractures with predominantly distal involvement. Some patients exhibit muscle weakness (Tajsharghi et al., 2008). Considerable inter- and intrafamilial variability has been reported (Xu et al., 2018).
Oculocerebrodental syndrome- MedGen UID:
- 1674537
- •Concept ID:
- C5193101
- •
- Disease or Syndrome
Oculoskeletodental syndrome (OCSKD) is characterized by congenital cataract, short stature and various skeletal anomalies, dysmorphic facial features and dental anomalies, developmental delay, and stroke. Other recurrent features include hearing loss, secondary glaucoma, and nephrocalcinosis (Tiosano et al., 2019).
Neurodevelopmental disorder with or without variable brain abnormalities; NEDBA- MedGen UID:
- 1675664
- •Concept ID:
- C5193102
- •
- Disease or Syndrome
Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is characterized by global developmental delay apparent from infancy or early childhood, resulting in mildly delayed walking, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half of patients have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and although some patients may have nonspecific dysmorphic facial features, there is no common or consistent gestalt (summary by Platzer et al., 2019).
Developmental delay with or without dysmorphic facies and autism- MedGen UID:
- 1679263
- •Concept ID:
- C5193106
- •
- Disease or Syndrome
Developmental delay with or without dysmorphic facies and autism (DEDDFA) is a complex neurodevelopmental disorder apparent from infancy or early childhood and associated with variably impaired intellectual development. Some patients may be severely affected with no speech and inability to walk, whereas others may be able to attend special schools or have normal intellectual function associated with autism spectrum disorder and mild speech delay. Genetic analysis has suggested that the phenotype can be broadly categorized into 2 main groups. Patients with TRRAP mutations affecting residues 1031-1159 have a more severe disorder, often with multisystem involvement, including renal, cardiac, and genitourinary systems, as well as structural brain abnormalities. Patients with mutations outside of that region tend to have a less severe phenotype with a higher incidence of autism and usually no systemic involvement. Patients in both groups usually have somewhat similar dysmorphic facial features, such as upslanting palpebral fissures, hypertelorism, low-set ears, and broad or depressed nasal bridge, although these features are highly variable (summary by Cogne et al., 2019).
Khan-Khan-Katsanis syndrome- MedGen UID:
- 1682553
- •Concept ID:
- C5193110
- •
- Disease or Syndrome
Khan-Khan-Katsanis syndrome (3KS) is an autosomal recessive neurodevelopmental disorder with variable involvement of the ocular, renal, skeletal, and sometimes cardiac systems. Affected individuals present at birth with multiple congenital anomalies, defects in urogenital and limb morphogenesis, poor overall growth with microcephaly, and global developmental delay (summary by Khan et al., 2019).
Contractures, pterygia, and variable skeletal fusions syndrome 1B- MedGen UID:
- 1676457
- •Concept ID:
- C5193114
- •
- Disease or Syndrome
Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1B (CPSFS1B) is characterized by contractures of proximal and distal joints, pterygia involving the neck, elbows, fingers, and/or knees, and variable vertebral, carpal, and tarsal fusions. Inter- and intrafamilial variability has been observed (Cameron-Christie et al., 2018).
An autosomal dominant form of contractures, pterygia, and spondylocarpotarsal fusion syndrome (CPSFS1A; 178110) is caused by heterozygous mutation in the MYH3 gene.
Arthrogryposis multiplex congenita 3, myogenic type- MedGen UID:
- 1680655
- •Concept ID:
- C5193121
- •
- Disease or Syndrome
Myogenic-type arthrogryposis multiplex congenita-3 (AMC3) is an autosomal recessive disorder characterized by decreased fetal movements, hypotonia, variable skeletal defects, including clubfoot and scoliosis, and delayed motor milestones with difficulty walking (summary by Baumann et al., 2017).
Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities- MedGen UID:
- 1672905
- •Concept ID:
- C5193124
- •
- Disease or Syndrome
Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay, poor or absent speech, hypotonia, variable ocular movement and visual abnormalities, and respiratory difficulties, including hypoventilation, and sleep apnea. Patients may have significant breathing problems during respiratory infections that may lead to early death (summary by Rahikkala et al., 2019).
Congenital hypotonia, epilepsy, developmental delay, and digital anomalies- MedGen UID:
- 1674629
- •Concept ID:
- C5193125
- •
- Disease or Syndrome
ATN1-related neurodevelopmental disorder (ATN1-NDD) is characterized by developmental delay / intellectual disability. Other neurologic findings can include infantile hypotonia, brain malformations, epilepsy, cortical visual impairment, and hearing loss. Feeding difficulties, present in some individuals, may require gastrostomy support when severe; similarly, respiratory issues, present in some, may require respiratory support after the neonatal period. Distinctive facial features and hand and foot differences are common. Other variable findings can include cardiac malformations and congenital anomalies of the kidney and urinary tract (CAKUT). To date, 18 individuals with ATN1-NDD have been identified.
Hyper-IgE recurrent infection syndrome 4, autosomal recessive- MedGen UID:
- 1673363
- •Concept ID:
- C5193141
- •
- Disease or Syndrome
Hyper-IgE syndrome-4B with recurrent infections (HIES4B) is an autosomal recessive immunologic disorder characterized by early childhood onset of recurrent infections and skeletal abnormalities, including craniosynostosis and scoliosis. Patients are mainly susceptible to bacterial infections that affect the respiratory tract, skin, and eye. Immunologic workup shows increased serum IgE, intermittent eosinophilia, and impaired IL6 (147620) and IL27 (608273) downstream signaling that affects the development and function of certain B- and T-cell populations, as well as the acute-phase response; IL11 (147681) signaling in fibroblasts is also affected (summary by Shahin et al., 2019).
For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).
Congenital cerebellar hypoplasia- MedGen UID:
- 1695950
- •Concept ID:
- C5231391
- •
- Disease or Syndrome
Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of hypotonia and developmental delay with subsequent impaired intellectual development and severe speech delay. In childhood, affected individuals show delayed walking and develop epilepsy that is usually controlled by medication. Brain imaging shows cerebellar hypoplasia/atrophy (summary by Wang et al., 2019).
Myopathy, congenital, with tremor- MedGen UID:
- 1684886
- •Concept ID:
- C5231401
- •
- Disease or Syndrome
Congenital myopathy-16 (CMYO16) is an autosomal dominant muscle disorder characterized by onset of hypotonia and tremor in infancy. Patients have mildly delayed walking, unsteady gait, proximal muscle weakness, and a high-frequency tremor of the limbs. Some may develop secondary mild contractures or spinal deformities. Cognition is normal and the disease course tends to stabilize after adolescence (summary by Stavusis et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Neurodevelopmental disorder with visual defects and brain anomalies- MedGen UID:
- 1684774
- •Concept ID:
- C5231404
- •
- Disease or Syndrome
Neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) is characterized by global developmental delay with impaired intellectual development and speech delay, variable visual defects, including retinitis pigmentosa and optic atrophy, hypotonia or hypertonia, and variable structural brain abnormalities. Other nonspecific features may be found (summary by Okur et al., 2019).
Developmental and epileptic encephalopathy, 77- MedGen UID:
- 1684735
- •Concept ID:
- C5231405
- •
- Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months of life. Patients have severe global developmental delay, and may have additional variable features, including dysmorphic or coarse facial features, visual defects, and mild skeletal or renal anomalies. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Starr et al., 2019).
For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080).
For a discussion of genetic heterogeneity of DEE, see 308350.
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies- MedGen UID:
- 1684661
- •Concept ID:
- C5231414
- •
- Disease or Syndrome
Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies- MedGen UID:
- 1684725
- •Concept ID:
- C5231416
- •
- Disease or Syndrome
Myopathy, congenital, progressive, with scoliosis- MedGen UID:
- 1684769
- •Concept ID:
- C5231417
- •
- Disease or Syndrome
Congenital myopathy-19 (CMYO19) is an autosomal recessive skeletal muscle disorder characterized by infantile-onset of progressive muscle weakness and atrophy associated with scoliosis, variably impaired walking, and dysmorphic facial features (Feichtinger et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Glycosylphosphatidylinositol biosynthesis defect 21- MedGen UID:
- 1684749
- •Concept ID:
- C5231419
- •
- Disease or Syndrome
Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis (NEDBSS) is an autosomal recessive disorder characterized by severely impaired psychomotor development, hypotonia, seizures, and structural brain anomalies, including thin corpus callosum and cerebellar atrophy. Other features include scoliosis, dysmorphic facies, and visual impairment. Affected individuals are usually unable to walk or speak and may require tube feeding in severe cases. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Knaus et al., 2019).
For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies- MedGen UID:
- 1684881
- •Concept ID:
- C5231426
- •
- Disease or Syndrome
Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS) is characterized by mildly impaired global development, speech delay with nasal speech, and dysmorphic facial features, including high forehead, midface hypoplasia, micrognathia or high-arched palate, hypo/hypertelorism, upslanting palpebral fissures, and thin upper lip. Some patients may have skeletal anomalies, such as brachydactyly, 2-3 toe syndactyly, and flat feet (summary by Alesi et al., 2019 and Uehara et al., 2019).
Intellectual developmental disorder with impaired language and dysmorphic facies- MedGen UID:
- 1684804
- •Concept ID:
- C5231444
- •
- Disease or Syndrome
Intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF) is an autosomal dominant disorder characterized by global developmental delay apparent from infancy, impaired language development, and dysmorphic facial features, including hypertelorism, epicanthal folds, and abnormal palpebral fissures. Some patients may have additional findings, including feeding difficulties, mild cardiac or genitourinary defects, and distal skeletal anomalies (summary by Balak et al., 2019).
Myopathy, congenital, with structured cores and z-line abnormalities- MedGen UID:
- 1684705
- •Concept ID:
- C5231445
- •
- Disease or Syndrome
Congenital myopathy-8 (CMYO8) is an autosomal dominant disorder of the skeletal muscle characterized by hypotonia and delayed motor development apparent from infancy or childhood, resulting in difficulties walking or loss of ambulation within the first few decades. Affected individuals show respiratory insufficiency, high-arched palate, and scoliosis; external ophthalmoplegia may also be present. Skeletal muscle biopsy shows cores and myofibrillar disorganization (Lornage et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies- MedGen UID:
- 1684792
- •Concept ID:
- C5231448
- •
- Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019).
