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Joint hypermobility

MedGen UID:
336793
Concept ID:
C1844820
Finding
Synonyms: Extensible joints; Hyperextensibility of joints; Hyperextensible joints; Hypermobility of joints; Joint hyperextensibility; Joint mobility increased
SNOMED CT: Hypermobility of joint (788453008); Joint hypermobility (788453008); Range of joint movement increased (298181000)
 
HPO: HP:0001382

Definition

The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes. [from HPO]

Conditions with this feature

Complete trisomy 21 syndrome
MedGen UID:
4385
Concept ID:
C0013080
Disease or Syndrome
Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.
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.
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).
Wilson disease
MedGen UID:
42426
Concept ID:
C0019202
Disease or Syndrome
Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to older than 50 years; symptoms vary among and within families. Liver disease includes recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations include movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Psychiatric disturbance includes depression, neurotic behaviors, disorganization of personality, and, occasionally, intellectual deterioration. Kayser-Fleischer rings, frequently present, result from copper deposition in Descemet's membrane of the cornea and reflect a high degree of copper storage in the body.
Infantile cortical hyperostosis
MedGen UID:
43781
Concept ID:
C0020497
Disease or Syndrome
Caffey disease is characterized by massive subperiosteal new bone formation (usually involving the diaphyses of the long bones as well as the ribs, mandible, scapulae, and clavicles) typically associated with fever, joint swelling, and pain in children, with onset between birth and five months and spontaneous resolution by age two years. Episodes of recurrence of the manifestations of Caffey disease have been reported multiple times in individuals with the classic infantile presentation. Limited follow-up information suggests that adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, short stature, and an increased risk for bone fractures and/or deformities.
Menkes kinky-hair syndrome
MedGen UID:
44030
Concept ID:
C0022716
Disease or Syndrome
Menkes disease (MNK) is an X-linked recessive disorder characterized by generalized copper deficiency. The clinical features result from the dysfunction of several copper-dependent enzymes.
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.
Osteogenesis imperfecta type I
MedGen UID:
9799
Concept ID:
C0023931
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).
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.
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB
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.
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.
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.
Johanson-Blizzard syndrome
MedGen UID:
59798
Concept ID:
C0175692
Disease or Syndrome
Johanson-Blizzard syndrome is an autosomal recessive disorder characterized by poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency (summary by Al-Dosari et al., 2008).
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.
Williams syndrome
MedGen UID:
59799
Concept ID:
C0175702
Disease or Syndrome
Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones.
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.
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).
Cardiac valvular dysplasia, X-linked
MedGen UID:
78083
Concept ID:
C0262436
Disease or Syndrome
FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia.
Cohen syndrome
MedGen UID:
78539
Concept ID:
C0265223
Congenital Abnormality
Cohen syndrome is characterized by failure to thrive in infancy and childhood; truncal obesity in the teen years; early-onset hypotonia and developmental delays; microcephaly developing during the first year of life; moderate to profound psychomotor retardation; progressive retinochoroidal dystrophy and high myopia; neutropenia in many with recurrent infections and aphthous ulcers in some; a cheerful disposition; joint hypermobility; and characteristic facial features.
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).
Ehlers-Danlos syndrome, classic type, 1
MedGen UID:
78660
Concept ID:
C0268335
Disease or Syndrome
Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses.
Ehlers-Danlos syndrome, classic type, 2
MedGen UID:
120628
Concept ID:
C0268336
Disease or Syndrome
Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses.
Ehlers-Danlos syndrome, type 3
MedGen UID:
75670
Concept ID:
C0268337
Disease or Syndrome
Hypermobile Ehlers-Danlos syndrome (hEDS) is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can and do occur. The skin is often soft and may be mildly hyperextensible. Subluxations and dislocations are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint disease is common. Chronic pain, distinct from that associated with acute dislocations, is a serious complication of the condition and can be both physically and psychologically disabling. Easy bruising, functional bowel disorders, and cardiovascular autonomic dysfunction are common. Aortic root dilation, when present, is typically of a mild degree with no increased risk of dissection in the absence of significant dilation. Psychological dysfunction, psychosocial impairment, and emotional problems are common.
Ehlers-Danlos syndrome, type 4
MedGen UID:
82790
Concept ID:
C0268338
Disease or Syndrome
Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication.
Ehlers-Danlos syndrome, kyphoscoliotic type 1
MedGen UID:
75672
Concept ID:
C0268342
Disease or Syndrome
PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure.
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, autosomal recessive, type 1A
MedGen UID:
78663
Concept ID:
C0268351
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.
Cutis laxa, X-linked
MedGen UID:
82793
Concept ID:
C0268353
Congenital Abnormality
Occipital horn syndrome (OHS) is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995).
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.
Follicular atrophoderma and basal cell epitheliomata
MedGen UID:
87539
Concept ID:
C0346104
Neoplastic Process
Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward (Yung and Newton-Bishop, 2005). Rombo syndrome (180730) has similar features, but shows autosomal dominant inheritance.
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.
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.
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.
Cranioectodermal dysplasia 1
MedGen UID:
96586
Concept ID:
C0432235
Disease or Syndrome
Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Osteoporosis with pseudoglioma
MedGen UID:
98480
Concept ID:
C0432252
Disease or Syndrome
Osteoporosis-pseudoglioma syndrome is a rare condition characterized by severe thinning of the bones (osteoporosis) and eye abnormalities that lead to vision loss. In people with this condition, osteoporosis is usually recognized in early childhood. It is caused by a shortage of minerals, such as calcium, in bones (decreased bone mineral density), which makes the bones brittle and prone to fracture. Affected individuals often have multiple bone fractures, including in the bones that form the spine (vertebrae). Multiple fractures can cause collapse of the affected vertebrae (compressed vertebrae), abnormal side-to-side curvature of the spine (scoliosis), short stature, and limb deformities. Decreased bone mineral density can also cause softening or thinning of the skull (craniotabes).\n\nMost affected individuals have impaired vision at birth or by early infancy and are blind by young adulthood. Vision problems are usually caused by one of several eye conditions, grouped together as pseudoglioma, that affect the light-sensitive tissue at the back of the eye (the retina), although other eye conditions have been identified in affected individuals. Pseudogliomas are so named because, on examination, the conditions resemble an eye tumor known as a retinal glioma.\n\nRarely, people with osteoporosis-pseudoglioma syndrome have additional signs or symptoms such as mild intellectual disability, weak muscle tone (hypotonia), abnormally flexible joints, or seizures.
Lenz-Majewski hyperostosis syndrome
MedGen UID:
98483
Concept ID:
C0432269
Congenital Abnormality
Lenz-Majewski hyperostotic dwarfism is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, distinct craniofacial and dental anomalies, loose skin, and distal limb anomalies, particularly brachydactyly and symphalangism. Patients have multiple radiographic abnormalities due to progressive generalized hyperostosis that affects the cranium, vertebrae, and diaphyses of tubular bones, leading to severe growth retardation (summary by Sousa et al., 2014).
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.
Floating-Harbor syndrome
MedGen UID:
152667
Concept ID:
C0729582
Disease or Syndrome
Floating-Harbor syndrome (FHS) is characterized by typical craniofacial features; low birth weight, normal head circumference, and short stature; bone age delay that normalizes between ages six and 12 years; skeletal anomalies (brachydactyly, clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities); severe receptive and expressive language impairment; hypernasality and high-pitched voice; and intellectual disability that is typically mild to moderate. Difficulties with temperament and behavior that are present in many children tend to improve in adulthood. Other features can include hyperopia and/or strabismus, conductive hearing loss, seizures, gastroesophageal reflux, renal anomalies (e.g., hydronephrosis / renal pelviectasis, cysts, and/or agenesis), and genital anomalies (e.g., hypospadias and/or undescended testes).
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.
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.
X-linked intellectual disability with marfanoid habitus
MedGen UID:
167096
Concept ID:
C0796022
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.
Blepharophimosis - intellectual disability syndrome, Ohdo type
MedGen UID:
162905
Concept ID:
C0796094
Disease or Syndrome
A rare multiple congenital malformation syndrome with characteristics of blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability. Abnormal ears, microcephaly, and growth retardation have been reported occasionally. Male patients may show cryptorchidism and scrotal hypoplasia. Most reported cases are sporadic, except the original cases of Ohdo who described two affected sisters and a first cousin, suggesting autosomal recessive inheritance. Autosomal dominant, X-linked- and mitochondrial inheritance have also been suggested.
Primrose syndrome
MedGen UID:
162911
Concept ID:
C0796121
Disease or Syndrome
Primrose syndrome is characterized by macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, a recognizable facial phenotype, radiographic features, and altered glucose metabolism. Additional features seen in adults: sparse body hair, distal muscle wasting, and contractures. Characteristic craniofacial features include brachycephaly, high anterior hairline, deeply set eyes, ptosis, downslanted palpebral fissures, high palate with torus palatinus, broad jaw, and large ears with small or absent lobes. Radiographic features include calcification of the external ear cartilage, multiple Wormian bones, platybasia, bathrocephaly, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Additional features include hearing impairment, ocular anomalies, cryptorchidism, and nonspecific findings on brain MRI.
X-linked intellectual disability-short stature-overweight syndrome
MedGen UID:
901885
Concept ID:
C0796218
Disease or Syndrome
X-linked intellectual developmental disorder-12 (XLID12) is characterized by borderline to severe intellectual disability with variable neurologic features, short stature, and elevated body mass index (BMI) (Kumar et al., 2015).
3MC syndrome 2
MedGen UID:
167115
Concept ID:
C0796279
Disease or Syndrome
The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by Rooryck et al., 2011). For a discussion of genetic heterogeneity of 3MC syndrome, see 3MC1 (257920).
