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Clubfoot

MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Synonyms: CLUB FOOT; CLUBFOOT, CONGENITAL, WITH OR WITHOUT DEFICIENCY OF LONG BONES AND/OR MIRROR-IMAGE POLYDACTYLY; Congenital Talipes Equinovarus; PITX1-Related Congenital Clubfoot; Talipes equinovarus
SNOMED CT: Talipes equinovarus (397932003); Clubfoot (397932003); TEV - Talipes equinovarus (397932003); Equinovarus deformity (397932003); Congenital talipes equinovarus (1156475005); Congenital clubfoot (1156475005)
 
Gene (location): PITX1 (5q31.1)
 
HPO: HP:0001762
Monarch Initiative: MONDO:0007342
OMIM®: 119800

Definition

Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012). [from OMIM]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Bilateral talipes equinovarus
MedGen UID:
332956
Concept ID:
C1837835
Congenital Abnormality
Bilateral clubfoot deformity.
Patellar hypoplasia
MedGen UID:
327021
Concept ID:
C1840068
Finding
Underdevelopment of the patella.
Preaxial foot polydactyly
MedGen UID:
389171
Concept ID:
C2112942
Finding
Duplication of all or part of the first ray.
Absent tibia
MedGen UID:
478374
Concept ID:
C3276744
Finding
Absence of the tibia.
Mirror image foot polydactyly
MedGen UID:
866883
Concept ID:
C4021238
Congenital Abnormality
Mirror image duplication of digits affecting the feet.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Enlarged cisterna magna
MedGen UID:
344031
Concept ID:
C1853377
Finding
Increase in size of the cisterna magna, one of three principal openings in the subarachnoid space between the arachnoid and pia mater, located between the cerebellum and the dorsal surface of the medulla oblongata.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Median cleft palate
MedGen UID:
340670
Concept ID:
C1850968
Congenital Abnormality
Cleft palate of the midline of the palate.
Popliteal pterygium
MedGen UID:
811750
Concept ID:
C3805420
Finding
A pterygium (or pterygia) occurring in the popliteal region (the back of the knee).
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVClubfoot
Follow this link to review classifications for Clubfoot in Orphanet.