Short stature and microcephaly with genital anomalies- MedGen UID:
- 1684791
- •Concept ID:
- C5231467
- •
- Disease or Syndrome
Short stature and microcephaly with genital anomalies (SSMGA) is characterized by severe growth failure, with extreme short stature, microcephaly, and delayed and dissociated bone age. Global psychomotor developmental delay may be present, although the brain appears structurally normal. Pubertal delay and genital anomalies have been observed (Hung et al., 2017).
Spondyloepimetaphyseal dysplasia, Isidor-Toutain type- MedGen UID:
- 1684771
- •Concept ID:
- C5231478
- •
- Disease or Syndrome
The Isidor-Toutain type of spondyloepimetaphyseal dysplasia (SEMDIST) is characterized by normal birth length, early postnatal growth deficiency, severe short stature, and genu varum. Skeletal radiographs show platyspondyly and severe epiphyseal and metaphyseal changes in the lower limbs (Le Caignec et al., 2019).
Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies- MedGen UID:
- 1684772
- •Concept ID:
- C5231481
- •
- Disease or Syndrome
Structural brain anomalies with impaired intellectual development and craniosynostosis- MedGen UID:
- 1684861
- •Concept ID:
- C5231485
- •
- Disease or Syndrome
Patients with BAIDCS have small head circumference with abnormalities in brain anatomy including variable deficiency of the corpus callosum (including agenesis), abnormal conformation of the ventricles and posterior fossa, hypoplasia of both cerebellar hemispheres, colpocephaly, and partial rhombencephalosynapsis (absence of the cerebellar vermis with fusion of the cerebellar hemispheres). Intellectual development is moderately to severely impaired. Bicoronal synostosis, scoliosis, and tethered cord may be present (Twigg et al., 2015; Vandervore et al., 2018).
Craniosynostosis-6 (CRS6; 616602) is an allelic disorder.
ALDH18A1-related de Barsy syndrome- MedGen UID:
- 1720006
- •Concept ID:
- C5234852
- •
- Disease or Syndrome
De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008).
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100.
Genetic Heterogeneity of de Barsy Syndrome
Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25.
Intellectual disability, X-linked 102- MedGen UID:
- 1715418
- •Concept ID:
- C5393299
- •
- Disease or Syndrome
DDX3X-related neurodevelopmental disorder (DDX3X-NDD) typically occurs in females and very rarely in males. All affected individuals reported to date have developmental delay / intellectual disability (ID) ranging from mild to severe; about 50% of affected girls remain nonverbal after age five years. Hypotonia, a common finding, can be associated with feeding difficulty in infancy. Behavioral issues can include autism spectrum disorder, attention-deficit/hyperactivity disorder and hyperactivity, self-injurious behavior, poor impulse control, and aggression. Other findings can include seizures, movement disorders (dyskinesia, spasticity, abnormal gait), vision and hearing impairment, congenital heart defects, respiratory difficulties, joint laxity, and scoliosis. Neuroblastoma has been observed in three individuals.
Intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type- MedGen UID:
- 1716269
- •Concept ID:
- C5393302
- •
- Disease or Syndrome
Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD) is an X-linked recessive phenotype characterized by global developmental delay with hypotonia, delayed speech, and mildly delayed walking associated with somatic marfanoid features, including tall stature, long fingers, and mildly dysmorphic facies. Some patients may have cardiac defects, such as mitral valve regurgitation, as well as other anomalies related to connective tissue defects, such as scoliosis (summary by Fiordaliso et al., 2019).
Wieacker-Wolff syndrome, female-restricted- MedGen UID:
- 1715791
- •Concept ID:
- C5393303
- •
- Disease or Syndrome
Female-restricted Wieacker-Wolff syndrome (WRWFFR) is an X-linked dominant syndromic form of neurogenic arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Affected individuals have decreased fetal movements causing the development of contractures in utero and resulting in AMC and diffuse contractures involving the large and small joints apparent at birth. There is global developmental delay with difficulty walking or inability to walk, hypotonia that often evolves to spasticity, and variably impaired intellectual development with poor or absent speech and language. Dysmorphic facial features, including hypotonic facies, ptosis, microretrognathia, and small mouth, are seen in most patients. Seizures are uncommon; some patients have evidence of a peripheral motor neuropathy with distal muscle weakness. The level of X inactivation in lymphocytes and fibroblasts is often skewed, but may not predict the severity of the phenotype. Most cases occur sporadically; rare X-linked dominant inheritance has been reported in families (summary by Frints et al., 2019).
Developmental and epileptic encephalopathy, 85, with or without midline brain defects- MedGen UID:
- 1708832
- •Concept ID:
- C5393312
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is an X-linked neurologic disorder characterized by onset of severe refractory seizures in the first year of life, global developmental delay with impaired intellectual development and poor or absent speech, and dysmorphic facial features. The seizures tend to show a cyclic pattern with clustering. Many patients have midline brain defects on brain imaging, including thin corpus callosum and/or variable forms of holoprosencephaly (HPE). The severity and clinical manifestations are variable. Almost all reported patients are females with de novo mutations predicted to result in a loss of function (LOF). However, some patients may show skewed X inactivation, and the pathogenic mechanism may be due to a dominant-negative effect. The SMC1A protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; DEE85 can thus be classified as a 'cohesinopathy' (summary by Symonds et al., 2017 and Kruszka et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy- MedGen UID:
- 1717952
- •Concept ID:
- C5394027
- •
- Disease or Syndrome
Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) is an autosomal recessive disorder characterized by severely impaired global development apparent soon after birth. Affected individuals develop seizures in the first year of life and achieve almost no psychomotor progress, resulting in feeding difficulties and an inability to walk or speak. Other features include hypotonia, peripheral spasticity with contractures, cortical visual impairment, and dysmorphic features, including microcephaly. Death in childhood may occur (summary by Van Bergen et al., 2020).
Van Bergen et al. (2020) noted that the molecular mechanism of this disorder can be classified into a group of similar phenotypes resulting from mutations in genes associated with transport protein particles, sometimes referred to as 'TRAPPopathies' (review by Sacher et al., 2019).
Intellectual developmental disorder 62- MedGen UID:
- 1712636
- •Concept ID:
- C5394083
- •
- Disease or Syndrome
DLG4-related synaptopathy is a condition that affects neurological development. This condition is characterized by delayed development and mild to moderate intellectual disabilities that typically becomes evident before age 2. Over time, many individuals with DLG4-related synaptopathy lose skills that they have learned, such as speech or motor skills. About 20 percent of people with this condition cannot speak. Affected individuals often have neurodevelopmental disorders, such as autism spectrum disorder or attention-deficit/hyperactivity disorder. About half of individuals with this condition have recurrent seizures (epilepsy) that typically begin in childhood. Brain changes can also occur. These include brain tissue loss (atrophy) and abnormalities of the tissue connecting the left and right halves of the brain (corpus callosum) or the hippocampus, which is a region of the brain that is involved in learning and memory.\n\nIndividuals with DLG4-related synaptopathy can also have weak muscle tone (hyptonia), loose joints (joint laxity), or a spine that curves to the side (scoliosis). Movement problems, including impaired muscle coordination (ataxia), involuntary muscle coordination (dystonia), or rhythmic shaking (tremor) are common in people with this condition. Other problems can include migraine, sleep problems, or anxiety. Some people with DLG4-related synaptopathy have a distinctive body type that includes a long face, slim body, and long fingers.\n\nLess commonly, DLG4-related synaptopathy can affect a person's vision. Affected individuals can have eyes that do not point in the same direction (strabismus), farsightedness (hyperopia), or involuntary movements of the eyes (nystagmus). Some affected individuals have blindness because the area of the brain responsible for processing vision is impaired. \n\nDLG4-related synaptopathy can also cause gastrointestinal difficulties that make it difficult to eat. These can include a backflow of stomach acids into the esophagus (gastroesophageal reflux disease or GERD).\n\n
Mitochondrial DNA depletion syndrome 18- MedGen UID:
- 1713890
- •Concept ID:
- C5394140
- •
- Disease or Syndrome
Mitochondrial DNA depletion syndrome-18 (MTDPS18) is an autosomal recessive neuromuscular disorder characterized by early-onset progressive weakness and atrophy of the distal limb muscles, resulting in loss of ambulation as well as atrophy of the intrinsic hand muscles with clawed hands. Affected individuals may also develop scoliosis and have hypo- or hyperreflexia and decreased pulmonary vital capacity. Examination of skeletal muscle shows neurogenic atrophy and combined mitochondrial oxidative phosphorylation deficiency associated with mtDNA depletion. The clinical phenotype is reminiscent of spinal muscular atrophy (see SMA, 253300) and the metabolic profile is reminiscent of 2-aminoadipic 2-oxoadipic aciduria (AMOXAD; 204750), which is caused by mutation in the DHTKD1 gene (614984) (summary by Boczonadi et al., 2018).
For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Intellectual developmental disorder, autosomal dominant 63, with macrocephaly- MedGen UID:
- 1716581
- •Concept ID:
- C5394205
- •
- Disease or Syndrome
Skeletal dysplasia, mild, with joint laxity and advanced bone age- MedGen UID:
- 1711043
- •Concept ID:
- C5394341
- •
- Disease or Syndrome
CSGALNACT1 deficiency is characterized by mild skeletal dysplasia, joint hypermobility, and advanced bone age. Shortness of long bones is evident prenatally, and patients exhibit short stature and relative macrocephaly. Advanced carpotarsal bone age and monkey-wrench appearance of the femur observed in infancy may disappear with age (Mizumoto et al., 2020).
Liberfarb syndrome- MedGen UID:
- 1709796
- •Concept ID:
- C5394404
- •
- Disease or Syndrome
Liberfarb syndrome is a progressive disorder involving connective tissue, bone, retina, ear, and brain. Patients exhibit severe short stature and scoliosis with thoracic kyphosis and lumbar hyperlordosis. Severe joint laxity results in dislocations of elbows, hips, and knees. Eye findings are consistent with early-onset retinal degeneration, and there is moderate to severe early-onset hearing loss. Microcephaly is apparent by school age, and patients exhibit developmental delay and intellectual deficits (Peter et al., 2019). Clinical variability has been observed, with some patients presenting differences in the severity and location of skeletal dysplasia involvement as well as variation in other features of the syndrome (Girisha et al., 2019; Zhao et al., 2019).
Intellectual developmental disorder with autistic features and language delay, with or without seizures- MedGen UID:
- 1715081
- •Concept ID:
- C5394447
- •
- Disease or Syndrome
Intellectual developmental disorder with autistic features and language delay, with or without seizures (IDDALDS), is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, impaired speech development, and behavioral abnormalities, most commonly on the autism spectrum. About half of patients develop seizures; brain imaging is typically normal. Additional features are highly variable, but may include chronic constipation, walking difficulties, and dysmorphic facial features (summary by Guo et al., 2019).