Acromegaloid facial appearance syndrome
MedGen UID:
167116
Concept ID:
C0796280
Disease or Syndrome
Acromegaloid facial appearance (AFA) syndrome is a multiple congenital anomalies/dysmorphic syndrome with a probable autosomal dominant inheritance, characterized by a progressively coarse acromegaloid-like facial appearance with thickening of the lips and intraoral mucosa, large and doughy hands and, in some cases, developmental delay. AFA syndrome appears to be part of a phenotypic spectrum that includes hypertrichotic osteochondrodysplasia, Cantu type and hypertrichosis-acromegaloid facial appearance syndrome.
SHORT syndrome
MedGen UID:
164212
Concept ID:
C0878684
Disease or Syndrome
SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in SHORT syndrome are mild intrauterine growth restriction (IUGR); mild to moderate short stature; partial lipodystrophy (evident in the face, and later in the chest and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt. Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Other frequent features include Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis, delayed dentition and other dental issues, and sensorineural hearing loss.
Hajdu-Cheney syndrome
MedGen UID:
182961
Concept ID:
C0917715
Disease or Syndrome
Hajdu-Cheney syndrome (HJCYS) is a rare autosomal dominant skeletal disorder characterized by short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies. Facial features include hypertelorism, bushy eyebrows, micrognathia, small mouth with dental anomalies, low-set ears, and short neck. There is progressive focal bone destruction, including acroosteolysis and generalized osteoporosis. Additional and variable features include hearing loss, renal cysts, and cardiovascular anomalies (summary by Ramos et al., 1998; Simpson et al., 2011; Isidor et al., 2011).
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.
Achard syndrome
MedGen UID:
272277
Concept ID:
C1332135
Disease or Syndrome
A rare genetic syndrome featuring connective tissue abnormalities. Clinical signs include brachycephaly, arachnodactyly, receding mandible and joint laxity at the hands and feet.
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.
Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome
MedGen UID:
330396
Concept ID:
C1832167
Disease or Syndrome
Traboulsi syndrome is characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual nontraumatic conjunctival cysts (filtering blebs), presumably caused by abnormal thinning of the sclera (Patel et al., 2014).
Spondyloepiphyseal dysplasia, Reardon type
MedGen UID:
322238
Concept ID:
C1833603
Disease or Syndrome
Spondyloepiphyseal dysplasia, Reardon type is an extremely rare type of spondyloepiphyseal dysplasia (see this term) described in several members of a single family to date and characterized by short stature, vertebral and femoral abnormalities, cervical instability and neurologic manifestations secondary to anomalies of the odontoid process.
Metaphyseal dysplasia without hypotrichosis
MedGen UID:
320444
Concept ID:
C1834821
Disease or Syndrome
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.
Epiphyseal dysplasia, Baumann type
MedGen UID:
322764
Concept ID:
C1835830
Disease or Syndrome
Macular degeneration, age-related, 3
MedGen UID:
373276
Concept ID:
C1837187
Disease or Syndrome
Age-related macular degeneration-3 (ARMD3) is characterized by numerous small round yellow lesions visible at the temporal edge of the macula. Larger, less distinct yellow areas near the center of the macula are also observed, which represent areas of pigment epithelial detachment (Stone et al., 2004). For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see 603075.
Larsen-like osseous dysplasia-short stature syndrome
MedGen UID:
325280
Concept ID:
C1837884
Disease or Syndrome
Larsen-like osseous dysplasia-short stature syndrome is a rare primary bone dysplasia characterized by a Larsen-like phenotype including multiple, congenital, large joint dislocations, craniofacial abnormalities (i.e. macrocephaly, flat occiput, prominent forehead, hypertelorism, low-set, malformed ears, flat nose, cleft palate), spinal abnormalities, cylindrical fingers, and talipes equinovarus, as well as growth retardation (resulting in short stature) and delayed bone age. Other reported clinical manifestations include severe developmental delay, hypotonia, clinodactyly, congenital heart defect and renal dysplasia.
Warburg micro syndrome 1
MedGen UID:
333142
Concept ID:
C1838625
Disease or Syndrome
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
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).
ALG2-congenital disorder of glycosylation
MedGen UID:
334618
Concept ID:
C1842836
Disease or Syndrome
Congenital disorder of glycosylation type Ii (CDG1I) is a rare autosomal recessive disorder characterized by neurologic involvement, including a convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression (summary by Papazoglu et al., 2021). For a general discussion of CDGs, see CDG1A (212065).
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).
Microphthalmia with cyst, bilateral facial clefts, and limb anomalies
MedGen UID:
375210
Concept ID:
C1843492
Disease or Syndrome
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).
X-linked intellectual disability Cabezas type
MedGen UID:
337334
Concept ID:
C1845861
Disease or Syndrome
The Cabezas type of X-linked syndromic intellectual developmental disorder is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).
Creatine transporter deficiency
MedGen UID:
337451
Concept ID:
C1845862
Disease or Syndrome
The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.
X-linked myotubular myopathy-abnormal genitalia syndrome
MedGen UID:
335354
Concept ID:
C1846169
Disease or Syndrome
A rare chromosomal anomaly, partial deletion of the long arm of chromosome X, with characteristics of a combination of clinical manifestations of X-linked myotubular myopathy and a 46,XY disorder of sex development. Patients present with a severe form of congenital myopathy and abnormal male genitalia.
Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome
MedGen UID:
337424
Concept ID:
C1846242
Disease or Syndrome
The AMME complex is an X-linked contiguous gene deletion syndrome with features of Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis in affected males (summary by Meloni et al., 2002).
Ehlers-Danlos syndrome due to tenascin-X deficiency
MedGen UID:
336244
Concept ID:
C1848029
Disease or Syndrome
The clinical features of TNXB-related classical-like Ehlers-Danlos syndrome (clEDS) strongly resemble those seen in classic EDS (cEDS). Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS. There are also several other distinguishing clinical findings including anomalies of feet and hands, edema in the legs in the absence of cardiac failure, mild proximal and distal muscle weakness, and axonal polyneuropathy. Vaginal, uterine, and/or rectal prolapse can also occur. Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals. Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported. Fatigue has been reported in more than half of affected individuals. The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound as a result of severe and painful foot deformities and fatigue.
X-linked spondyloepimetaphyseal dysplasia
MedGen UID:
376281
Concept ID:
C1848097
Disease or Syndrome
A rare genetic primary bone dysplasia disorder with characteristics of disproportionate short stature with mesomelic short limbs, leg bowing, lumbar lordosis, brachydactyly, joint laxity and a waddling gait. Radiographs show platyspondyly with central protrusion of anterior vertebral bodies, kyphotic angulation and very short long bones with dysplastic epiphyses and flared, irregular, cupped metaphyses.
Pili torti-developmental delay-neurological abnormalities syndrome
MedGen UID:
342358
Concept ID:
C1849811
Disease or Syndrome
Abnormal hair, joint laxity, and developmental delay (HJDD) is characterized by normal hair at birth that gradually becomes sparse, twisted, brittle, and easily broken, with pili torti and trichorrhexis nodosa observed on light microscopy. Other features include increased joint mobility and cognitive delay (Sharma et al., 2019).
Osteopenia-intellectual disability-sparse hair syndrome
MedGen UID:
337979
Concept ID:
C1850140
Disease or Syndrome
A rare syndrome described in two sisters of Mennonite descent, with characteristics of sparse hair, osteopenia, intellectual disability, minor facial abnormalities, joint laxity and hypotonia. There have been no further descriptions in the literature since 1992.
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.
Keipert syndrome
MedGen UID:
338088
Concept ID:
C1850627
Disease or Syndrome
Keipert syndrome (KPTS) is characterized by craniofacial and digital abnormalities and variable learning difficulties. The distinctive facial appearance includes broad forehead, hypertelorism, prominent nose, wide mouth, and prominent upper lip with cupid bow configuration. Digital anomalies are also distinctive, with widening of all distal phalanges, particularly of the thumbs and great toes (Amor et al., 2019).
Congenital multicore myopathy with external ophthalmoplegia
MedGen UID:
340597
Concept ID:
C1850674
Disease or Syndrome
Congenital myopathy-1B (CMYP1B) 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 CMYP1A (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.
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.
Phelan-McDermid syndrome
MedGen UID:
339994
Concept ID:
C1853490
Disease or Syndrome
Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.
Intellectual disability, short stature, facial anomalies, and joint dislocations
MedGen UID:
342897
Concept ID:
C1853507
Disease or Syndrome
Autism, susceptibility to, 5
MedGen UID:
340048
Concept ID:
C1853755
Disease or Syndrome
IDDAS is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, autism spectrum disorder, and language deficits (Deriziotis et al., 2014; den Hoed et al., 2018).
Macrocephaly-autism syndrome
MedGen UID:
381416
Concept ID:
C1854416
Disease or Syndrome
Macrocephaly/autism syndrome is an autosomal dominant disorder characterized by increased head circumference, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation (Herman et al., 2007). Some patients may have a primary immunodeficiency disorder with recurrent infections associated with variably abnormal T- and B-cell function (Tsujita et al., 2016).
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.
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.
Hydrocephaly-tall stature-joint laxity syndrome
MedGen UID:
383828
Concept ID:
C1856051
Disease or Syndrome
A multiple congenital anomalies syndrome described in two sisters and with the presence of hydrocephalus (onset in infancy), tall stature, joint laxity, and thoracolumbar kyphosis. There have been no further descriptions in the literature since 1989.
Ehlers-Danlos syndrome, fibronectinemic type
MedGen UID:
346497
Concept ID:
C1857038
Disease or Syndrome
Ehlers-Danlos syndromes (EDS) form a heterogeneous group of inherited connective tissue disorders characterized by variable joint hypermobility and cutaneous hyperextensibility. Type X is distinguished by platelet dysfunction associated with a fibronectin abnormality. Type X EDS has been described in only one family so far. Age of onset is about 13-25 years. Transmission is autosomal recessive.
Stickler syndrome type 2
MedGen UID:
347615
Concept ID:
C1858084
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.
Poikiloderma with neutropenia
MedGen UID:
388129
Concept ID:
C1858723
Disease or Syndrome
Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (ages 6-12 months) followed by post-inflammatory poikiloderma (age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome and, rarely, acute myelogenous leukemia. Other ectodermal findings include nail dystrophy and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers.
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).
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.
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).
Acromesomelic dysplasia 1, Maroteaux type
MedGen UID:
355199
Concept ID:
C1864356
Disease or Syndrome
The acromesomelic dysplasias are disorders in which there is disproportionate shortening of skeletal elements, predominantly affecting the middle segments (forearms and forelegs) and distal segments (hands and feet) of the appendicular skeleton. Acromesomelic dysplasia-1 (AMD1) is characterized by severe dwarfism (height below 120 cm) with shortening of the middle and distal segments of the limbs. This condition is usually diagnosed at birth and becomes more obvious in the first 2 years of life. X-rays show short broad fingers, square flat feet, and shortening of the long bones (particularly the forearms). The radius is bowed; the ulna is shorter than the radius, and its distal end is occasionally hypoplastic. The skull is dolichocephalic and a shortness of the trunk, with decreased vertebral height and narrowing of the lumbar interpedicular distances, is consistently observed. Facial appearance and intelligence are normal (summary by Faivre et al., 2000). Genetic Heterogeneity of Acromesomelic Dysplasia Additional autosomal recessive forms of acromesomelic dysplasia include acromesomelic dysplasia-2A (200700), -2B (228900), and -2C (201250), all caused by mutation in the GDF5 gene (601146) on chromosome 20q11; AMD3 (200700), caused by mutation in the BMPR1B gene (603248) on chromosome 4q22; and AMD4 (619636), caused by mutation in the PRKG2 gene (601591) on chromosome 4q21. An autosomal dominant form of acromesomelic dysplasia has also been reported (see 112910).
Syndromic microphthalmia type 5
MedGen UID:
350491
Concept ID:
C1864690
Disease or Syndrome
The association of a range of ocular anomalies (anophthalmia, microphthalmia and retinal abnormalities) with variable developmental delay and central nervous system malformations. Less than 20 cases have been reported in the literature so far. The clinical picture is highly variable, even between affected members of the same family. Severe developmental delay was noted in some patients, whilst others showed normal cognitive development. Pituitary dysfunction, leading to growth hormone deficiency and short stature, or combined pituitary hormone deficiency, has also been reported. The syndrome is caused by heterozygous mutations in the OTX2 gene (14q22.3).
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.
Spondyloepimetaphyseal dysplasia, Genevieve type
MedGen UID:
355314
Concept ID:
C1864872
Disease or Syndrome
Spondyloepiphyseal dysplasia of the Genevieve type (SEMDG) is characterized by infantile-onset severe developmental delay and skeletal dysplasia, including short stature, premature carpal ossification, platyspondyly, longitudinal metaphyseal striations, and small epiphyses (summary by van Karnebeek et al., 2016).
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).
Megalencephaly-capillary malformation-polymicrogyria syndrome
MedGen UID:
355421
Concept ID:
C1865285
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.
Pierre Robin sequence with pectus excavatum and rib and scapular anomalies
MedGen UID:
355549
Concept ID:
C1865783
Disease or Syndrome
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.
Polyhydramnios, megalencephaly, and symptomatic epilepsy
MedGen UID:
370203
Concept ID:
C1970203
Disease or Syndrome
A rare genetic neurological disorder with characteristics of pregnancy complicated by polyhydramnios, severe intractable epilepsy presenting in infancy, severe hypotonia, decreased muscle mass, global developmental delay, craniofacial dysmorphism (long face, large forehead, peaked eyebrows, broad nasal bridge, hypertelorism, large mouth with thick lips), and macrocephaly due to megalencephaly and hydrocephalus in most patients. Additional features that have been reported include cardiac anomalies like atrial septal defects, diabetes insipidus and nephrocalcinosis among others.
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.
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.
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.
Chromosome 6pter-p24 deletion syndrome
MedGen UID:
393396
Concept ID:
C2675486
Disease or Syndrome
Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.
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.
Ehlers-Danlos syndrome, spondylocheirodysplastic type
MedGen UID:
393515
Concept ID:
C2676510
Disease or Syndrome
Ehlers-Danlos syndrome spondylodysplastic type 3 (EDSSPD3) is characterized by short stature, hyperelastic skin and hypermobile joints, protuberant eyes with bluish sclerae, finely wrinkled palms, and characteristic radiologic features (Giunta et al., 2008). For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070.
Syndactyly-telecanthus-anogenital and renal malformations syndrome
MedGen UID:
394424
Concept ID:
C2678045
Disease or Syndrome
Syndrome with the association of toe syndactyly, facial dysmorphism including telecanthus and a broad nasal tip, urogenital malformations and anal atresia. Around ten cases have been reported so far. The syndrome is caused by mutations in the FAM58A gene (located on the X chromosome) encoding a protein of unknown function.
3M syndrome 1
MedGen UID:
395592
Concept ID:
C2678312
Disease or Syndrome
Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias.
Ehlers-Danlos syndrome, dermatosparaxis type
MedGen UID:
397792
Concept ID:
C2700425
Disease or Syndrome
Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.
Spondyloepimetaphyseal dysplasia, aggrecan type
MedGen UID:
411237
Concept ID:
C2748544
Disease or Syndrome
A new form of skeletal dysplasia with manifestations of severe short stature, facial dysmorphism and characteristic radiographic findings. To date, three cases have been described, all originating from the same family. The disease results from a missense mutation affecting the C-type lectin domain of aggrecan (AGC1 gene; chromosome 15) which regulates endochondral ossification. Transmission is autosomal recessive.
Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies
MedGen UID:
442566
Concept ID:
C2750804
Disease or Syndrome
LTBP4-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective tissue disorder such as inguinal hernias and hollow visceral diverticula (e.g., intestine, bladder). Other manifestations can include pyloric stenosis, diaphragmatic hernia, rectal prolapse, gastrointestinal elongation/tortuosity, cardiovascular abnormality, pulmonary hypertension, hypotonia and frequent pulmonary infections. Bladder diverticula and hydronephrosis are common. Early demise has been associated with pulmonary emphysema.
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.
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).
Osteogenesis imperfecta type 5
MedGen UID:
419332
Concept ID:
C2931093
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). Glorieux et al. (2000) described a novel autosomal dominant form of OI, which they designated OI type V (OI5), in 7 patients. The disorder was similar to OI type IV but had distinctive clinical, histologic, and molecular characteristics. OI type V is characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation (summary by Cho et al., 2012). OI type V has a variable phenotype. For example, in patients with the more common c.-14C-T variant (614757.0001), distinctive radiographic findings (calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation) are often seen, whereas these findings are not seen in patients with the less common S40L variant (614757.0002).
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).
Chromosome 6q11-q14 deletion syndrome
MedGen UID:
462140
Concept ID:
C3150790
Disease or Syndrome
The cardinal features of chromosome 6q11-q14 interstitial deletions include hypotonia, short stature, skeletal/limb anomalies, umbilical hernia, and urinary tract anomalies, as well as characteristic facial features including upslanting palpebral fissures, low-set and/or dysplastic ears, and high-arched palate (summary by Wang et al., 2009).
CBL-related disorder
MedGen UID:
462153
Concept ID:
C3150803
Disease or Syndrome
Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; 163950) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by Martinelli et al., 2010). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as also seen in patients with Noonan syndrome (summary by Niemeyer et al., 2010).
Cranioectodermal dysplasia 2
MedGen UID:
462224
Concept ID:
C3150874
Disease or Syndrome
Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Intellectual disability, anterior maxillary protrusion, and strabismus
MedGen UID:
462274
Concept ID:
C3150924
Disease or Syndrome
A rare genetic multiple congenital anomalies/dysmorphic syndrome with the association of severe intellectual disability, strabismus and anterior maxillary protrusion with vertical maxillary excess, open bite and prominent crowded teeth. Mild cochlear hearing loss has been reported in addition.
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.
Meier-Gorlin syndrome 2
MedGen UID:
462447
Concept ID:
C3151097
Disease or Syndrome
Most people with Meier-Gorlin syndrome have distinctive facial features. In addition to being abnormally small, the ears may be low-set or rotated backward. Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge.\n\nSome people with Meier-Gorlin syndrome have other skeletal abnormalities, such as unusually narrow long bones in the arms and legs, a deformity of the knee joint that allows the knee to bend backwards (genu recurvatum), and slowed mineralization of bones (delayed bone age).\n\nMeier-Gorlin syndrome is a condition primarily characterized by short stature. It is considered a form of primordial dwarfism because the growth problems begin before birth (intrauterine growth retardation). After birth, affected individuals continue to grow at a slow rate. Other characteristic features of this condition are underdeveloped or missing kneecaps (patellae), small ears, and, often, an abnormally small head (microcephaly). Despite a small head size, most people with Meier-Gorlin syndrome have normal intellect.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\n\nAbnormalities in sexual development may also occur in Meier-Gorlin syndrome. In some males with this condition, the testes are small or undescended (cryptorchidism). Affected females may have unusually small external genital folds (hypoplasia of the labia majora) and small breasts. Both males and females with this condition can have sparse or absent underarm (axillary) hair.
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).
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.
Kabuki syndrome 2
MedGen UID:
477126
Concept ID:
C3275495
Disease or Syndrome
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.
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.
Osteogenesis imperfecta type 6
MedGen UID:
481194
Concept ID:
C3279564
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. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011).
Cranioectodermal dysplasia 3
MedGen UID:
481437
Concept ID:
C3279807
Disease or Syndrome
Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
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.
Brittle cornea syndrome 2
MedGen UID:
481641
Concept ID:
C3280011
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). For a discussion of genetic heterogeneity of brittle cornea syndrome, see BCS1 (229200).
Rafiq syndrome
MedGen UID:
481757
Concept ID:
C3280127
Disease or Syndrome
Rafiq syndrome (RAFQS) is an autosomal recessive disorder characterized by variably impaired intellectual and motor development, a characteristic facial dysmorphism, truncal obesity, and hypotonia. The facial dysmorphism comprises prominent eyebrows with lateral thinning, downward-slanting palpebral fissures, bulbous tip of the nose, large ears, and a thin upper lip. Behavioral problems, including overeating, verbal and physical aggression, have been reported in some cases. Serum transferrin isoelectric focusing shows a type 2 pattern (summary by Balasubramanian et al., 2019).
3M syndrome 3
MedGen UID:
481776
Concept ID:
C3280146
Disease or Syndrome
Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias.
Cranioectodermal dysplasia 4
MedGen UID:
482246
Concept ID:
C3280616