Conditions with this feature

Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Ellis-van Creveld syndrome
MedGen UID:
8584
Concept ID:
C0013903
Disease or Syndrome
Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000). The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002).
Glycogen storage disease, type IV
MedGen UID:
6642
Concept ID:
C0017923
Disease or Syndrome
The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The fatal perinatal neuromuscular subtype presents in utero with fetal akinesia deformation sequence, including decreased fetal movements, polyhydramnios, and fetal hydrops. Death usually occurs in the neonatal period. The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy. Death usually occurs in early infancy. Infants with the classic (progressive) hepatic subtype may appear normal at birth, but rapidly develop failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; and cardiomyopathy. Without liver transplantation, death from liver failure usually occurs by age five years. Children with the non-progressive hepatic subtype tend to present with hepatomegaly, liver dysfunction, myopathy, and hypotonia; however, they are likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle, or neurologic involvement. The childhood neuromuscular subtype is rare and the course is variable, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade.
Multiple symmetric lipomatosis
MedGen UID:
7349
Concept ID:
C0023804
Disease or Syndrome
Multiple symmetric lipomatosis (MSL) is an autosomal recessive metabolic disorder characterized by the growth of unencapsulated masses of adipose tissue with predilection for the cervical and thoracic regions. The lipoma growth is striking and disfiguring, and growth around the neck may cause difficulty swallowing or breathing. The age at onset ranges from childhood to young adulthood. Most, but not all, patients develop axonal peripheral neuropathy, which can appear at any age and varies in severity. Laboratory studies in MSL show low leptin (164160), low adiponectin (605441), variably increased lactate, and increased FGF21 (609436). Some patients may have insulin resistance. The disorder is exclusively associated with a particular MFN2 mutation (R707W; 608507.0013), usually in the homozygous state, but sometimes in the compound heterozygous state (Rocha et al., 2017; Capel et al., 2018).
Melnick-Needles syndrome
MedGen UID:
6292
Concept ID:
C0025237
Disease or Syndrome
The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
Nail-patella syndrome
MedGen UID:
10257
Concept ID:
C0027341
Disease or Syndrome
Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage renal disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population.
Prune belly syndrome
MedGen UID:
18718
Concept ID:
C0033770
Disease or Syndrome
In its rare complete form, 'prune belly' syndrome (PBS) comprises megacystis (massively enlarged bladder) with disorganized detrusor muscle, cryptorchidism, and thin abdominal musculature with overlying lax skin (summary by Weber et al., 2011).
Asphyxiating thoracic dystrophy 3
MedGen UID:
19860
Concept ID:
C0036069
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Mucopolysaccharidosis type 7
MedGen UID:
43108
Concept ID:
C0085132
Disease or Syndrome
Mucopolysaccharidosis type VII (MPS7) is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al., 1993). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved.
Radial aplasia-thrombocytopenia syndrome
MedGen UID:
61235
Concept ID:
C0175703
Disease or Syndrome
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
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.
Arthrogryposis, distal, type 1A
MedGen UID:
113099
Concept ID:
C0220662
Congenital Abnormality
Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. The term "arthrogryposis" comes from the Greek words for joint (arthro-) and crooked or hooked (gryposis). The characteristic features of this condition include permanently bent fingers and toes (camptodactyly), overlapping fingers, and a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation). Clubfoot, which is an inward- and upward-turning foot, is also commonly seen with distal arthrogryposis type 1. The specific hand and foot abnormalities vary among affected individuals. However, this condition typically does not cause any signs and symptoms affecting other parts of the body.
Gordon syndrome
MedGen UID:
66314
Concept ID:
C0220666
Disease or Syndrome
DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA3 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 5 (DA5; 108145) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of ocular abnormalities and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition. For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Congenital contractural arachnodactyly
MedGen UID:
67391
Concept ID:
C0220668
Congenital Abnormality
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families.
Aase-Smith syndrome
MedGen UID:
66316
Concept ID:
C0220686
Disease or Syndrome
A very rare genetic disorder with characteristics of the following congenital malformations: hydrocephalus (due to Dandy-Walker anomaly), cleft palate and severe joint contractures. Less than 20 cases have been reported in the literature. The fingers are thin with absent knuckles and reduced creases over the joints and patients show an inability to make a full fist. Additional findings may include deformed ears, ptosis, an inability to open the mouth fully, heart defects, and clubfoot. There are currently no human genes associated with this disease.
Amniotic band syndrome
MedGen UID:
66322
Concept ID:
C0220724
Congenital Abnormality
Constriction rings syndrome is a congenital limb malformation disorder with an extremely variable clinical presentation characterized by the presence of partial to complete, congenital, fibrous, circumferential, constriction bands/rings on any part of the body, although a particular predilection for the upper or lower extremities is seen. Phenotypes range from only a mild skin indentation to complete amputation of parts of the fetus (e.g. digits, distal limb). Compression from the rings may lead to edema, skeletal anomalies (e.g. fractures, foot deformities) and, infrequently, neural compromise.
Diastrophic dysplasia
MedGen UID:
113103
Concept ID:
C0220726
Disease or Syndrome
Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized head, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion, the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence.
Oromandibular-limb hypogenesis spectrum
MedGen UID:
66357
Concept ID:
C0221060
Disease or Syndrome