Neuronopathy, distal hereditary motor, autosomal recessive 8- MedGen UID:
- 1714781
- •Concept ID:
- C5394466
- •
- Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8), or sorbitol dehydrogenase deficiency with peripheral neuropathy (SORDD), is characterized by onset of distal muscle weakness mainly affecting the lower limbs and resulting in difficulty walking. Onset of symptoms is usually in the first or second decades of life, although later adult onset has been reported; the disorder is slowly progressive. Nerve conduction velocities are most consistent with an axonal process. More variable features include distal sensory impairment, upper limb tremor, and scoliosis. Laboratory studies show increased serum sorbitol (summary by Cortese et al., 2020).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).
Developmental and epileptic encephalopathy, 87- MedGen UID:
- 1719688
- •Concept ID:
- C5394501
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-87 (DEE87) is a neurologic disorder characterized by global developmental delay, hypotonia, and onset of frequent refractory seizures or infantile spasms between 6 and 15 months of age. Affected individuals have severely impaired motor and cognitive development with little or absent speech and poor visual tracking. More variable features include facial dysmorphisms, joint laxity, and nonspecific brain imaging findings (summary by Chung et al., 2020).
IFAP syndrome 1, with or without BRESHECK syndrome- MedGen UID:
- 1746744
- •Concept ID:
- C5399971
- •
- Disease or Syndrome
The IFAP/BRESHECK syndrome is an X-linked multiple congenital anomaly disorder with variable severity. The classic triad, which defines IFAP, is ichthyosis follicularis, atrichia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae, which constitutes BRESHECK syndrome (summary by Naiki et al., 2012).
Genetic Heterogeneity of IFAP Syndrome
IFAP syndrome-2 (IFAP2; 619016) is caused by heterozygous mutation in the SREBF1 gene (184756) on chromosome 17p11.
Autosomal recessive Robinow syndrome- MedGen UID:
- 1770070
- •Concept ID:
- C5399974
- •
- Disease or Syndrome
ROR2-related Robinow syndrome is characterized by distinctive craniofacial features, skeletal abnormalities, and other anomalies. Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism, prominent eyes, midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia. Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly. Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy. The disorder is recognizable at birth or in early childhood.
Chromosome 17q11.2 deletion syndrome, 1.4Mb- MedGen UID:
- 1726802
- •Concept ID:
- C5401456
- •
- Disease or Syndrome
Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).
Rajab interstitial lung disease with brain calcifications 1- MedGen UID:
- 1750003
- •Concept ID:
- C5436276
- •
- Disease or Syndrome
Rajab interstitial lung disease with brain calcifications-1 (RILDBC1) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by Xu et al., 2018).
Genetic Heterogeneity of Rajab Interstitial Lung Disease with Brain Calcifications
Also see Rajab interstitial disease with brain calcifications-2 (RILDBC2; 619013), caused by mutation in the FARSA gene (602918).
Arthrogryposis multiplex congenita 5- MedGen UID:
- 1731112
- •Concept ID:
- C5436453
- •
- Disease or Syndrome
Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by Kariminejad et al., 2017).
Deeah syndrome- MedGen UID:
- 1756624
- •Concept ID:
- C5436579
- •
- Disease or Syndrome
DEEAH syndrome is an autosomal recessive multisystemic disorder with onset in early infancy. Affected individuals usually present in the perinatal period with respiratory insufficiency, apneic episodes, and generalized hypotonia. The patients have failure to thrive and severely impaired global development with poor acquisition of motor, cognitive, and language skills. Other common features include endocrine, pancreatic exocrine, and autonomic dysfunction, as well as hematologic disturbances, mainly low hemoglobin. Patients also have dysmorphic and myopathic facial features. Additional more variable features include seizures, undescended testes, and distal skeletal anomalies. Death in early childhood may occur (summary by Schneeberger et al., 2020).
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia- MedGen UID:
- 1776912
- •Concept ID:
- C5436585
- •
- Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is an autosomal recessive disorder characterized by global developmental delay and mildly to severely impaired intellectual development with poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. Aside from dysmorphic facial features and occasional findings such as scoliosis or undescended testes, other organ systems are not involved (summary by Schneeberger et al., 2020).
Rajab interstitial lung disease with brain calcifications 2- MedGen UID:
- 1770895
- •Concept ID:
- C5436603
- •
- Disease or Syndrome
Rajab interstitial lung disease with brain calcifications-2 (RILDBC2) is an autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts (Krenke et al., 2019).
For a discussion of genetic heterogeneity of RILDBC, see RILDBC1 (613658).
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities- MedGen UID:
- 1736667
- •Concept ID:
- C5436628
- •
- Disease or Syndrome
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA) is an autosomal recessive disorder characterized by impaired psychomotor development apparent in infancy. Affected individuals show poor overall growth, progressive microcephaly, and axial hypotonia, with later onset of spasticity. The disorder is progressive. Some patients show normal early development, but later have regression of motor, cognitive, and language skills. More variable features include seizures, joint contractures, ocular disturbances, episodic respiratory failure, and nonspecific dysmorphic facial features. The intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words. Brain imaging shows variable white matter abnormalities, including thin corpus callosum and poor myelination (summary by Husain et al., 2020).
Spinal muscular atrophy, infantile, James type- MedGen UID:
- 1764556
- •Concept ID:
- C5436669
- •
- Disease or Syndrome
The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait.
Mitochondrial complex 4 deficiency, nuclear type 12- MedGen UID:
- 1745691
- •Concept ID:
- C5436695
- •
- Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 12 (MC4DN12) is an autosomal recessive metabolic disorder characterized by the onset of neurologic dysfunction in early infancy. Affected individuals demonstrate hypotonia with poor head control, profoundly delayed global development with inability to fix and follow, poor overall growth, abnormal spasms or myoclonus, and seizures. Most patients die in the first years of life; those that survive have spastic quadriplegia, feeding difficulties necessitating tube feeding, and profoundly impaired intellectual development with poor or absent communication. More variable features include cortical blindness, nystagmus, scoliosis, and hearing impairment. Brain imaging shows abnormalities consistent with Leigh syndrome (see 256000), as well as cystic cavitation. Laboratory studies show lactic acidosis, increased serum creatine kinase, and decreased levels and activity of mitochondrial respiratory complex IV (summary by Lim et al., 2014).
For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 15- MedGen UID:
- 1773430
- •Concept ID:
- C5436712
- •
- Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 15 (MC4DN15) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show global developmental delay, poor feeding, short stature with microcephaly, proximal muscle weakness, and distal spasticity. Other manifestations include scoliosis, primary pulmonary hypertension, childhood-onset refractory seizures, and inability to walk. Brain imaging shows features consistent with Leigh syndrome (see 256000) and enlarged ventricles. Laboratory studies show increased serum and CSF lactate, as well as decreased levels and activity of mitochondrial respiratory complex IV (summary by Hallmann et al., 2016).
For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Leukodystrophy, hypomyelinating, 20- MedGen UID:
- 1765130
- •Concept ID:
- C5436730
- •
- Disease or Syndrome
Hypomyelinating leukodystrophy-20 (HLD20) is an autosomal recessive neurodegenerative disorder characterized by the loss of developmental milestones at about 12 to 16 months of age after normal early development. Patients lose motor, language, and cognitive skills and show poor overall growth with microcephaly. The disorder is progressive, resulting in feeding difficulties and spastic quadriplegia. Some patients may have seizures. Brain imaging shows subcortical white matter abnormalities and a thin corpus callosum, suggesting a myelination defect. Death usually occurs in childhood (Al-Abdi et al., 2020).
For a discussion of genetic heterogeneity of HLD, see 312080.
Noonan syndrome 13- MedGen UID:
- 1761918
- •Concept ID:
- C5436773
- •
- Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy- MedGen UID:
- 1765507
- •Concept ID:
- C5436781
- •
- Disease or Syndrome
Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN) is a complex neurologic disorder characterized by impaired motor and intellectual development, hypotonia, poor overall growth, usually with short stature and microcephaly, and subtly dysmorphic facial features. Affected individuals have distal muscle weakness and muscle atrophy resulting in delayed acquisition of motor skills and persistent gait abnormalities. Although many patients have clinical and/or electrophysiologic features consistent with an axonal sensorimotor peripheral neuropathy, such as hyporeflexia, impaired sensation, foot drop, and pes cavus, the signs and severity are highly variable. Additional features may include hearing loss, pigmentary retinopathy, and abnormalities on brain imaging, including cerebral or cerebellar atrophy, hypomyelination, and lesions in the basal ganglia or brainstem. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN syndrome), which highlights the expanding clinical spectrum associated with MORC2 mutations and may render classification of patients into one or the other disorder challenging (summary by Guillen Sacoto et al., 2020).
Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities- MedGen UID:
- 1731507
- •Concept ID:
- C5436783
- •
- Disease or Syndrome
Neurodevelopmental disorder with microcephaly, language delay, and gait abnormalities (NEDMILG) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. More variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease follows a neurodegenerative course in many patients; clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).
Arthrogryposis, distal, type 1C- MedGen UID:
- 1722257
- •Concept ID:
- C5436834
- •
- Disease or Syndrome
Distal arthrogryposis type 1C (DA1C) is characterized by multiple congenital contractures, scoliosis, and short stature. Contractures involving the proximal joints appear to be more common in MYLPF-associated DA than in other forms of DA, and segmental amyoplasia has been observed (Chong et al., 2020).
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1- MedGen UID:
- 1763836
- •Concept ID:
- C5436842
- •
- Disease or Syndrome
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-1 (OIEDS1) is an autosomal dominant generalized connective tissue disorder characterized by features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae) and Ehlers-Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility) (summary by Cabral et al., 2007; Malfait et al., 2013).
Genetic Heterogeneity of Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome
Also see OIEDS2 (619120), caused by mutation in the COL1A2 gene (120160) on chromosome 7q21.
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities- MedGen UID:
- 1750805
- •Concept ID:
- C5436848
- •
- Disease or Syndrome
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) is an autosomal recessive multisystemic disorder characterized by global neurodevelopmental delay, severely impaired intellectual development, poor overall growth, and spasticity of the lower limbs resulting in gait difficulties. Most affected individuals also develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Additional more variable features include dysmorphic facies and axonal sensory peripheral neuropathy. Brain imaging tends to show thin corpus callosum and polymicrogyria (summary by Garcia-Cazorla et al., 2020).