Disease or Syndrome
Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Cutis laxa, autosomal recessive, type 1B
MedGen UID:
482428
Concept ID:
C3280798
Disease or Syndrome
EFEMP2-related cutis laxa, or autosomal recessive cutis laxa type 1B (ARCL1B), is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms, and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems.
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.
Hereditary spastic paraplegia 53
MedGen UID:
761340
Concept ID:
C3539494
Disease or Syndrome
SPG53 is an autosomal recessive neurologic disorder characterized by onset in infancy of delayed motor development progressing to upper and lower limb spasticity with impaired walking. Affected individuals also show mild to moderate cognitive impairment (summary by Zivony-Elboum et al., 2012).
Peroxisome biogenesis disorder 5B
MedGen UID:
762202
Concept ID:
C3542026
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX2 gene have cells of complementation group 5 (CG5, equivalent to CG10 and CGF). For information on the history of PBD complementation groups, see 214100.
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).
TMEM165-congenital disorder of glycosylation
MedGen UID:
766485
Concept ID:
C3553571
Disease or Syndrome
CDG2K is an autosomal recessive disorder with a variable phenotype. Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern (summary by Foulquier et al., 2012). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).
Joubert syndrome 18
MedGen UID:
766672
Concept ID:
C3553758
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.
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.
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.
Intellectual disability, X-linked 99
MedGen UID:
813076
Concept ID:
C3806746
Mental or Behavioral Dysfunction
Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the USP9X gene.
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.
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.
Ehlers-Danlos syndrome, spondylodysplastic type, 2
MedGen UID:
815540
Concept ID:
C3809210
Disease or Syndrome
The features of Ehlers-Danlos syndrome spondylodysplastic type 2 (EDSSPD2) include an aged appearance, developmental delay, short stature, craniofacial disproportion, generalized osteopenia, defective wound healing, hypermobile joints, hypotonic muscles, and loose but elastic skin (Okajima et al., 1999). For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070.
Ehlers-Danlos syndrome, musculocontractural type 2
MedGen UID:
816175
Concept ID:
C3809845
Disease or Syndrome
The musculocontractural type of Ehlers-Danlos syndrome (EDSMC2) is characterized by progressive multisystem fragility-related manifestations, including joint dislocations and deformities; skin hyperextensibility, bruisability, and fragility, with recurrent large subcutaneous hematomas; cardiac valvular, respiratory, gastrointestinal, and ophthalmologic complications; and myopathy, featuring muscle hypoplasia, muscle weakness, and an abnormal muscle fiber pattern in histology in adulthood, resulting in gross motor developmental delay (summary by Muller et al., 2013). For a discussion of genetic heterogeneity of the musculocontractural type of Ehlers-Danlos syndrome, see EDSMC1 (601776).
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.
Rienhoff syndrome
MedGen UID:
816342
Concept ID:
C3810012
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.
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).
Proximal myopathy with extrapyramidal signs
MedGen UID:
816615
Concept ID:
C3810285
Disease or Syndrome
Myopathy with extrapyramidal signs is an autosomal recessive disorder characterized by early childhood onset of proximal muscle weakness and learning disabilities. While the muscle weakness is static, most patients develop progressive extrapyramidal signs that may become disabling (summary by Logan et al., 2014). Brain MRI in 1 patient showed congenital malformations, including polymicrogyria and cerebellar dysplasia (Wilton et al., 2020).
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.
Desbuquois dysplasia 2
MedGen UID:
862731
Concept ID:
C4014294
Disease or Syndrome
Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification (summary by Bui et al., 2014). For a discussion of genetic heterogeneity of Desbuquois dysplasia, see DBQD1 (251450).
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).
Intellectual disability, autosomal dominant 24
MedGen UID:
862851
Concept ID:
C4014414
Disease or Syndrome
Vulto-van Silfout-de Vries syndrome (VSVS) is an intellectual developmental disorder characterized by delayed psychomotor development, poor expressive speech, and behavioral abnormalities, including autistic features and poor eye contact. Most patients have additional nonspecific features, including hypotonia and gait abnormalities, seizures, which may be refractory, high pain threshold, and sleep disturbances (summary by Nabais Sa et al., 2019).
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.
Vesicoureteral reflux 8
MedGen UID:
863268
Concept ID:
C4014831
Disease or Syndrome
Any vesicoureteral reflux in which the cause of the disease is a mutation in the TNXB gene.
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.
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).
Osteogenesis imperfecta type 16
MedGen UID:
864047
Concept ID:
C4015610
Disease or Syndrome
Osteogenesis imperfecta type XVI (OI16) is characterized by prenatal onset of multiple fractures of ribs and long bones, blue sclerae, decreased ossification of the skull, and severe demineralization. Heterozygous family members may exhibit recurrent fractures with minimal trauma, osteopenia, and blue sclerae (Keller et al., 2018; Lindahl et al., 2018).
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).
Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures
MedGen UID:
865814
Concept ID:
C4017377
Disease or Syndrome
Any spondyloepimetaphyseal dysplasia with joint laxity in which the cause of the disease is a mutation in the B3GALT6 gene.
Al-Raqad syndrome
MedGen UID:
897610
Concept ID:
C4085595
Disease or Syndrome
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
MedGen UID:
895943
Concept ID:
C4225229
Disease or Syndrome
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, axial hypotonia, palate abnormalities (including cleft palate and/or high and narrow palate), dysmorphic facial features (including prominent forehead, hypertelorism, downslanting palpebral fissures, wide nasal bridge, thin lips and widely spaced teeth), and short stature. Additional manifestations may include digital anomalies (such as brachydactyly, clinodactyly, and hypoplastic toenails), a single palmar crease, lower limb hypertonia, joint hypermobility, as well as ocular and urogenital anomalies.
SLC39A8-CDG
MedGen UID:
899837
Concept ID:
C4225234
Disease or Syndrome
Congenital disorder of glycosylation type IIn (CDG2N) is an autosomal recessive severe multisystem developmental disorder characterized by delayed psychomotor development apparent from infancy, hypotonia, and variable additional features, such as short stature, seizures, visual impairment, and cerebellar atrophy. Serum transferrin analysis shows a CDG type II pattern (summary by Boycott et al., 2015 and Park et al., 2015). For a discussion of genetic heterogeneity of CDG type II, see CDG2A (212066).
PMP22-RAI1 contiguous gene duplication syndrome
MedGen UID:
894862
Concept ID:
C4225255
Disease or Syndrome
Yuan-Harel-Lupski syndrome is a complex neurodevelopmental disorder characterized by global developmental delay and early-onset peripheral neuropathy. The disorder comprises features of both demyelinating Charcot-Marie-Tooth disease type 1A (CMT1A; 118220), which results from duplication of the PMP22 gene on 17p12, and Potocki-Lupski syndrome (PTLS; 610883), which results from duplication of a slightly proximal region on 17p11.2 that includes the RAI1 gene. These 2 loci are about 2.5 Mb apart. The resultant YUHAL phenotype may be more severe in comparison to the individual contributions of each gene, with particularly early onset of peripheral neuropathy and features of both central and peripheral nervous system involvement (summary by Yuan et al., 2015).
Cutis laxa, autosomal dominant 3
MedGen UID:
899774
Concept ID:
C4225268
Disease or Syndrome
Autosomal dominant cutis laxa-3 is characterized by thin skin with visible veins and wrinkles, cataract or corneal clouding, clenched fingers, pre- and postnatal growth retardation, and moderate intellectual disability. In addition, patients exhibit a combination of muscular hypotonia with brisk muscle reflexes (Fischer-Zirnsak et al., 2015). For a general phenotypic description and discussion of genetic heterogeneity of autosomal dominant cutis laxa, see ARCL1 (123700).
Osteogenesis imperfecta type 17
MedGen UID:
903845
Concept ID:
C4225301
Disease or Syndrome
Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly affect the bones. The term "osteogenesis imperfecta" means imperfect bone formation. People with this condition have bones that break (fracture) easily, often from mild trauma or with no apparent cause. Multiple fractures are common, and in severe cases, can occur even before birth. Milder cases may involve only a few fractures over a person's lifetime.\n\nThere are at least 19 recognized forms of osteogenesis imperfecta, designated type I through type XIX. Several types are distinguished by their signs and symptoms, although their characteristic features overlap. Increasingly, genetic causes are used to define rarer forms of osteogenesis imperfecta. Type I (also known as classic non-deforming osteogenesis imperfecta with blue sclerae) is the mildest form of osteogenesis imperfecta. Type II (also known as perinatally lethal osteogenesis imperfecta) is the most severe. Other types of this condition, including types III (progressively deforming osteogenesis imperfecta) and IV (common variable osteogenesis imperfecta with normal sclerae), have signs and symptoms that fall somewhere between these two extremes.\n\nOther types of osteogenesis imperfecta are more severe, causing frequent bone fractures that are present at birth and result from little or no trauma. Additional features of these types can include blue sclerae of the eyes, short stature, curvature of the spine (scoliosis), joint deformities (contractures), hearing loss, respiratory problems, and a disorder of tooth development called dentinogenesis imperfecta. Mobility can be reduced in affected individuals, and some may use a walker or wheelchair. The most severe forms of osteogenesis imperfecta, particularly type II, can include an abnormally small, fragile rib cage and underdeveloped lungs. Infants with these abnormalities may have life-threatening problems with breathing and can die shortly after birth.\n\nThe milder forms of osteogenesis imperfecta, including type I, are characterized by bone fractures during childhood and adolescence that often result from minor trauma, such as falling while learning to walk. Fractures occur less frequently in adulthood. People with mild forms of the condition typically have a blue or grey tint to the part of the eye that is usually white (the sclera), and about half develop hearing loss in adulthood. Unlike more severely affected individuals, people with type I are usually of normal or near normal height.
Ullrich congenital muscular dystrophy 2
MedGen UID:
899150
Concept ID:
C4225314
Disease or Syndrome
Ullrich congenital muscular dystrophy-2 (UCMD2) is a severe autosomal recessive disorder characterized by joint hypermobility, proximal contractures, and muscle weakness precluding ambulation (summary by Zou et al., 2014). For a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1A (254090).
Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
MedGen UID:
897984
Concept ID:
C4225351
Disease or Syndrome
White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females.
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).
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).
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.
Ehlers-Danlos syndrome, cardiac valvular type
MedGen UID:
929458
Concept ID:
C4303789
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\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\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.
Intellectual developmental disorder with dysmorphic facies and ptosis
MedGen UID:
934584
Concept ID:
C4310617
Disease or Syndrome
Intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (summary by Mattioli et al., 2017). See also chromosome 3p deletion syndrome (613792).
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).
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.
Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay
MedGen UID:
934653
Concept ID:
C4310686
Disease or Syndrome
The core features of short stature-micrognathia syndrome (SSMG) are intrauterine growth restriction (IUGR), postnatal short stature that is often rhizomelic, and micrognathia. Other common features include preterm birth, microcephaly, developmental delay, and genitourinary malformations in males. Transient liver dysfunction and glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, and cataracts have also been observed. Inter- and intrafamilial phenotypic severity varies greatly, from a relatively mild disorder to intrauterine death or stillbirth (Ritter et al., 2022).
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).
Joubert syndrome 28
MedGen UID:
934672
Concept ID:
C4310705
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.
Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy
MedGen UID:
934687
Concept ID:
C4310720
Disease or Syndrome
GRIDHH is an autosomal recessive multisystem disorder characterized by poor overall growth, impaired intellectual development, hypotonia, and variable liver dysfunction. Additional features, such as seizures and hearing loss, may also be present (summary by Kopajtich et al., 2016).
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.
Bone marrow failure syndrome 3
MedGen UID:
934711
Concept ID:
C4310744
Disease or Syndrome
Bone marrow failure syndrome-3 is an autosomal recessive disorder characterized by onset of pancytopenia in early childhood. Patients may have additional variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies (summary by Tummala et al., 2016). BMFS3 has a distinct phenotype and may include features that overlap with Shwachman-Diamond syndrome (SDS1; 260400), such as pancreatic insufficiency and short stature, and with dyskeratosis congenita (see, e.g., DKCA1, 127550), such as dental and hair abnormalities and shortened telomeres. In addition, some patients may have joint and skeletal abnormalities, impaired development, and retinal dysplasia (summary by D'Amours et al., 2018). For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).
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).
Intellectual disability, autosomal dominant 42
MedGen UID:
934741
Concept ID:
C4310774
Mental or Behavioral Dysfunction
GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.
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).
Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis
MedGen UID:
934777
Concept ID:
C4310810
Disease or Syndrome
Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis is an X-linked recessive disorder with onset of features in early childhood. Anemia is sometimes present. Some patients may show mild early motor or speech delay, but cognition is normal (summary by Andreoletti et al., 2017).
Meester-Loeys syndrome
MedGen UID:
934778
Concept ID:
C4310811
Disease or Syndrome
Meester-Loeys syndrome (MRLS) is an X-linked disorder characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia (Meester et al., 2017).
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.
Immunodeficiency 47
MedGen UID:
934786
Concept ID:
C4310819
Disease or Syndrome
Immunodeficiency-47 (IMD47) is an X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Some patients also have neurologic abnormalities (summary by Jansen et al., 2016).
Dias-Logan syndrome
MedGen UID:
934800
Concept ID:
C4310833
Disease or Syndrome
BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.
Atypical glycine encephalopathy
MedGen UID:
934910
Concept ID:
C4310943
Disease or Syndrome
GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity can be observed. Generalized hypotonia develops later into axial hypotonia with limb hypertonicity and a startle-like response to vocal and visual stimuli which should not be confused with seizures. To date, three of the six affected children reported from three families died between ages two days and seven months; the oldest reported living child is severely globally impaired at age three years. Because of the limited number of affected individuals reported to date, the phenotype has not yet been completely described.
Noonan syndrome-like disorder with loose anagen hair 1
MedGen UID:
1379805
Concept ID:
C4478716
Disease or Syndrome
Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017). Reviews Komatsuzaki et al. (2010) reviewed the clinical manifestations of patients with Noonan syndrome, Costello syndrome (218040), and cardiofaciocutaneous syndrome (CFC; see 115150) compared to patients with mutations in the SHOC2 gene. They noted that although there is phenotypic overlap among the disorders, loose anagen/easily pluckable hair had not been reported in mutation-positive patients with Noonan, CFC, or Costello syndrome, and appeared to be a distinctive feature of SHOC2 mutation-positive patients. Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23.
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.
Autosomal recessive cutis laxa type 2C
MedGen UID:
1385755
Concept ID:
C4479387
Disease or Syndrome
Autosomal recessive cutis laxa type IIC (ARCL2C) is characterized by generalized skin wrinkling with sparse subcutaneous fat and dysmorphic progeroid facial features. Most patients also exhibit severe hypotonia as well as cardiovascular involvement (summary by Van Damme et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
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.
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.
Developmental and epileptic encephalopathy, 55
MedGen UID:
1622363
Concept ID:
C4539843
Disease or Syndrome
Developmental and epileptic encephalopathy-55 (DEE55) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first weeks or months of life. Affected individuals have an extremely poor outcome, with profoundly impaired intellectual development, absent speech, spastic quadriplegia, and dyskinetic movements. Most have cortical visual impairment and require a feeding tube. Brain imaging shows nonspecific abnormalities, including cerebral atrophy, thin corpus callosum, and abnormal signals in the white matter. Death in childhood may occur. Biochemically, the disorder is associated with impaired synthesis of GPI-anchored proteins (summary by Vetro et al., 2020). 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).
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).
Joint laxity, short stature, and myopia
MedGen UID:
1621331
Concept ID:
C4540020
Disease or Syndrome
A rare developmental defect with connective tissue involvement and characteristics of joint hyperextensibility and multiple dislocations of large joints, severe myopia and short stature. Other common features include retinal detachment, iris and chorioretinal coloboma, kyphoscoliosis and other spine deformities, pectus carinatum, talipes equinovarus and progressive hearing loss.
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.
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).
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).
Intellectual disability, autosomal dominant 53
MedGen UID:
1623344
Concept ID:
C4540481
Mental or Behavioral Dysfunction
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).
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.
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).
Knobloch syndrome 1
MedGen UID:
1642123
Concept ID:
C4551775
Disease or Syndrome
Knobloch syndrome-1 (KNO1) is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by Aldahmesh et al., 2011). Genetic Heterogeneity of Knobloch Syndrome KNO2 (618458) is caused by mutation in the PAK2 gene (605022) on chromosome 3q29.
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.
Myopathy, lactic acidosis, and sideroblastic anemia 1
MedGen UID:
1634824
Concept ID:
C4551958
Disease or Syndrome
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow (Bykhovskaya et al., 2004). Genetic Heterogeneity of Myopathy, Lactic Acidosis, and Sideroblastic Anemia MLASA2 (613561) is caused by mutation in the YARS2 gene (610957) on chromosome 12p11. MLASA3 (500011) is caused by heteroplasmic mutation in the mitochondrially-encoded MTATP6 gene (516060).
Anauxetic dysplasia 1
MedGen UID:
1638106
Concept ID:
C4551965
Disease or Syndrome
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.
Meier-Gorlin syndrome 1
MedGen UID:
1641240
Concept ID:
C4552001
Disease or Syndrome
The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011). Genetic Heterogeneity of Meier-Gorlin Syndrome Most forms of Meier-Gorlin syndrome are autosomal recessive disorders, including Meier-Gorlin syndrome-1; Meier-Gorlin syndrome-2 (613800), caused by mutation in the ORC4 gene (603056) on chromosome 2q23; Meier-Gorlin syndrome-3 (613803), caused by mutation in the ORC6 gene (607213) on chromosome 16q11; Meier-Gorlin syndrome-4 (613804), caused by mutation in the CDT1 gene (605525) on chromosome 16q24; Meier-Gorlin syndrome-5 (613805), caused by mutation in the CDC6 gene (602627) on chromosome 17q21; Meier-Gorlin syndrome-7 (617063), caused by mutation in the CDC45L gene (603465) on chromosome 22q11; and Meier-Gorlin syndrome-8 (617564), caused by mutation in the MCM5 gene (602696) on chromosome 22q12. An autosomal dominant form of the disorder, Meier-Gorlin syndrome-6 (616835), is caused by mutation in the GMNN gene (602842) on chromosome 6p22.
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).
Chromosome 1p35 deletion syndrome
MedGen UID:
1632676
Concept ID:
C4693669
Disease or Syndrome
Osteogenesis imperfecta, type 18
MedGen UID:
1635201
Concept ID:
C4693736
Disease or Syndrome
Osteogenesis imperfecta type XVIII (OI18) is characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life (Doyard et al., 2018).
Jaberi-Elahi syndrome
MedGen UID:
1647359
Concept ID:
C4693848
Disease or Syndrome
JABELS is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and intellectual disability 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).
PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome
MedGen UID:
1641154
Concept ID:
C4693860
Disease or Syndrome
Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity. The severity of the phenotype and additional features are variable (summary by Jansen et al., 2018).
Ehlers-Danlos syndrome, classic-like, 2
MedGen UID:
1632001
Concept ID:
C4693870
Disease or Syndrome
Ehlers-Danlos syndrome classic-like-2 (EDSCLL2) is characterized by severe joint and skin laxity, osteoporosis involving the hips and spine, osteoarthritis, soft redundant skin that can be acrogeria-like, delayed wound healing with abnormal atrophic scarring, and shoulder, hip, knee, and ankle dislocations. Variable features include gastrointestinal and genitourinary manifestations, such as bowel rupture, gut dysmotility, cryptorchidism, and hernias; vascular complications, such as mitral valve prolapse and aortic root dilation; and skeletal anomalies (Blackburn et al., 2018). See 606408 for another classic-like EDS syndrome. For a discussion of the classification of EDS, see 130000.
Hyper-IgE recurrent infection syndrome 1, autosomal dominant
MedGen UID:
1648470
Concept ID:
C4721531
Disease or Syndrome
STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency.
Orthostatic hypotension 1
MedGen UID:
1648402
Concept ID:
C4746777
Disease or Syndrome
Dopamine beta-hydroxylase (DBH) deficiency is characterized by lack of sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function that predispose to orthostatic hypotension. Although DBH deficiency appears to be present from birth, the diagnosis is not generally recognized until late childhood. The combination of ptosis of the eyelids in infants and children, together with hypotension, is suggestive of the disease. In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization; children have reduced exercise capacity. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain; symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Life expectancy is unknown, but some affected individuals have lived beyond age 60 years.