The most basic description of Moebius syndrome is a congenital facial palsy with impairment of ocular abduction. The facial nerve (cranial nerve VII) and abducens nerve (CN VI) are most frequently involved, but other cranial nerves may be involved as well. Other variable features include orofacial dysmorphism and limb malformations. Mental retardation has been reported in a subset of patients. Most cases of Moebius syndrome are sporadic, but familial occurrence has been reported (Verzijl et al., 2003). The definition of and diagnostic criteria for Moebius syndrome have been controversial and problematic. The syndrome has most frequently been confused with hereditary congenital facial paresis (HCFP; see 601471), which is restricted to involvement of the facial nerve and no other abnormalities. Verzijl et al. (2003) and Verzijl et al. (2005) concluded that HCFP and Moebius syndrome are distinct disorders, and that Moebius syndrome is a complex developmental disorder of the brainstem. Moebius syndrome was defined at the Moebius Syndrome Foundation Research Conference in 2007 as congenital, nonprogressive facial weakness with limited abduction of one or both eyes. Additional features can include hearing loss and other cranial nerve dysfunction, as well as motor, orofacial, musculoskeletal, neurodevelopmental, and social problems (summary by Webb et al., 2012). Kumar (1990) provided a review of Moebius syndrome, which was critiqued by Lipson et al. (1990). Briegel (2006) provided a review of Moebius sequence with special emphasis on neuropsychiatric findings.
Weaver syndrome
MedGen UID:
120511
Concept ID:
C0265210
Disease or Syndrome
EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency.
Freeman-Sheldon syndrome
MedGen UID:
120516
Concept ID:
C0265224
Disease or Syndrome
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Hecht syndrome
MedGen UID:
78540
Concept ID:
C0265226
Disease or Syndrome
The trismus-pseudocamptodactyly syndrome is a distal arthrogryposis characterized by an inability to open the mouth fully (trismus) and pseudocamptodactyly in which wrist dorsiflexion, but not volar flexion, produces involuntary flexion contracture of distal and proximal interphalangeal joints. In these patients, trismus complicates dental care, feeding during infancy, and intubation for anesthesia, and the pseudocamptodactyly impairs manual dexterity, with consequent occupational and social disability (summary by Veugelers et al., 2004).
Schinzel-Giedion syndrome
MedGen UID:
120517
Concept ID:
C0265227
Disease or Syndrome
Schinzel-Giedion syndrome is a highly recognizable syndrome characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, and cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia (summary by Hoischen et al., 2010).
Nager syndrome
MedGen UID:
120519
Concept ID:
C0265245
Disease or Syndrome
Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (263750), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by Bernier et al., 2012).
Autosomal recessive multiple pterygium syndrome
MedGen UID:
82696
Concept ID:
C0265261
Congenital Abnormality
Multiple pterygium syndromes comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal (253290) and nonlethal (Escobar) types.
Femoral hypoplasia - unusual facies syndrome
MedGen UID:
120523
Concept ID:
C0265263
Disease or Syndrome
Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facies syndrome (FHUFS), is a rare and sporadic multiple congenital anomaly syndrome comprising bilateral femoral hypoplasia and characteristic facial features, such as long philtrum, thin upper lip, micrognathia with or without cleft palate, upward-slanting palpebral fissures, and a short nose with broad tip. Other features, such as renal anomalies, are more variable (summary by Nowaczyk et al., 2010).
Achondrogenesis, type IA
MedGen UID:
78546
Concept ID:
C0265273
Congenital Abnormality
The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Genetic Heterogeneity of Achondrogenesis Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).
Atelosteogenesis type I
MedGen UID:
82701
Concept ID:
C0265283
Congenital Abnormality
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Dyggve-Melchior-Clausen syndrome
MedGen UID:
120527
Concept ID:
C0265286
Disease or Syndrome
Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests (summary by El Ghouzzi et al., 2003).
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 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.
Dihydropyrimidinase deficiency
MedGen UID:
83353
Concept ID:
C0342803
Disease or Syndrome
Dihydropyrimidinase deficiency (DPYSD) is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder.
Bifunctional peroxisomal enzyme deficiency
MedGen UID:
137982
Concept ID:
C0342870
Pathologic Function
D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.
Congenital laryngeal abductor palsy
MedGen UID:
96004
Concept ID:
C0396059
Congenital Abnormality
Laryngeal abductor paralysis is an autosomal dominant condition characterized by variable penetrance and expressivity ranging from mild symptoms to neonatal asphyxia. (summary by Morelli et al., 1982; Manaligod and Smith, 1998).
Neonatal pseudo-hydrocephalic progeroid syndrome
MedGen UID:
140806
Concept ID:
C0406586
Disease or Syndrome
Wiedemann-Rautenstrauch syndrome (WDRTS) is a rare autosomal recessive neonatal progeroid disorder characterized by intrauterine growth retardation, failure to thrive, short stature, a progeroid appearance, hypotonia, and variable mental impairment (summary by Toriello, 1990). Average survival in WDRTS is 7 months, although survival into the third decade of life has been reported (Akawi et al., 2013).
Wrinkly skin syndrome
MedGen UID:
98030
Concept ID:
C0406587
Disease or Syndrome
ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression.
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.
Myopathy, centronuclear, 2
MedGen UID:
98049
Concept ID:
C0410204
Disease or Syndrome
Any centronuclear myopathy in which the cause of the disease is a mutation in the BIN1 gene.
Pseudodiastrophic dysplasia
MedGen UID:
140924
Concept ID:
C0432206
Disease or Syndrome
Pseudodiastrophic dysplasia (PDD) is an extremely rare and severe skeletal dysplasia associated with prenatal manifestation and early lethality. Phenotypic features include short-limbed short stature at birth, facial dysmorphism, and distinctive skeletal abnormalities including short ribs, mild to moderate platyspondyly, shortened long bones with metaphyseal flaring, elongation of the proximal and middle phalanges with subluxation of the proximal interphalangeal joints, subluxation of the elbow, and talipes equinovarus (summary by Byrne et al., 2020). Based on genetic analysis of patients with a clinical diagnosis of PDD, Byrne et al. (2020) proposed that PDD is likely not a separate genetic disorder, but rather the most severe phenotypic manifestation of skeletal dysplasia arising from defects in proteoglycan (PG) biosynthesis (see MOLECULAR GENETICS).