Developmental and epileptic encephalopathy 89- MedGen UID:
- 1761611
- •Concept ID:
- C5436853
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-89 (DEE89) is a severe autosomal recessive disorder characterized by profound global developmental delay with impaired intellectual development, absent speech, inability to sit or walk due to axial hypotonia and spastic quadriparesis, and onset of seizures in the first days or months of life. EEG shows suppression-burst pattern or hypsarrhythmia, consistent with DEE or a clinical diagnosis of West syndrome. More variable features include joint contractures with foot deformities, dysmorphic facial features with cleft palate, and omphalocele. Affected individuals have poor motor skills, poor eye contact, and lack of language development; some die in infancy or early childhood. Brain imaging may be normal or show nonspecific abnormalities (summary by Chatron et al., 2020).
Kaya-Barakat-Masson syndrome- MedGen UID:
- 1725501
- •Concept ID:
- C5436856
- •
- Disease or Syndrome
Kaya-Barakat-Masson syndrome (KABAMAS) is a severe autosomal recessive neurodevelopmental disorder characterized by profoundly impaired global development with variable motor abnormalities, such as axial hypotonia, peripheral spasticity, dystonia, and poor coordination, resulting in the inability to sit or walk. Affected individuals have impaired intellectual development with absent speech, poor eye contact, and feeding difficulties, resulting in poor overall growth, sometimes with microcephaly. Dysmorphic features are generally not present. Additional more variable features include early-onset seizures, ocular anomalies, foot deformities, and nonspecific brain imaging findings, such as thin corpus callosum and cerebral, cerebellar, or pontine atrophy. Some patients may die in infancy or early childhood (summary by AlMuhaizea et al., 2020 and Diaz et al., 2020).
Osteogenesis imperfecta, type 21- MedGen UID:
- 1723598
- •Concept ID:
- C5436875
- •
- Disease or Syndrome
Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).
Blepharophimosis-impaired intellectual development syndrome- MedGen UID:
- 1779966
- •Concept ID:
- C5443984
- •
- Disease or Syndrome
Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity (summary by Cappuccio et al., 2020).
Coffin-Siris syndrome 12- MedGen UID:
- 1782096
- •Concept ID:
- C5444111
- •
- Disease or Syndrome
Coffin-Siris syndrome-12 (CSS12) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, speech and language delay, and behavioral abnormalities, such as autism or hyperactivity. Affected individuals may have hypotonia and poor feeding in infancy. There are variable dysmorphic facial features, although most patients do not have the classic hypoplastic fifth digit/nail abnormalities that are often observed in other forms of CSS (Barish et al., 2020).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Dysostosis multiplex, Ain-Naz type- MedGen UID:
- 1780944
- •Concept ID:
- C5444223
- •
- Disease or Syndrome
The Ain-Naz type of dysostosis multiplex (DMAN) is a severe progressive skeletal dysplasia with features of a metabolic disorder. Patients exhibit marked short stature, coarse facies with broad nose and prominent lips, and a distended abdomen, and experience severe physical disability. Early death has been observed in some patients (Ain et al., 2021).
Odontochondrodysplasia 1- MedGen UID:
- 1784281
- •Concept ID:
- C5542277
- •
- Disease or Syndrome
Odontochondrodysplasia-1 (ODCD1) is characterized by mesomelic shortening of tubular bones, ligamentous laxity, and scoliosis, in association with dentinogenesis imperfecta involving both primary and secondary dentition. Affected individuals show variable severity. Radiologic features include trident pelvis, posteriorly flattened vertebrae, and brachydactyly with cone-shaped epiphyses (Maroteaux et al., 1996). Clinical variability and extraskeletal manifestations have been observed (Wehrle et al., 2019).
Genetic Heterogeneity of Odontochondrodysplasia
Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2; 619269) is caused by mutation in the TANGO1 gene (MIA3; 613455) on chromosome 1q41.
Microcephaly 26, primary, autosomal dominant- MedGen UID:
- 1779629
- •Concept ID:
- C5543048
- •
- Disease or Syndrome
Autosomal dominant primary microcephaly-26 (MCPH26) is characterized by progressive microcephaly beginning at birth and associated with global developmental delay with variably impaired intellectual development. Some patients may have only mild learning difficulties or speech delay, whereas other are more severely affected with the inability to walk or speak. Additional features may include short stature, spasticity, feeding difficulties requiring tube feeding, and nonspecific dysmorphic facial features. Brain imaging in some patients shows a simplified gyral pattern or dysgenesis of the corpus callosum, suggesting abnormal neuronal migration (summary by Cristofoli et al., 2020).
For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2- MedGen UID:
- 1782253
- •Concept ID:
- C5543057
- •
- Disease or Syndrome
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies-2 (SSFSC2) is characterized by thin and short long bones, distinctive facial dysmorphism, and dental and skeletal abnormalities, in the absence of developmental delay or intellectual disability. Cardiac anomalies have been reported in some patients (Lin et al., 2021).
For a discussion of genetic heterogeneity of SSFSC, see SSFSC1 (617877).
Neurofacioskeletal syndrome with or without renal agenesis- MedGen UID:
- 1778926
- •Concept ID:
- C5543070
- •
- Disease or Syndrome
Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) is characterized by developmental delay and/or intellectual disability; corpus callosum hypoplasia or agenesis; facial dysmorphism, including upslanting palpebral fissures, broad nasal tip, and wide mouth; and skeletal abnormalities, including short stature, scoliosis, and flexion contractures, with broad fingertips and/or toes. Renal agenesis, unilateral or bilateral, has also been observed in some patients (Schneeberger et al., 2020).
Kohlschutter-Tonz syndrome-like- MedGen UID:
- 1781649
- •Concept ID:
- C5543202
- •
- Disease or Syndrome
Den Hoed-de Boer-Voisin syndrome (DHDBV) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; 226750). More variable features of DHDBV include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by den Hoed et al., 2021).
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis- MedGen UID:
- 1780157
- •Concept ID:
- C5543257
- •
- Disease or Syndrome
SHILCA is characterized by early-onset retinal degeneration in association with sensorineural hearing loss, short stature, vertebral anomalies, and epiphyseal dysplasia, as well as motor and intellectual delay. Delayed myelination, leukoencephalopathy, and hypoplasia of the corpus callosum and cerebellum have been observed on brain MRI (Bedoni et al., 2020).
Odontochondrodysplasia 2 with hearing loss and diabetes- MedGen UID:
- 1782909
- •Concept ID:
- C5543275
- •
- Disease or Syndrome
Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability (Cauwels et al., 2005; Lekszas et al., 2020).
For a discussion of genetic heterogeneity of ODCD, see ODCD1 (184260).
KINSSHIP syndrome- MedGen UID:
- 1779339
- •Concept ID:
- C5543317
- •
- Disease or Syndrome
KINSSHIP syndrome (KINS) is an autosomal dominant disorder characterized by a recognizable pattern of anomalies including developmental delay, impaired intellectual development, seizures, mesomelic dysplasia, dysmorphic facial features, horseshoe or hypoplastic kidney, and failure to thrive (summary by Voisin et al., 2021).
Radio-Tartaglia syndrome- MedGen UID:
- 1778557
- •Concept ID:
- C5543339
- •
- Disease or Syndrome
Radio-Tartaglia syndrome (RATARS) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, speech delay, and variable behavioral abnormalities. Affected individuals show hypotonia, mild motor difficulties, and craniofacial dysmorphism. Brain imaging may show nonspecific defects; rare patients have seizures or pyramidal signs. A subset of individuals may have congenital heart defects, precocious puberty, and obesity in females. Some of the features are similar to those observed in patients with chromosome 1p36 deletion syndrome (607872) (summary by Radio et al., 2021).
Developmental and epileptic encephalopathy 6B- MedGen UID:
- 1779648
- •Concept ID:
- C5543353
- •
- Disease or Syndrome
SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family.
Fibromuscular dysplasia, multifocal- MedGen UID:
- 1778238
- •Concept ID:
- C5543412
- •
- Disease or Syndrome
Multifocal fibromuscular dysplasia (FMDMF) is characterized histologically by medial fibroplasia and angiographically by multiple arterial stenoses with intervening mural dilations. Arterial tortuosity, macroaneurysms, dissections, and rupture may occur (summary by Richer et al., 2020).
Ataxia, intention tremor, and hypotonia syndrome, childhood-onset- MedGen UID:
- 1787902
- •Concept ID:
- C5543478
- •
- Disease or Syndrome
Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) is a neurodevelopmental disorder characterized by delayed walking due to ataxia, intention tremor, and hypotonia apparent from early childhood. Affected individuals have global developmental delay with mildly impaired intellectual development and speech delay or learning disabilities. Eye movement abnormalities may also be present. Brain imaging shows cerebellar atrophy in some patients (summary by Webb et al., 2021).
Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities- MedGen UID:
- 1780615
- •Concept ID:
- C5543591
- •
- Disease or Syndrome
Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) is an autosomal recessive neurologic syndrome characterized by global developmental delay with severely impaired intellectual development, hypotonia and muscle weakness, often resulting in the inability to walk or sit, and characteristic coarse facial features. Additional features include feeding difficulties, respiratory distress, scoliosis, poor visual function, and rotary nystagmus. Brain imaging shows variable abnormalities, including enlarged ventricles, decreased white matter volume, white matter changes, thin corpus callosum, and cerebellar hypoplasia (summary by Loddo et al., 2020).
Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum- MedGen UID:
- 1790413
- •Concept ID:
- C5551361
- •
- Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum (NEDDFAC) is characterized by global developmental delay, impaired intellectual development with poor or absent speech and language, and dysmorphic facial features. Brain imaging tends to show thin corpus callosum and decreased white matter volume. Additional features such as seizures, cardiac defects, and behavioral abnormalities may also occur. The phenotype is variable (summary by Bina et al., 2020).
Ritscher-Schinzel syndrome 4- MedGen UID:
- 1794149
- •Concept ID:
- C5561939
- •
- Disease or Syndrome
Ritscher-Schinzel syndrome-4 (RTSC4) is characterized by a constellation of congenital anomalies, including dysmorphic craniofacial features and structural brain anomalies, such as Dandy-Walker malformation (220200), hindbrain malformations, or agenesis of the corpus callosum, associated with global developmental delay and impaired intellectual development. Congenital cardiac defects have been reported in 1 family (summary by Ritscher et al., 1987 and Jeanne et al., 2021).