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).
Regressive spondylometaphyseal dysplasia
MedGen UID:
1648288
Concept ID:
C4747922
Disease or Syndrome
Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly (SKPHA) is an autosomal recessive disorder characterized by rhizomelic skeletal dysplasia of variable severity with or without abnormal nuclear shape and chromatin organization in blood granulocytes (Hoffmann et al., 2002; Borovik et al., 2013; Collins et al., 2020). Initial skeletal features may improve with age (Sobreira et al., 2014).
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).
Intellectual disability, autosomal dominant 58
MedGen UID:
1648488
Concept ID:
C4748195
Disease or Syndrome
Glycosylphosphatidylinositol biosynthesis defect 18
MedGen UID:
1648478
Concept ID:
C4748357
Disease or Syndrome
DEE95 is a severe autosomal recessive developmental 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).
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).
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).
Intellectual disability, autosomal recessive 66
MedGen UID:
1648460
Concept ID:
C4748732
Disease or Syndrome
MRT66 is a nonsyndromic autosomal recessive intellectual developmental disorder with delayed speech development, neuropsychiatric symptoms, and relatively normal life span (Philips et al., 2017).
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).
Hyper-IgE recurrent infection syndrome 3, autosomal recessive
MedGen UID:
1648483
Concept ID:
C4748969
Disease or Syndrome
Hyper-IgE syndrome-3 with recurrent infections (HIES3) is an autosomal recessive immunologic disorder characterized by childhood onset of atopic dermatitis, skin infections particularly with Staphylococcus aureus, recurrent sinopulmonary infections, and increased serum IgE and IgG. Patients are susceptible to bacterial and fungal infections, including chronic mucocutaneous candidiasis. Immunologic workup shows impaired differentiation of CD4+ T cells into T-helper 17 cells, decreased memory B cells, and often decreased NK cells (summary by Beziat et al., 2018). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060).
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).
Menke-Hennekam syndrome 2
MedGen UID:
1676668
Concept ID:
C5193035
Disease or Syndrome
Menke-Hennekam syndrome-2 (MKHK2) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, and hearing impairment are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-2 (RSTS2; 613684), patients with MKHK1 do not resemble the striking phenotype of RSTS2. For a discussion of genetic heterogeneity of Menke-Hennekam syndrome, see MKHK1 (618332).
Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
MedGen UID:
1675672
Concept ID:
C5193040
Disease or Syndrome
Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome is an autosomal recessive disorder with a highly variable phenotype. Although all patients have polymicrogyria and other variable structural brain anomalies on imaging, only some show developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death (summary by Vandervore et al., 2017).
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).
Turnpenny-fry syndrome
MedGen UID:
1683283
Concept ID:
C5193060
Disease or Syndrome
Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (Turnpenny et al., 2018).
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).
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.
Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
MedGen UID:
1682403
Concept ID:
C5193134
Disease or Syndrome
Stolerman neurodevelopmental syndrome (NEDSST) is a highly variable disorder characterized by developmental delay, often with motor and speech delay, mildly impaired intellectual development (in most patients), learning difficulties, and behavioral abnormalities, including autism spectrum disorder. Psychosis is observed in a small percentage of individuals over the age of 12 years. Most individuals have nonspecific and mild dysmorphic facial features without a common gestalt. A subset of patients may have involvement of other organ systems, including gastrointestinal with poor early feeding or gastroesophageal reflux, distal skeletal anomalies, and congenital heart defects. Most mutations occur de novo, but rare autosomal dominant inheritance with incomplete penetrance has been observed (Stolerman et al., 2019; Rots et al., 2023).
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).
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).
Neurodevelopmental disorder with absent language and variable seizures
MedGen UID:
1684803
Concept ID:
C5231469
Disease or Syndrome
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 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).
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
Beck-Fahrner syndrome
MedGen UID:
1711894
Concept ID:
C5394097
Disease or Syndrome
Beck-Fahrner syndrome (BEFAHRS) is a developmental disorder characterized by global developmental delay with variably impaired intellectual development. Affected individuals often have behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD), as well as learning disabilities. Most patients have hypotonia and dysmorphic facies. Some may have growth abnormalities, including overgrowth or poor growth, poor feeding, and rarely, seizures. Although both monoallelic and biallelic mutations have been reported, some heterozygous carriers in autosomal recessive families may have milder symptoms; thus, both groups are included in this entry (summary by Beck et al., 2020).
Diets-Jongmans syndrome
MedGen UID:
1714920
Concept ID:
C5394263
Disease or Syndrome
Diets-Jongmans syndrome (DIJOS) is an autosomal dominant disorder characterized by mild to moderately impaired intellectual development with a recognizable facial gestalt (summary by Diets et al., 2019).
Anauxetic dysplasia 3
MedGen UID:
1718444
Concept ID:
C5394289
Disease or Syndrome
Anauxetic dysplasia-3 (ANXD3) is characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. Radiographs show short metacarpals, broad middle phalanges, and metaphyseal irregularities. Most patients also exhibit motor and cognitive delays (Narayanan et al., 2019). For a discussion of genetic heterogeneity of anauxetic dysplasia, see ANXD1 (607095).
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).
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).
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 (RILCBC1) 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).
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 speech impairment and dysmorphic facies
MedGen UID:
1758434
Concept ID:
C5436699
Disease or Syndrome
Neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) is characterized by developmental delay associated with mild to moderately impaired intellectual development or learning difficulties, behavioral or psychiatric abnormalities, and delayed speech and language acquisition. Additional features include dysmorphic facies, distal limb anomalies, gastrointestinal problems or feeding difficulties, and hypotonia. The phenotypic features and severity of the disorder are variable (summary by Kummeling et al., 2021).
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.
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.
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
MedGen UID:
1751229
Concept ID:
C5436847
Disease or Syndrome
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome-2 (OIEDS2) 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 Raff et al., 2000 and Malfait et al., 2013). For a discussion of genetic heterogeneity of combined osteogenesis imperfecta and Ehlers-Danlos syndrome, see 619115.
Vertebral hypersegmentation and orofacial anomalies
MedGen UID:
1746640
Concept ID:
C5436851
Disease or Syndrome
Vertebral hypersegmentation and orofacial anomalies (VHO) is characterized by supernumerary cervical, thoracic, and/or lumbar vertebrae, in association with supernumerary ribs. Most patients also exhibit orofacial clefting and ear anomalies (Cox et al., 2019).
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).
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.
Martsolf syndrome 1
MedGen UID:
1778114
Concept ID:
C5542298
Disease or Syndrome
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
Microcephaly 27, primary, autosomal dominant
MedGen UID:
1783457
Concept ID:
C5543051
Disease or Syndrome
Autosomal dominant primary microcephaly-27 (MCPH27) is characterized by small head circumference apparent in early childhood and associated with global developmental delay manifest as delayed walking, inability to walk, impaired intellectual development, and poor or absent speech. Most patients have variable and nonspecific additional features, including facial dysmorphism, hypotonia, limb hypertonia, poor feeding, and distal skeletal anomalies. Brain imaging may show enlarged ventricles or gyral abnormalities, but most have normal imaging (Parry et al., 2021). 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).
Joubert syndrome 37
MedGen UID:
1786742
Concept ID:
C5543064
Disease or Syndrome
Joubert syndrome-37 (JBTS37) is an autosomal recessive neurodevelopmental ciliopathy characterized classically by a distinctive hindbrain malformation affecting the midbrain and cerebellum, recognizable as the 'molar tooth sign' on brain imaging. Affected individuals have hypotonia, ataxia, and variably impaired intellectual development. Additional variable features, such as postaxial polydactyly, liver or kidney anomalies, retinal dystrophy, and coloboma, may also occur. In severe cases, affected fetuses with these malformations may be terminated (summary by Latour et al., 2020). For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).
Endove syndrome, limb-brain type
MedGen UID:
1782954
Concept ID:
C5543142
Disease or Syndrome
Limb-brain ENDOVE syndrome (ENDOVESLB) is characterized by marked mesomelic shortening of the lower limbs due to severe hypoplasia of the tibia and fibula. The talus is absent and foot bones are rudimentary. Hands show short and malformed fingers with a missing digit, and nails are absent on some fingers. In addition, there is cerebellar aplasia with hypoplasia of the brainstem (Allou et al., 2021).
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).
Short stature, oligodontia, dysmorphic facies, and motor delay
MedGen UID:
1787876
Concept ID:
C5543206
Disease or Syndrome
SOFM is characterized by marked short stature, oligodontia, mild facial dysmorphism, and motor delay. Endosteal hyperostosis has also been observed, and patients may exhibit some features of progeria (Terhal et al., 2020; Beauregard-Lacroix et al., 2020).
Global developmental delay with speech and behavioral abnormalities
MedGen UID:
1787991
Concept ID:
C5543226
Disease or Syndrome
Global developmental delay with speech and behavioral abnormalities (GDSBA) is characterized by developmental delay apparent from infancy or early childhood. Affected individuals have mildly delayed fine and motor skills with walking by 3 years of age, mildly impaired intellectual development, speech and language delay, and variable behavioral abnormalities, mostly autism and ADHD. Some patients may have additional nonspecific features, such as facial dysmorphism, myopia or strabismus, and skeletal defects, including joint hypermobility, pes planus, or slender fingers (summary by Granadillo et al., 2020).
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).
Faundes-Banka syndrome
MedGen UID:
1782083
Concept ID:
C5543554
Disease or Syndrome
Faundes-Banka syndrome (FABAS) is an autosomal dominant disorder characterized by variable combinations of developmental delay and microcephaly, as well as micrognathia and other dysmorphic features (Faundes et al., 2021).
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2
MedGen UID:
1778117
Concept ID:
C5543623
Disease or Syndrome
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by Williams et al., 2019 and Zeiad et al., 2021). For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (616263).
White-Kernohan syndrome
MedGen UID:
1785087
Concept ID:
C5543635
Disease or Syndrome
White-Kernohan syndrome (WHIKERS) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, hypotonia, and characteristic facial features. Some patients may have abnormalities of other systems, including genitourinary and skeletal (summary by White et al., 2021).
Intellectual disability, X-linked 21
MedGen UID:
1790509
Concept ID:
C5551510
Disease or Syndrome
NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.
Focal segmental glomerulosclerosis and neurodevelopmental syndrome
MedGen UID:
1794148
Concept ID:
C5561938
Disease or Syndrome
Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) is characterized by global developmental delay and renal dysfunction manifest as proteinuria and nephrotic syndrome apparent from infancy or early childhood. Some patients present with renal disease, whereas others present with developmental delay and develop renal disease later in childhood. Renal biopsy shows focal segmental glomerulosclerosis (FSGS), but the course of the disease is variable: some patients have transient proteinuria and others require renal transplant. Neurodevelopmental features are also variable, with some patients having only mildly impaired intellectual development, and others having a severe developmental disorder associated with early-onset refractory seizures or epileptic encephalopathy. Additional features, including feeding difficulties, poor overall growth, and nonspecific dysmorphic facial features, are commonly observed (summary by Assoum et al., 2018 and Weng et al., 2021).
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).
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).
Neurodevelopmental disorder with hypotonia and dysmorphic facies
MedGen UID:
1794184
Concept ID:
C5561974
Disease or Syndrome
Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).
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).
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).
Biliary, renal, neurologic, and skeletal syndrome
MedGen UID:
1794200
Concept ID:
C5561990
Disease or Syndrome
Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by Shaheen et al., 2020 and David et al., 2020).
Boudin-Mortier syndrome
MedGen UID:
1794202
Concept ID:
C5561992
Disease or Syndrome
Boudin-Mortier syndrome (BOMOS) is characterized by tall stature, arachnodactyly, disproportionately elongated great toes, and multiple extra epiphyses. Some patients also show joint hypermobility and dilation of the aortic root (Boudin et al., 2018). Mutation in the NPR2 gene (108961) results in a similar phenotype of increased stature and elongation of the digits, particularly of the great toes, with multiple extra epiphyses (epiphyseal chondrodysplasia, Miura type; 615923).
Usmani-Riazuddin syndrome, autosomal recessive
MedGen UID:
1794204
Concept ID:
C5561994
Disease or Syndrome
Autosomal recessive Usmani-Riazzudin syndrome (USRISR) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and speech delay, hypotonia, spasticity, and behavioral abnormalities, most commonly aggressive behavior. More variable additional features may include seizures, scoliosis, and joint laxity (Usmani et al., 2021).
Developmental delay with or without intellectual impairment or behavioral abnormalities
MedGen UID:
1794214
Concept ID:
C5562004
Disease or Syndrome
Developmental delay with or without intellectual impairment or behavioral abnormalities (DDIB) is an autosomal dominant disorder with a nonspecific phenotype of developmental delay. Additional features may include neonatal feeding problems, hypotonia, and dysmorphic facial features (Dulovic-Mahlow et al., 2019; van Woerden et al., 2021).
Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities
MedGen UID:
1794222
Concept ID:
C5562012
Disease or Syndrome
Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) is an early-onset neurodevelopmental disorder characterized by these features. Affected individuals also have nonspecific and variable dysmorphic facial features that do not constitute a recognizable gestalt. Although the disorder is caused by truncating mutations in the SRCAP gene as is FLHS, the DEHMBA phenotype is clinically distinguishable from FLHS by the lack of short stature, brachydactyly, and delayed bone age, as well as absence of a specific facial appearance. There are some overlapping features between the 2 disorders, mainly impaired intellectual development and speech delay (summary by Rots et al., 2021).
Trichothiodystrophy 9, nonphotosensitive
MedGen UID:
1794268
Concept ID:
C5562058
Disease or Syndrome
Nonphotosensitive trichothiodystrophy-9 (TTD9) is characterized by brittle hair and nails and scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. Hair analysis shows low sulfur content, and skin fibroblasts demonstrate normal DNA repair efficiency after UV irradiation (Botta et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (601675).
Intellectual disability, autosomal dominant 40
MedGen UID:
1810363
Concept ID:
C5676894
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features (NEDHILD) is a rare neurodevelopmental disorder associated with impaired intellectual development, speech and language impairment, microcephaly, seizures, hypotonia, ophthalmologic issues, constipation/gastroesophageal reflux, and behavioral problems, including autism and sleep disturbances (summary by Garrity 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.
Bryant-Li-Bhoj neurodevelopmental syndrome 1
MedGen UID:
1801103
Concept ID:
C5676905
Disease or Syndrome
Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) 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 abnormal head shape, 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). Genetic Heterogeneity of Bryant-Li-Bhoj Neurodevelopmental Syndrome See also BRYLIB2 (619721), caused by heterozygous mutation in the H3F3B gene (601058).
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).
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).
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).
Intellectual developmental disorder, autosomal recessive 77
MedGen UID:
1823966
Concept ID:
C5774193
Mental or Behavioral Dysfunction
Autosomal recessive intellectual developmental disorder-77 (MRT77) is a nonsyndromic neurodevelopmental disorder characterized by global developmental delay with variably impaired cognitive development apparent from infancy. Affected individuals usually have delayed walking, sometimes with an unsteady gait, and may have poor speech and communication. Brain imaging is normal, and there are no additional significant neurologic abnormalities (Khoshbakht et al., 2021). Mutation in the CEP104 gene also causes a form of Joubert syndrome (JBTS25; 616781).
Liver disease, severe congenital
MedGen UID:
1823968
Concept ID:
C5774195
Disease or Syndrome
Severe congenital liver disease (SCOLIV) is an autosomal recessive disorder characterized by the onset of progressive hepatic dysfunction usually in the first years of life. Affected individuals show feeding difficulties with failure to thrive and features such as jaundice, hepatomegaly, and abdominal distension. Laboratory workup is consistent with hepatic insufficiency and may also show coagulation defects, anemia, or metabolic disturbances. Cirrhosis and hypernodularity are commonly observed on liver biopsy. Many patients die of liver failure in early childhood (Moreno Traspas et al., 2022).
Developmental delay, behavioral abnormalities, and neuropsychiatric disorders
MedGen UID:
1823997
Concept ID:
C5774224
Disease or Syndrome
Developmental delay, behavioral abnormalities, and neuropsychiatric disorders (DEDBANP) is a neurodevelopmental disorder characterized by mild global developmental delay and normal or variably impaired intellectual development. Most individuals have behavioral or neuropsychiatric disorders, including autism spectrum disorder (ASD), attention deficit-hyperactivity disorder (ADHD), and executive functioning deficits. Additional features may include speech delay, dysmorphic features, hypotonia, sleep disturbances, and seizures (Vitobello et al., 2022).
Neuronopathy, distal hereditary motor, autosomal dominant 10
MedGen UID:
1824007
Concept ID:
C5774234
Disease or Syndrome
Autosomal dominant distal hereditary motor neuronopathy-10 (HMND10) is a neurologic disorder of the peripheral nerves characterized clinically by length-dependent motor neuropathy primarily affecting the lower limbs. Affected individuals have onset of distal muscle weakness and atrophy in early childhood that results in walking difficulties and gait abnormalities. Some have pyramidal signs, including hyperreflexia, suggesting the involvement of upper motor neurons. Electrophysiologic studies are consistent with a neurogenic process. More variable features may include mild intellectual disability, minor gyration defects on brain imaging, foot deformities, and connective tissue defects (1 family) (Capuano et al., 2016; Iacomino et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).
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).
Congenital myopathy 15
MedGen UID:
1824046
Concept ID:
C5774273
Disease or Syndrome
Congenital myopathy-15 (CMYP15) is a skeletal muscle disorder characterized by symptom onset soon after birth. Affected infants are hypotonic and have severe respiratory insufficiency and feeding problems, sometimes requiring mechanical ventilation or tube feeding. The disorder is unique in that there is gradual improvement of the severe muscle weakness with time, although forced vital capacity remains decreased. Additional features include facial weakness, scoliosis, joint contractures, and persistent ptosis or external ophthalmoplegia (van de Locht et al., 2021). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities
MedGen UID:
1824058
Concept ID:
C5774285
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities (NEDHFS) is an autosomal recessive disorder characterized by severe global developmental delay with impaired intellectual development and poor or absent speech. Affected individuals have dysmorphic facies, including large abnormally shaped ears and strabismus, hypotonia, and dry skin with keratosis pilaris. Some patients develop seizures. Metabolic studies are unremarkable (Morava et al., 2021).
Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia
MedGen UID:
1824071
Concept ID:
C5774298
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (NEDFIH) is an autosomal recessive disorder characterized by these features and moderate to severe global developmental delay. Affected individuals show episodic regression during periods of stress, including seizures or infection, the latter of which may be associated with lymphopenia. Brain imaging shows diminished white matter volume, enlarged ventricles, and thin corpus callosum (Muffels et al., 2023).
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).
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).
Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities
MedGen UID:
1841073
Concept ID:
C5830437
Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-71 with behavioral abnormalities (MRD71) is a neurodevelopmental disorder characterized by global developmental delay with hypotonia, speech delay, and variably impaired cognitive development. Almost all affected individuals show marked behavioral manifestations, including autism spectrum disorder (ASD), ADHD, hypersensitivity, and aggression. Many have dysmorphic features, although there is not a common gestalt (Harris et al., 2021).
RECON progeroid syndrome
MedGen UID:
1841140
Concept ID:
C5830504
Disease or Syndrome
RECON progeroid syndrome (RECON) is a chromosomal instability disorder characterized by postnatal growth retardation, progeroid facial appearance, hypoplastic nose, prominent premaxilla, skin photosensitivity and xeroderma, muscle wasting with reduced subcutaneous fat, and slender elongated thumbs (Abu-Libdeh et al., 2022).