For a discussion of genetic heterogeneity of Ritscher-Schinzel syndrome, see RTSC1 (220210).
Cutis laxa, autosomal recessive, type 2E- MedGen UID:
- 1794154
- •Concept ID:
- C5561944
- •
- Disease or Syndrome
Autosomal recessive cutis laxa type IIE (ARCL2E) is characterized by connective tissue features, including generalized cutis laxa and inguinal hernia, craniofacial dysmorphology, variable mild heart defects, and prominent skeletal features, including craniosynostosis, short stature, brachydactyly, clinodactyly, and syndactyly (Pottie et al., 2021).
For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive- MedGen UID:
- 1794157
- •Concept ID:
- C5561947
- •
- Disease or Syndrome
Autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B) is characterized by severe generalized muscle weakness apparent from birth; decreased fetal movements may be apparent in utero. Affected infants have generalized hypotonia with poor cry and feeding, head lag, and facial muscle weakness with ptosis. Some patients may have respiratory involvement. Electrophysiologic studies show decreased compound muscle action potentials (CMAPs) and a decremental response to repetitive nerve stimulation. Treatment with 3,4-diaminopyridine and pyridostigmine may result in clinical improvement (summary by Bauche et al., 2020).
VISS syndrome- MedGen UID:
- 1794165
- •Concept ID:
- C5561955
- •
- Disease or Syndrome
VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).
Developmental delay, impaired speech, and behavioral abnormalities- MedGen UID:
- 1794167
- •Concept ID:
- C5561957
- •
- Disease or Syndrome
Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021).
Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction- MedGen UID:
- 1794173
- •Concept ID:
- C5561963
- •
- Disease or Syndrome
Congenital central hypoventilation syndrome-2 and autonomic dysfunction (CCHS2) is an autosomal recessive disorder characterized by shallow breathing and apneic spells apparent in the neonatal period. Affected infants require mechanical ventilation due to impaired ventilatory response to hypercapnia, as well as tube feeding due to poor swallowing, aspiration, and gastrointestinal dysmotility. Some patients have other features of autonomic dysfunction, including bladder dysfunction, sinus bradycardia, and temperature dysregulation. Although mild global developmental delay with learning difficulties and seizures were present in the single family reported, it was unclear if these features were related to the hypoventilation phenotype (Spielmann et al., 2017).
For a discussion of genetic heterogeneity of CCHS, see CCHS1 (209880).
Aicardi-Goutieres syndrome 9- MedGen UID:
- 1794176
- •Concept ID:
- C5561966
- •
- Disease or Syndrome
Aicardi-Goutieres syndrome-9 (AGS9) is a type I interferonopathy characterized by severe developmental delay and progressive neurologic deterioration. Patients present in infancy with irritability and spasticity. Brain imaging shows diffusely abnormal white matter, cerebral atrophy, and intracranial calcification. Premature death has been associated with renal and/or hepatic failure (Uggenti et al., 2020).
For a general phenotypic description and discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).
Chopra-Amiel-Gordon syndrome- MedGen UID:
- 1794185
- •Concept ID:
- C5561975
- •
- Disease or Syndrome
Chopra-Amiel-Gordon syndrome (CAGS) is an autosomal dominant disorder characterized by developmental delay and/or impaired intellectual development, speech delay, facial dysmorphism, and variable other features, including recurrent bacterial infections, ophthalmologic abnormalities, and nonspecific brain abnormalities (Chopra et al., 2021).
Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome- MedGen UID:
- 1794190
- •Concept ID:
- C5561980
- •
- Disease or Syndrome
Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is an autosomal recessive systemic disorder characterized by progressive muscle weakness, sensorineural hearing loss, and endocrine abnormalities, mainly primary amenorrhea due to ovarian insufficiency. Features of the disorder appear soon after birth, although endocrine anomalies are not noted until puberty. The severity of the phenotype is variable: some patients may lose ambulation and have significant respiratory insufficiency, whereas others retain the ability to walk (Foley et al., 2020).
Charcot-Marie-Tooth disease, axonal, type 2FF- MedGen UID:
- 1794191
- •Concept ID:
- C5561981
- •
- Disease or Syndrome
Charcot-Marie-Tooth disease type 2FF (CMT2FF) is an autosomal dominant progressive axonal sensorimotor peripheral neuropathy characterized by early-childhood onset of difficulties walking or running due to atrophy and weakness of the lower limbs. Most patients have foot and ankle deformities, requiring surgery or walking aids. Some patients lose independent ambulation. There is also prominent involvement of the upper limbs, with weakness and atrophy of the forearm, wrist, and intrinsic hand muscles. Proximal muscle function is preserved. Affected individuals have variable distal sensory impairment. Most patients have hyporeflexia, although brisk reflexes, suggesting upper motor involvement, have been described in 1 family. Sural nerve biopsy showed abnormal myelination (Rebelo et al., 2021).
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).
Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities- MedGen UID:
- 1794194
- •Concept ID:
- C5561984
- •
- Disease or Syndrome
Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC) is an autosomal dominant disorder characterized by dysmorphic craniofacial features associated with mild developmental delay, mildly impaired intellectual development or learning difficulties, speech delay, and behavioral abnormalities. About half of patients have congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital cardiac defects, including septal defects (Connaughton et al., 2020).
Congenital disorder of glycosylation, type IIw- MedGen UID:
- 1794196
- •Concept ID:
- C5561986
- •
- Disease or Syndrome
Congenital disorder of glycosylation type IIw (CDG2W) is an autosomal dominant metabolic disorder characterized by liver dysfunction, coagulation deficiencies, and profound abnormalities in N-glycosylation of serum specific proteins. All reported patients carry the same mutation (602671.0017) (summary by Ng et al., 2021).
For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).
Pontocerebellar hypoplasia, type 16- MedGen UID:
- 1794197
- •Concept ID:
- C5561987
- •
- Disease or Syndrome
Pontocerebellar hypoplasia type 16 (PCH16) is an autosomal recessive severe neurodevelopmental disorder characterized by hypotonia and severe global developmental delay apparent from early infancy. Although the severity of the disorder is variable, most affected individuals achieve only a few, if any, developmental milestones. Most are unable to walk or speak, have eye abnormalities with poor visual contact, and develop early-onset epilepsy. Other features may include stereotypic movements, spasticity, and progressive microcephaly. Brain imaging shows pontocerebellar hypoplasia, often with thin corpus callosum, atrophy of the thalamus and basal ganglia, enlarged ventricles, and white matter abnormalities (summary by Ucuncu et al., 2020).
For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Short stature, impaired intellectual development, microcephaly, hypotonia, and ocular anomalies- MedGen UID:
- 1794208
- •Concept ID:
- C5561998
- •
- Disease or Syndrome
SIMHA syndrome is characterized by short stature, impaired intellectual development, microcephaly, hypotonia, and ocular anomalies. Inter- and intrafamilial phenotypic variability has been observed (Kambouris et al., 2014; Zahra et al., 2020).
Muscular dystrophy, limb-girdle, autosomal recessive 27- MedGen UID:
- 1794212
- •Concept ID:
- C5562002
- •
- Disease or Syndrome
Autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27) is characterized by progressive muscle weakness primarily affecting the lower limbs and resulting in walking difficulty or loss of ambulation. The age at onset is highly variable, from infancy to young adulthood. Patients with infantile onset may have a more severe disease course with rapid progression. Upper limb involvement and distal muscle weakness may also occur. Additional more variable features include neck muscle weakness, scoliosis, and joint contractures. Less common features include impaired intellectual development or speech delay, cardiomyopathy, and cardiac arrhythmia. Muscle biopsy shows nonspecific dystrophic changes (Coppens et al., 2021).
For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Charcot-Marie-Tooth disease, axonal, Type 2HH- MedGen UID:
- 1794213
- •Concept ID:
- C5562003
- •
- Disease or Syndrome
Axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH) is an autosomal dominant peripheral neuropathy characterized predominantly by onset of vocal cord weakness resulting in stridor in infancy or early childhood. The vocal cord paresis remains throughout life and may be severe enough to require tracheostomy. Additional features of the disorder usually include pes cavus and scoliosis. Some patients have mild distal muscle weakness and atrophy primarily affecting the lower limbs, although the upper limbs may also be involved, and distal sensory impairment, often with hyporeflexia (Sullivan et al., 2020).
For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Cerebellar ataxia, brain abnormalities, and cardiac conduction defects- MedGen UID:
- 1794215
- •Concept ID:
- C5562005
- •
- Disease or Syndrome
Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC) is an autosomal recessive primarily neurologic disorder with variable manifestations. Common features included infantile-onset hypotonia, poor motor development, poor feeding and overall growth, and ataxic gait due to cerebellar ataxia. Other features include dysarthria, nystagmus, variable ocular anomalies, spasticity, hyperreflexia, and nonspecific dysmorphic features. Most, but not all, patients have global developmental delay with impaired intellectual development and speech delay. Brain imaging shows cerebellar hypoplasia, often with brainstem hypoplasia, enlarged ventricles, delayed myelination, and thin corpus callosum. A significant number of patients develop cardiac conduction defects in childhood or adolescence, often requiring pacemaker placement (summary by Slavotinek et al., 2020).
Neurodevelopmental disorder with hearing loss and spasticity- MedGen UID:
- 1794234
- •Concept ID:
- C5562024
- •
- Disease or Syndrome
Neurodevelopmental disorder with hearing loss and spasticity (NEDHLS) is characterized by hearing loss, global developmental delay/impaired intellectual development, spastic-dystonic cerebral palsy, focal or generalized epilepsy, and microcephaly. Some children present with hypotonia (Richard et al., 2021).
Zaki syndrome- MedGen UID:
- 1794247
- •Concept ID:
- C5562037
- •
- Disease or Syndrome
Zaki syndrome (ZKS) is characterized by developmental delay, progressive microcephaly, and short stature, as well as dysmorphic features including sparse scalp hair, cupped ears, wide nose and mouth, short philtrum, and high-arched palate. Other variable features have been observed, including ocular, skeletal, cardiac, and renal anomalies (Chai et al., 2021).
Loeys-Dietz syndrome 6- MedGen UID:
- 1794251
- •Concept ID:
- C5562041
- •
- Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Mucopolysaccharidosis, type 10- MedGen UID:
- 1794274
- •Concept ID:
- C5562064
- •
- Disease or Syndrome
Mucopolysaccharidosis type X (MPS10) is an autosomal recessive childhood-onset disorder associated with disproportionate short-trunk short stature and skeletal, cardiac, and ophthalmologic abnormalities (Verheyen et al., 2022).
Yoon-Bellen neurodevelopmental syndrome- MedGen UID:
- 1794276
- •Concept ID:
- C5562066
- •
- Disease or Syndrome
Yoon-Bellen neurodevelopmental syndrome (YOBELN) is an autosomal recessive disorder characterized mainly by global developmental delay with variably impaired intellectual development. The manifestations and severity of the phenotype are highly variable. Additional neurologic features may include hypotonia, spasticity, ataxia, hearing loss, visual problems, seizures, and nonspecific anomalies on brain imaging (summary by Yap et al., 2021).
Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome- MedGen UID:
- 1798652
- •Concept ID:
- C5567229
- •
- Disease or Syndrome
A rare genetic neurological disorder with characteristics of early-onset severe global developmental delay with regression, congenital or acquired microcephaly, hearing loss, truncal hypotonia, appendicular spasticity, and dystonia and/or myoclonus. Additional reported manifestations include seizures, optic atrophy, cortical visual impairment, scoliosis, and dysphagia. Brain imaging shows pontine hypoplasia, partial agenesis of the corpus callosum, and diffuse cerebral atrophy with relative sparing of the cerebellum.
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3- MedGen UID:
- 1798903
- •Concept ID:
- C5567480
- •
- Disease or Syndrome
Infantile hypotonia with psychomotor retardation and characteristic facies-3 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Most affected individuals show very poor, if any, normal psychomotor development, poor speech, and inability to walk independently (summary by Bhoj et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).
Autosomal recessive spastic paraplegia type 76- MedGen UID:
- 1798906
- •Concept ID:
- C5567483
- •
- Disease or Syndrome
Spastic paraplegia-76 is an autosomal recessive neurologic disorder characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. Cognition is unaffected (summary by Gan-Or et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome- MedGen UID:
- 1799985
- •Concept ID:
- C5568562
- •
- Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome- MedGen UID:
- 1800305
- •Concept ID:
- C5568882
- •
- Disease or Syndrome
A rare genetic multiple congenital anomalies/dysmorphic syndrome with characteristics of global developmental delay and intellectual disability, progressive spondyloepimetaphyseal dysplasia, short stature, short fourth metatarsals and dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose, depressed nasal bridge, full lips, small, low-set ears and short neck). Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described.
Charcot-Marie-Tooth disease axonal type 2Z- MedGen UID:
- 1800448
- •Concept ID:
- C5569025
- •
- Disease or Syndrome
Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant axonal peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood. Rare occurrence of global developmental delay with impaired intellectual development or learning difficulties has been observed. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN), which highlights the clinical spectrum associated with MORC2 mutations and may render the classification of patients into one or the other disorder challenging (summary by Sevilla et al., 2016, Ando et al., 2017, Guillen Sacoto et al., 2020).
For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Schaaf-Yang syndrome- MedGen UID:
- 1807366
- •Concept ID:
- C5575066
- •
- Disease or Syndrome
Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism.
Carey-Fineman-Ziter syndrome 1- MedGen UID:
- 1804638
- •Concept ID:
- C5676876
- •
- Disease or Syndrome
Carey-Fineman-Ziter syndrome-1 (CFZS1) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS1 may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016).
Di Gioia et al. (2017) determined that CFZS1 represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion.
Genetic Heterogeneity of Carey-Fineman-Ziter Syndrome
Carey-Fineman-Ziter syndrome-2 (CFZS2) is caused by mutation in the MYMX gene (619912) on chromosome 6p21.
Stüve-Wiedemann syndrome 1- MedGen UID:
- 1803541
- •Concept ID:
- C5676888
- •
- Disease or Syndrome
Stuve-Wiedemann syndrome is an autosomal recessive disorder characterized by bowing of the long bones and other skeletal anomalies, episodic hyperthermia, respiratory distress, and feeding difficulties usually resulting in early death (Dagoneau et al., 2004).
See also 'classic' Schwartz-Jampel syndrome type 1 (SJS1; 255800), a phenotypically similar but genetically distinct disorder caused by mutation in the HSPG2 gene (142461) on chromosome 1p36.
Genetic Heterogeneity of Stuve-Wiedemann Syndrome
Stuve-Wiedemann syndrome-2 (STWS2; 619751) is caused by mutation in the IL6ST gene (600694) on chromosome 5q11.
Intellectual developmental disorder, autosomal recessive 73- MedGen UID:
- 1802013
- •Concept ID:
- C5676902
- •
- Mental or Behavioral Dysfunction
Autosomal recessive intellectual developmental disorder-73 (MRT73) is characterized by global developmental delay with hypotonia and mildly delayed walking, impaired intellectual development with poor or absent speech, and mildly dysmorphic features (summary by Morrison et al., 2021).
Hypogonadotropic hypogonadism 26 with or without anosmia- MedGen UID:
- 1811919
- •Concept ID:
- C5676903
- •
- Disease or Syndrome
HH26 is characterized by micropenis and cryptorchidism at birth in male patients, and absent puberty and anosmia in male or female patients. Some affected individuals also exhibit craniosynostosis (Davis et al., 2020).
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'
For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.
Intellectual disability and myopathy syndrome- MedGen UID:
- 1808193
- •Concept ID:
- C5676904
- •
- Disease or Syndrome
Intellectual disability and myopathy syndrome (IDMYS) is an autosomal recessive developmental disorder characterized by global developmental delay with mildly impaired intellectual development, hypotonia, muscle weakness and fatigue, and white matter abnormalities on brain imaging. Variable additional features may include sensorineural hearing loss, dysmorphic facies, and progressive heart disease (summary by Smeland et al., 2019).
Bryant-Li-Bhoj neurodevelopmental syndrome 2- MedGen UID:
- 1811435
- •Concept ID:
- C5676906
- •
- Disease or Syndrome
Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020).
For a discussion of genetic heterogeneity of Bryant-Li-Bhoj neurodevelopmental syndrome, see BRYLIB1 (619720).
Spastic paraplegia 86, autosomal recessive- MedGen UID:
- 1801286
- •Concept ID:
- C5676910
- •
- Disease or Syndrome
Autosomal recessive spastic paraplegia-86 (SPG86) is a complex neurologic disorder characterized by global developmental delay apparent from early childhood combined with early-onset progressive spasticity mainly affecting the lower limbs, but also affecting the upper limbs. Affected individuals have hyperreflexia, extensor plantar responses, pyramidal signs, and difficulty walking or inability to walk. Some may have joint contractures and foot or ankle deformities. Patients with SPG86 have impaired intellectual development with poor or absent speech, often with behavioral abnormalities. Brain imaging shows thin corpus callosum and white matter abnormalities. Rare patients may have seizures. The disorder is thus a complicated form of SPG (summary by Yahia et al., 2021, Miyake et al., 2022).
For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Combined oxidative phosphorylation deficiency 54- MedGen UID:
- 1812715
- •Concept ID:
- C5676912
- •
- Disease or Syndrome
Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by Hochberg et al., 2021).
For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Immunodeficiency 94 with autoinflammation and dysmorphic facies- MedGen UID:
- 1802872
- •Concept ID:
- C5676918
- •
- Disease or Syndrome
Immunodeficiency-94 with autoinflammation and dysmorphic facies (IMD94) is a systemic immunologic disorder with onset in early infancy. Primary features include lymphadenopathy, autoinflammation, immunodeficiency with hypogammaglobulinemia, and dysmorphic facial features. Intellectual development is normal and serum IgE is not elevated. The disease results from constitutive activation of the IL6 signaling cascade, resulting in immune dysregulation and a hyperinflammatory state (summary by Materna-Kiryluk et al., 2021).
Stuve-Wiedemann syndrome 2- MedGen UID:
- 1805977
- •Concept ID:
- C5676919
- •
- Disease or Syndrome
Stuve-Wiedemann syndrome-2 (STWS2) is an autosomal recessive lethal skeletal dysplasia characterized by short stature, small chest, bowing of the long bones, and neonatal cardiopulmonary and autonomous dysfunction. Additional variable features include congenital thrombocytopenia, eczematoid dermatitis, renal anomalies, and defective acute-phase response (Chen et al., 2020).
For a general phenotypic description and discussion of genetic heterogeneity of Stuve-Wiedemann syndrome, see STWS1 (601559).
Hyper-IgE recurrent infection syndrome 4A, autosomal dominant- MedGen UID:
- 1809613
- •Concept ID:
- C5676920
- •
- Disease or Syndrome
Hyper-IgE syndrome-4A with recurrent infections (HIES4A) is an autosomal dominant immunologic disorder characterized by recurrent, mainly sinopulmonary infections associated with increased serum IgE. The phenotype is variable, even within families. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures. The IL6ST mutations are loss-of-function, although the truncated mutant proteins are expressed and interfere with the wildtype protein in a dominant-negative manner by disrupting IL6 (147620) and IL11 (147681) signaling (summary by Beziat et al., 2020).
For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).
Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism- MedGen UID:
- 1808634
- •Concept ID:
- C5676924
- •
- Disease or Syndrome
Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism (CDIDHH) is characterized by delayed motor development, ataxia, severe progressive scoliosis, moderate to severe intellectual disability, and delayed sexual development. Cerebellar hypoplasia has been observed in some patients (Whittaker et al., 2021).
Kury-Isidor syndrome- MedGen UID:
- 1807460
- •Concept ID:
- C5676925
- •
- Disease or Syndrome
Kury-Isidor syndrome (KURIS) is a neurodevelopmental disorder with a highly variable phenotype. It is characterized mainly by mild global developmental delay apparent from infancy or early childhood with walking delayed by a few years and speech delay, often with language deficits. Intellectual development may be mildly delayed, borderline, or even normal; most patients have behavioral problems, including autism. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and nonspecific dysmorphic facial features (summary by Kury et al., 2022).
Developmental and epileptic encephalopathy 100- MedGen UID:
- 1809351
- •Concept ID:
- C5676932
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-100 (DEE100) is a severe neurologic disorder characterized by global developmental delay and onset of variable types of seizures in the first months or years of life. Most patients have refractory seizures and show developmental regression after seizure onset. Affected individuals have ataxic gait or inability to walk and severe to profoundly impaired intellectual development, often with absent speech. Additional more variable features may include axial hypotonia, hyperkinetic movements, dysmorphic facial features, and brain imaging abnormalities (summary by Schneider et al., 2021).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Neurodevelopmental disorder with central hypotonia and dysmorphic facies- MedGen UID:
- 1807420
- •Concept ID:
- C5676944
- •
- Disease or Syndrome
Neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF) is an autosomal dominant disorder characterized by global developmental delay, impaired intellectual development, seizures, distinctive facial features, scoliosis, delayed closure of the anterior fontanel, and nonspecific brain abnormalities (Wakeling et al., 2021).