Professional guidelines

PubMed

Atwell K, Michael W, Dubey J, James S, Martonffy A, Anderson S, Rudin N, Schrager S
J Am Board Fam Med 2021 Jul-Aug;34(4):838-848. doi: 10.3122/jabfm.2021.04.200374. PMID: 34312277
Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Colombi M, Dordoni C, Chiarelli N, Ritelli M
Am J Med Genet C Semin Med Genet 2015 Mar;169C(1):6-22. doi: 10.1002/ajmg.c.31429. PMID: 25821090

Recent clinical studies

Etiology

Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V
Orphanet J Rare Dis 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135Free PMC Article
Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH
Nat Rev Dis Primers 2020 Jul 30;6(1):64. doi: 10.1038/s41572-020-0194-9. PMID: 32732924
Syx D, De Wandele I, Rombaut L, Malfait F
Clin Exp Rheumatol 2017 Sep-Oct;35 Suppl 107(5):116-122. Epub 2017 Sep 28 PMID: 28967365
Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):8-26. doi: 10.1002/ajmg.c.31552. PMID: 28306229

Diagnosis

Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V
Orphanet J Rare Dis 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135Free PMC Article
Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH
Nat Rev Dis Primers 2020 Jul 30;6(1):64. doi: 10.1038/s41572-020-0194-9. PMID: 32732924
Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):8-26. doi: 10.1002/ajmg.c.31552. PMID: 28306229
Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):27-39. Epub 2017 Feb 13 doi: 10.1002/ajmg.c.31548. PMID: 28192633
Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):48-69. Epub 2017 Feb 1 doi: 10.1002/ajmg.c.31538. PMID: 28145611

Therapy

Chen G, Olver JS, Kanaan RA
J Psychosom Res 2021 Sep;148:110556. Epub 2021 Jun 24 doi: 10.1016/j.jpsychores.2021.110556. PMID: 34237584
Skwiot M, Śliwiński G, Milanese S, Śliwiński Z
PLoS One 2019;14(2):e0212188. Epub 2019 Feb 22 doi: 10.1371/journal.pone.0212188. PMID: 30794600Free PMC Article
Chang CL, Wang DH, Yang MC, Hsu WE, Hsu ML
Kaohsiung J Med Sci 2018 Apr;34(4):223-230. Epub 2018 Feb 7 doi: 10.1016/j.kjms.2018.01.004. PMID: 29655411
Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV
Am J Med Genet C Semin Med Genet 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230
Mantle D, Wilkins RM, Preedy V
Med Hypotheses 2005;64(2):279-83. doi: 10.1016/j.mehy.2004.07.023. PMID: 15607555

Prognosis

Rossi A, Blok LS, Neuser S, Klöckner C, Platzer K, Faivre LO, Weigand H, Dentici ML, Tartaglia M, Niceta M, Alfieri P, Srivastava S, Coulter D, Smith L, Vinorum K, Cappuccio G, Brunetti-Pierri N, Torun D, Arslan M, Lauridsen MF, Murch O, Irving R, Lynch SA, Mehta SG, Carmichael J, Zonneveld-Huijssoon E, de Vries B, Kleefstra T, Johannesen KM, Westphall IT, Hughes SS, Smithson S, Evans J, Dudding-Byth T, Simon M, van Binsbergen E, Herkert JC, Beunders G, Oppermann H, Bakal M, Møller RS, Rubboli G, Bayat A
Clin Genet 2023 Aug;104(2):186-197. Epub 2023 May 10 doi: 10.1111/cge.14353. PMID: 37165752Free PMC Article
Leone MP, Morlino S, Nardella G, Pracella R, Giachino D, Celli L, Baldo D, Turolla L, Piccione M, Salzano E, Busè M, Lastella P, Zollino M, Cantone R, Grosso E, Zonta A, Pasini B, Piscopo C, De Maggio I, Priolo M, Mammi C, Foiadelli T, Trabatti C, Savasta S, Iolascon A, Ferraris A, Lodato V, Di Giosaffatte N, Majore S, Selicorni A, Petracca A, Fusco C, Celli M, Guarnieri V, Micale L, Castori M
Hum Genet 2023 Jun;142(6):785-808. Epub 2023 Apr 20 doi: 10.1007/s00439-023-02547-z. PMID: 37079061
Petracek LS, Rowe PC
Neurosurg Clin N Am 2023 Jan;34(1):43-54. doi: 10.1016/j.nec.2022.09.002. PMID: 36424063
Stewart JM, Boris JR, Chelimsky G, Fischer PR, Fortunato JE, Grubb BP, Heyer GL, Jarjour IT, Medow MS, Numan MT, Pianosi PT, Singer W, Tarbell S, Chelimsky TC; Pediatric Writing Group of the American Autonomic Society
Pediatrics 2018 Jan;141(1) Epub 2017 Dec 8 doi: 10.1542/peds.2017-1673. PMID: 29222399Free PMC Article
Evans AM, Rome K
Eur J Phys Rehabil Med 2011 Mar;47(1):69-89. PMID: 21448121

Clinical prediction guides

Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V
Orphanet J Rare Dis 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135Free PMC Article
Leone MP, Morlino S, Nardella G, Pracella R, Giachino D, Celli L, Baldo D, Turolla L, Piccione M, Salzano E, Busè M, Lastella P, Zollino M, Cantone R, Grosso E, Zonta A, Pasini B, Piscopo C, De Maggio I, Priolo M, Mammi C, Foiadelli T, Trabatti C, Savasta S, Iolascon A, Ferraris A, Lodato V, Di Giosaffatte N, Majore S, Selicorni A, Petracca A, Fusco C, Celli M, Guarnieri V, Micale L, Castori M
Hum Genet 2023 Jun;142(6):785-808. Epub 2023 Apr 20 doi: 10.1007/s00439-023-02547-z. PMID: 37079061
Malek S, Reinhold EJ, Pearce GS
Rheumatol Int 2021 Oct;41(10):1707-1716. Epub 2021 Mar 18 doi: 10.1007/s00296-021-04832-4. PMID: 33738549Free PMC Article
Evans AM, Rome K
Eur J Phys Rehabil Med 2011 Mar;47(1):69-89. PMID: 21448121
Malfait F, Wenstrup RJ, De Paepe A
Genet Med 2010 Oct;12(10):597-605. doi: 10.1097/GIM.0b013e3181eed412. PMID: 20847697

Recent systematic reviews

Martín-Martín M, Cortés-Martín J, Tovar-Gálvez MI, Sánchez-García JC, Díaz-Rodríguez L, Rodríguez-Blanque R
Int J Environ Res Public Health 2022 Feb 7;19(3) doi: 10.3390/ijerph19031870. PMID: 35162892Free PMC Article
Chen G, Olver JS, Kanaan RA
J Psychosom Res 2021 Sep;148:110556. Epub 2021 Jun 24 doi: 10.1016/j.jpsychores.2021.110556. PMID: 34237584
Veit-Rubin N, Cartwright R, Singh AU, Digesu GA, Fernando R, Khullar V
Int Urogynecol J 2016 Oct;27(10):1469-78. Epub 2015 Dec 10 doi: 10.1007/s00192-015-2896-1. PMID: 26658756
Bates AV, Alexander CM
Gait Posture 2015 Feb;41(2):361-9. Epub 2015 Jan 20 doi: 10.1016/j.gaitpost.2015.01.009. PMID: 25684143
Sanches SH, Osório Fde L, Udina M, Martín-Santos R, Crippa JA
Braz J Psychiatry 2012 Jun;34 Suppl 1:S53-60. doi: 10.1590/s1516-44462012000500005. PMID: 22729449

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