Aortic aneurysm, familial thoracic 12- MedGen UID:
- 1802657
- •Concept ID:
- C5676959
- •
- Disease or Syndrome
Familial thoracic aortic aneurysm-12 (AAT12) is characterized by dilation of the arterial wall associated with a progressive loss of its ability to withstand the wall tension generated by high intraluminal pressure, which can lead to intramural or complete acute vessel wall rupture. Some patients have dolichostenomelia (summary by Elbitar et al., 2021).
For a general phenotypic description and a discussion of genetic heterogeneity of thoracic aortic aneurysm, see AAT1 (607086).
Neurodevelopmental disorder with neuromuscular and skeletal abnormalities- MedGen UID:
- 1803456
- •Concept ID:
- C5676965
- •
- Disease or Syndrome
Neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS) is an autosomal recessive disorder characterized by global developmental delay apparent from infancy or early childhood. The severity of the disorder is highly variable. Affected individuals show impaired intellectual development and motor delay associated with either severe hypotonia or hypertonia and spasticity. Most affected individuals have skeletal defects and dysmorphic facial features. Some may have ocular or auditory problems, peripheral neuropathy, behavioral abnormalities, and nonspecific findings on brain imaging (Kurolap et al., 2022).
Intellectual developmental disorder, autosomal dominant 66- MedGen UID:
- 1812470
- •Concept ID:
- C5677000
- •
- Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-66 (MRD66) is characterized by global developmental delay with mildly to moderately impaired intellectual development and mild speech delay. The phenotype and severity are highly variable. Some patients have behavioral problems or autism spectrum disorder, and about 50% have variable types of seizures. Additional features may include nonspecific dysmorphic facial features, tall or short stature, and mild skeletal anomalies (Rahimi et al., 2022).
Carey-Fineman-Ziter syndrome 2- MedGen UID:
- 1800921
- •Concept ID:
- C5677012
- •
- Disease or Syndrome
Carey-Fineman-Ziter syndrome-2 (CFZS2) is an autosomal recessive disorder characterized by weakness of the facial musculature, hypomimic facies, increased overbite, micrognathia, and facial dysmorphism. Other features may include failure to thrive, axial hypotonia, and progressive scoliosis (Ramirez-Martinez et al., 2022).
For a discussion of genetic heterogeneity of Carey-Fineman-Ziter syndrome, see CFZS1 (254940).
Tessadori-Van Haaften neurodevelopmental syndrome 4- MedGen UID:
- 1804234
- •Concept ID:
- C5677016
- •
- Disease or Syndrome
Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4) is characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022).
For a discussion of genetic heterogeneity of TEBIVANED, see TEBIVANED1 (619758).
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1- MedGen UID:
- 1808104
- •Concept ID:
- C5677021
- •
- Disease or Syndrome
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1) is characterized by cranial involvement with macrocrania at birth, brachycephaly, anomalies of middle fossa structures including hypoplasia of corpus callosum, enlargement of septum pellucidum, and dilated lateral ventricles, as well as cortical atrophy and hypodensity of the gray matter. Facial dysmorphisms include flat face, hypertelorism, epicanthal folds, synophrys, broad nasal bridge, cleft lip and cleft palate, and low-set posteriorly rotated ears. Patients also exhibit short neck and multiple costal and vertebral anomalies. The face is rather characteristic, and various authors have consistently reported affable/friendly personality, despite intellectual delay (summary by Alanay et al., 2014).
Genetic Heterogeneity of Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome
CFSMR2 (616994) is caused by mutation in the RAB5IF gene (619960) on chromosome 20q11.
Chilton-Okur-Chung neurodevelopmental syndrome- MedGen UID:
- 1803276
- •Concept ID:
- C5677022
- •
- Disease or Syndrome
Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (Chilton et al., 2020).
Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies- MedGen UID:
- 1823969
- •Concept ID:
- C5774196
- •
- Disease or Syndrome
Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies (NEDITPO) is an autosomal recessive multiple congenital anomaly syndrome characterized by mild to moderate intellectual disability, dysmorphic facial features, intention tremor, dyspraxia, and vertical strabismus (Rahikkala et al., 2022).
Intellectual developmental disorder with autism and dysmorphic facies- MedGen UID:
- 1823979
- •Concept ID:
- C5774206
- •
- Disease or Syndrome
Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is an autosomal recessive neurodevelopmental disorder characterized by moderate to severely impaired cognitive development associated with behavioral abnormalities, including autism spectrum disorder. Affected individuals have variable dysmorphic facial features (Al-Amri et al., 2022)
Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures- MedGen UID:
- 1823981
- •Concept ID:
- C5774208
- •
- Disease or Syndrome
Neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures (NEDMIMS) is an autosomal recessive disorder characterized by severe global developmental delay apparent from infancy, impaired intellectual development, progressive microcephaly, and early-onset seizures that may be refractory to treatment. Affected individuals have poor overall growth and may have various movement abnormalities, including hypo- and hypertonia. Behavioral problems may also be observed (Klockner et al., 2022).
Charcot-Marie-Tooth disease, axonal, IIa 2II- MedGen UID:
- 1824000
- •Concept ID:
- C5774227
- •
- Disease or Syndrome
Axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is an autosomal dominant neurologic disorder characterized by a slowly progressive sensorimotor peripheral neuropathy affecting mainly the lower limbs, resulting in distal muscle weakness and atrophy and subsequent walking difficulties. Some patients may have upper limb involvement with atrophy of the intrinsic hand muscles. The age at onset is highly variable, ranging from infancy to adulthood. Electrophysiologic studies are usually consistent with an axonal process, although some may show intermediate or even demyelinating values (Park et al., 2020; Ando et al., 2022). One family with possible autosomal recessive inheritance has been reported (Bogdanova-Mihaylova et al., 2021).
For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities- MedGen UID:
- 1824004
- •Concept ID:
- C5774231
- •
- Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities (NEDDFSB) is a multisystemic developmental disorder characterized by feeding difficulties, poor overall growth, and global developmental delay with moderate to severely impaired intellectual development and poor or absent speech. Affected individuals have dysmorphic facial features and skeletal defects, mainly affecting the distal extremities. More variable additional findings include hypotonia, seizures, and ocular defects. Brain imaging tends to show structural defects of the corpus callosum and cerebellar hypoplasia (Duijkers et al., 2019).
Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects- MedGen UID:
- 1824008
- •Concept ID:
- C5774235
- •
- Disease or Syndrome
Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects (NEDCDS) is characterized by global developmental delay, severely impaired intellectual development with poor or absent speech, characteristic facial features, and variable skeletal abnormalities. Additional features include feeding difficulties, inability to walk or walking with an abnormal gait, and cerebellar or other abnormalities on brain imaging (Reichert et al., 2020).
Developmental delay with variable intellectual disability and dysmorphic facies- MedGen UID:
- 1824015
- •Concept ID:
- C5774242
- •
- Disease or Syndrome
Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF) is a clinically heterogeneous disorder characterized by neurologic deficits and characteristic dysmorphic facial features apparent from infancy or early childhood. Affected individuals usually show impaired intellectual development, speech delay, learning difficulties, and/or behavioral problems. Additional features may include hypotonia, hand or foot deformities, and palatal defects (Verberne et al., 2021; Verberne et al., 2022).
Developmental delay, language impairment, and ocular abnormalities- MedGen UID:
- 1824035
- •Concept ID:
- C5774262
- •
- Disease or Syndrome
Developmental delay, language impairment, and ocular abnormalities (DEVLO) is characterized by delayed acquisition of skills particularly affecting speech and language development, although many patients show mild motor delay. Most affected individuals also have a small head circumference (down to -3 SD) and may have mild dysmorphic features. Variable ocular anomalies include strabismus, cataracts, and cortical visual impairment. Older patients require special schooling and often demonstrate behavioral abnormalities (Laboy Cintron et al., 2022).
Congenital disorder of glycosylation, type IIy- MedGen UID:
- 1824067
- •Concept ID:
- C5774294
- •
- Disease or Syndrome
Congenital disorder of glycosylation type IIy (CDG2Y) is an autosomal recessive multisystemic congenital disorder characterized by poor overall growth and global developmental delay with impaired intellectual development. Other features may include hypotonia, seizures, brain imaging abnormalities, dysmorphic features, and various skeletal defects. Laboratory studies show a subtle type II glycosylation defect of serum transferrin (Tambe et al., 2020).
For a general discussion of CDGs, see CDG1A (212065).
Tessadori-Van Haaften neurodevelopmental syndrome 3- MedGen UID:
- 1824083
- •Concept ID:
- C5774310
- •
- Disease or Syndrome
Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022).
For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758).
Hogue-Janssens syndrome 1- MedGen UID:
- 1830493
- •Concept ID:
- C5779996
- •
- Disease or Syndrome
PPP2R5D-related neurodevelopmental disorder is characterized by mild to severe neurodevelopmental delay. Pronounced hypotonia with delay in gross motor skills is common. Onset of independent walking varies widely and ataxia is reported. All reported individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is reported in six individuals. Macrocephaly is common. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Additional anomalies include skeletal, endocrine, and cardiac malformations, each reported in a few individuals. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported.
Intellectual developmental disorder, X-linked 112- MedGen UID:
- 1840225
- •Concept ID:
- C5829589
- •
- Disease or Syndrome
X-linked intellectual disorder-112 (XLID112) is a neurodevelopmental disorder characterized by developmental delay, with speech delay more prominent than motor delay, autism or autism traits, and variable dysmorphic features. Affected females have been reported, which appears to be related to skewed X-inactivation (summary by Hiatt et al., 2023).
Congenital myopathy 4B, autosomal recessive- MedGen UID:
- 1840525
- •Concept ID:
- C5829889
- •
- Disease or Syndrome
Congenital myopathy-4B (CMYO4B) is an autosomal recessive disorder of the skeletal muscle characterized by the onset of muscle weakness in infancy or early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show congenital contractures, delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty walking or inability to walk. Affected individuals have respiratory insufficiency due to muscle weakness, which may be life-threatening. Other common features include myopathic facies, chest deformities, distal joint laxity, and scoliosis. Variable histologic findings on skeletal muscle biopsy are observed, including nemaline rods, type 1 fiber predomination, and centralized nuclei (Tan et al., 1999; Lehtokari et al., 2008).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures- MedGen UID:
- 1840880
- •Concept ID:
- C5830244
- •
- Disease or Syndrome
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures (NEDFSS), is characterized by these features and global developmental delay with delayed or absent walking, moderate to severely impaired intellectual development, and poor or absent speech acquisition. Affected individuals may also have behavioral abnormalities. About half of patients develop various types of seizures that are usually well-controlled with medication. Rare patients are noted to have heat intolerance or insensitivity to pain (Lines et al., 2022).
Congenital myopathy 18- MedGen UID:
- 1840919
- •Concept ID:
- C5830283
- •
- Disease or Syndrome
Congenital myopathy-18 (CMYO18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood. Most affected individuals show delayed motor development with generalized hypotonia and progressive axial and limb muscle weakness beginning soon after birth or in infancy. Additional features may include swallowing difficulties, external ophthalmoplegia, ptosis, high-arched palate, and respiratory insufficiency, which can lead to death in severe cases. Muscle biopsy shows variable morphologic abnormalities, including alveolar changes in the intermyofibrillar network, fiber size variability, focal disorganization, internal nuclei, and dilated sarcoplasmic reticulum and T-tubules. The disorder results from a defect in excitation-contraction coupling in skeletal muscle (Schartner et al., 2017; Ravenscroft et al., 2021; Mauri et al., 2021; Yis et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum- MedGen UID:
- 1840932
- •Concept ID:
- C5830296
- •
- Disease or Syndrome
Neurodevelopmental disorder with seizures, spasticity, and partial or complete agenesis of the corpus callosum (NEDSSCC) is an autosomal recessive disorder characterized by axial hypotonia and global developmental delay apparent from the first days or months of life. Affected individuals often have feeding difficulties and develop early-onset seizures that tend to be well-controlled. Other features include peripheral spasticity with hyperreflexia, variable dysmorphic features, impaired intellectual development, behavioral abnormalities, and hypoplasia or absence of the corpus callosum on brain imaging (Faqeih et al., 2023).
Leukodystrophy, hypomyelinating, 26, with chondrodysplasia- MedGen UID:
- 1840948
- •Concept ID:
- C5830312
- •
- Disease or Syndrome
Hypomyelinating leukodystrophy-26 with chondrodysplasia (HLD26) is characterized by severe psychomotor delay, predominantly involving motor and expressive language development, with cerebral and cerebellar atrophy and corpus callosum hypoplasia. In addition, patients show pre- and postnatal growth retardation, early-onset scoliosis, and dislocations of large joints (Guasto et al., 2022).
For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see HLD1 (312080).
Amyotrophic lateral sclerosis 27, juvenile- MedGen UID:
- 1840995
- •Concept ID:
- C5830359
- •
- Disease or Syndrome
Juvenile amyotrophic lateral sclerosis-27 (ALS27) is an autosomal dominant disorder characterized by early childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities, followed by progressive lower motor neuron-mediated weakness without sensory signs or symptoms (Mohassel et al., 2021).
For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Congenital myopathy 20- MedGen UID:
- 1841029
- •Concept ID:
- C5830393
- •
- Disease or Syndrome
Congenital myopathy-20 (CMYO20) is an autosomal recessive neuromuscular disorder that shows wide phenotypic variability. Some patients present in early childhood with proximal muscle weakness affecting the lower and upper limbs resulting in difficulties running and climbing, whereas others present soon after birth with congenital limb or distal contractures. Additional features may include dysmorphic facial features and global developmental delay. Skeletal muscle biopsy may show nemaline rods (Nilipour et al., 2018; Pehlivan et al., 2019).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Cortical dysplasia, complex, with other brain malformations 12- MedGen UID:
- 1841043
- •Concept ID:
- C5830407
- •
- Disease or Syndrome
Complex cortical dysplasia with other brain malformations-12 (CDCBM12) is an autosomal recessive disorder of developmental neuronal migration characterized by severe to profound neurodevelopmental delay with absent speech, central hypotonia, peripheral spasticity, cortical visual impairment, and dysmorphic craniofacial features. Affected individuals usually have feeding difficulties and show minimal developmental progress of motor or cognitive skills. Most have microcephaly and develop early-onset refractory seizures. Brain imaging shows cortical abnormalities, such as lissencephaly and pachygyria, as well as other brain malformations, including thin or absent corpus callosum, dysplastic basal ganglia, and mild cerebellar hypoplasia. Due to the function of CAMSAP1 in microtubule stability and maintenance, this disorder can be classified as a 'tubulinopathy' (Khalaf-Nazzal et al., 2022).
For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).
Congenital myopathy 22A, classic- MedGen UID:
- 1841089
- •Concept ID:
- C5830453
- •
- Disease or Syndrome
Classic congenital myopathy-22A (CMYO22A) is an autosomal recessive muscle disorder characterized by onset of muscle weakness in utero or soon after birth. Early features may include fetal hypokinesia, breech presentation, and polyhydramnios. Affected individuals are born with severe hypotonia and require respiratory and feeding assistance. Those who survive the neonatal period show a 'classic' phenotype of congenital myopathy with delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. Some have persistent respiratory insufficiency; dysmorphic facial features may be present (Zaharieva et al., 2016).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Congenital myopathy 22B, severe fetal- MedGen UID:
- 1841137
- •Concept ID:
- C5830501
- •
- Disease or Syndrome
Severe fetal congenital myopathy-22B (CMYO22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016).
For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).
Nemaline myopathy 5B, autosomal recessive, childhood-onset- MedGen UID:
- 1841181
- •Concept ID:
- C5830545
- •
- Disease or Syndrome
Autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B) is a skeletal muscle disorder in which patients usually present with proximal muscle weakness of the lower and upper limbs in a limb-girdle distribution, resulting in gait abnormalities; however, most remain ambulatory even into late adulthood. Some affected individuals show delayed motor development. There is axial weakness and atrophy of the paraspinal muscles, along with kyphosis, scoliosis, and rigid spine, as well as variable limitations of the large joints. Most patients develop restrictive respiratory insufficiency with decreased forced vital capacity; some need noninvasive ventilation. Serum creatine kinase may be elevated. Muscle biopsy can show variable features, including nemaline rods, multiminicore lesions, endomysial fibrosis, and myofibrillar changes (Pellerin et al., 2020; Lee et al., 2022).
For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).
Nemaline myopathy 5C, autosomal dominant- MedGen UID:
- 1841185
- •Concept ID:
- C5830549
- •
- Disease or Syndrome
Autosomal dominant nemaline myopathy-5C (NEM5C) is a relatively mild skeletal muscle disorder with wide clinical variability, even within families. Affected individuals develop symptoms of muscle weakness in the first or second decades; those with earlier onset tend to have a more severe disease course. Features include difficulty walking on the heels, waddling gait, proximal muscle weakness affecting the upper and lower limbs, and Gowers sign. Additional features may include myopathic facies, high-arched palate, scoliosis or kyphosis, and ankle weakness. Patients remain ambulatory into late adulthood. Skeletal muscle biopsy shows hypotrophy of type 1 fibers, hypertrophy of type 2 fibers, fiber size variation, and myofibrillar disorganization. Nemaline rods in type 1 fibers are often observed, but are not always present (Konersman et al., 2017; Holling et al., 2022).
For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).
Spastic paraplegia 90A, autosomal dominant- MedGen UID:
- 1841210
- •Concept ID:
- C5830574
- •
- Disease or Syndrome
Autosomal dominant spastic paraplegia-90A (SPG90A) is characterized by motor impairment and progressive lower extremity spasticity as well as neurologic findings, cognitive impairment, and hearing loss (Srivastava et al., 2023).
For a discussion of genetic heterogeneity of autosomal dominant SPG, see SPG3A (182600).
Neurodevelopmental disorder with microcephaly and movement abnormalities- MedGen UID:
- 1841260
- •Concept ID:
- C5830624
- •
- Disease or Syndrome
Neurodevelopmental disorder with microcephaly and movement abnormalities (NEDMIM) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development with poor or absent speech, and delayed walking with an abnormal gait. Affected individuals may show hypotonia or hypertonia with spasticity, ataxia, and choreoathetoid movements. Most patients have microcephaly and short stature. Ophthalmic features, behavioral abnormalities, and nonspecific dysmorphic features are commonly observed. Additional more variable features include seizures, brain imaging abnormalities, and skeletal defects (Serey-Gaut et al., 2023).
Intellectual developmental disorder, autosomal dominant 73- MedGen UID:
- 1841272
- •Concept ID:
- C5830636
- •
- Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-73 (MRD73) is a highly variable neurodevelopmental disorder characterized by impaired intellectual development that ranges from mild to severe, speech delay, behavioral abnormalities, and nonspecific dysmorphic facial features (Janssen et al., 2022).
Neurodevelopmental disorder with language delay and variable cognitive abnormalities- MedGen UID:
- 1850358
- •Concept ID:
- C5882689
- •
- Disease or Syndrome
Neurodevelopmental disorder with language delay and variable cognitive abnormalities (NEDLC) is a phenotypically heterogeneous neurologic disorder. Affected individuals may show early motor delay, speech and language delay, impaired intellectual development, learning disabilities, and/or behavioral abnormalities, although the severity and manifestations vary widely. Repetitive behavior and sleep difficulties are commonly present. More severe features include seizures, hypotonia, ocular abnormalities, dysmorphic features, and psychiatric comorbidities (Cediel et al., 2022).
Fliedner-Zweier syndrome- MedGen UID:
- 1845438
- •Concept ID:
- C5882693
- •
- Disease or Syndrome
Fliedner-Zweier syndrome (FZS) is a neurodevelopmental disorder characterized by variable manifestations including mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies (Fliedner et al., 2020).
Spastic paraplegia 18a, autosomal dominant- MedGen UID:
- 1844217
- •Concept ID:
- C5882694
- •
- Disease or Syndrome
Spastic paraplegia-18A (SPG18A) is an autosomal dominant disorder characterized by a pure form of hereditary spastic paraplegia phenotype (summary by Rydning et al., 2018).
Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia- MedGen UID:
- 1846222
- •Concept ID:
- C5882701
- •
- Disease or Syndrome
Autosomal dominant spastic paraplegia-91 with or without cerebellar ataxia (SPG91) is a highly variable neurologic disorder characterized by early-onset gait abnormalities due to spastic paraplegia of the lower limbs, sometimes with cerebellar ataxia. The age at onset is highly variable (congenital to young adult), although most patients have symptom onset in the first decade. Some patients pre