Mesomelic dwarfism, Nievergelt type
MedGen UID:
98478
Concept ID:
C0432231
Disease or Syndrome
A rare primary bone dysplasia characterized by severe mesomelic shortness particularly of the lower limbs with distinctive triangular or rhomboid-shaped tibiae and fibulae, accompanied by bony protuberances and skin dimples. Additional manifestations include radioulnar synostosis, dislocation of the radial head, abnormalities of the hands (such as oligosyndactyly or fusiform-shaped fingers) and feet (pes equinovarus, synostoses of tarsals/metatarsals and phalanges), and dysmorphic facial features.
Kyphomelic dysplasia
MedGen UID:
140930
Concept ID:
C0432239
Disease or Syndrome
A rare primary bone dysplasia characterized, radiologically, by short, stubby long bones, severely angulated femurs and lesser bowing of other long bones (mild, moderate or no bowing), short and wide iliac wings with horizontal acetabular roofs, platyspondyly and a narrow thorax, clinically manifesting with severe, disproportionate short stature. Regression of femora angulation is observed with advancing age.
Osteopathia striata with cranial sclerosis
MedGen UID:
96590
Concept ID:
C0432268
Disease or Syndrome
Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. Males can present with a mild or severe phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant. The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.
Deletion of long arm of chromosome 18
MedGen UID:
96605
Concept ID:
C0432443
Disease or Syndrome
Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.
3-Methylglutaconic aciduria type 2
MedGen UID:
107893
Concept ID:
C0574083
Disease or Syndrome
Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.
Costello syndrome
MedGen UID:
108454
Concept ID:
C0587248
Disease or Syndrome
While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
Microphthalmia with limb anomalies
MedGen UID:
154638
Concept ID:
C0599973
Disease or Syndrome
Ophthalmo-acromelic syndrome is a condition that results in malformations of the eyes, hands, and feet. The features of this condition are present from birth. The eyes are often absent or severely underdeveloped (anophthalmia), or they may be abnormally small (microphthalmia). Usually both eyes are similarly affected in this condition, but if only one eye is small or missing, the other eye may have a defect such as a gap or split in its structures (coloboma).\n\nThe most common hand and foot malformation seen in ophthalmo-acromelic syndrome is missing fingers or toes (oligodactyly). Other frequent malformations include fingers or toes that are fused together (syndactyly) or extra fingers or toes (polydactyly). These skeletal malformations are often described as acromelic, meaning that they occur in the bones that are away from the center of the body. Additional skeletal abnormalities involving the long bones of the arms and legs or the spinal bones (vertebrae) can also occur. Affected individuals may have distinctive facial features, an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate), or intellectual disability.
Scapuloperoneal spinal muscular atrophy
MedGen UID:
148283
Concept ID:
C0751335
Disease or Syndrome
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Kleefstra syndrome 1
MedGen UID:
208639
Concept ID:
C0795833
Disease or Syndrome
Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.
MASA syndrome
MedGen UID:
162894
Concept ID:
C0795953
Disease or Syndrome
L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1. X-linked complicated corpus callosum agenesis. Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family.
Marden-Walker syndrome
MedGen UID:
163206
Concept ID:
C0796033
Disease or Syndrome
Marden-Walker syndrome (MWKS) is characterized by psychomotor retardation, a mask-like face with blepharophimosis, micrognathia and a high-arched or cleft palate, low-set ears, kyphoscoliosis, and joint contractures. Other features may include Dandy-Walker malformation with hydrocephalus and vertebral abnormalities (summary by Schrander-Stumpel et al., 1993). There are 2 distal arthrogryposis syndromes with features overlapping those of Marden-Walker syndrome that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and distal arthrogryposis type 5 (DA5; 108145), which are distinguished by the presence of cleft palate and ocular abnormalities, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition.
Simpson-Golabi-Behmel syndrome type 1
MedGen UID:
162917
Concept ID:
C0796154
Disease or Syndrome
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.
Syndromic X-linked intellectual disability Snyder type
MedGen UID:
162918
Concept ID:
C0796160
Disease or Syndrome
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.
Wieacker-Wolff syndrome
MedGen UID:
163227
Concept ID:
C0796200
Disease or Syndrome
Wieacker-Wolff syndrome (WRWF) is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia), which results in arthrogryposis multiplex congenita (AMC) apparent at birth. Affected boys are born with severe contractures, show delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and foot deformities. Additional features include global developmental delay with poor or absent speech and impaired intellectual development, feeding difficulties and poor growth, hypotonia, hypogenitalism, and spasticity. Carrier females may be unaffected or have mild features of the disorder (summary by Hirata et al., 2013 and Frints et al., 2019).
Schimke immuno-osseous dysplasia
MedGen UID:
164078
Concept ID:
C0877024
Congenital Abnormality
Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated.
Fetal akinesia deformation sequence 1
MedGen UID:
220903
Concept ID:
C1276035
Disease or Syndrome
Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).
Phosphoribosylaminoimidazole carboxylase deficiency
MedGen UID:
713858
Concept ID:
C1291561
Disease or Syndrome
Phosphoribosylaminoimidazole carboxylase deficiency (PAICSD) is an autosomal recessive disorder characterized by multiple congenital anomalies and early neonatal death (Pelet et al., 2019).
Microcephalic osteodysplastic dysplasia, Saul-Wilson type
MedGen UID:
722057
Concept ID:
C1300285
Disease or Syndrome
Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported.
Barber-Say syndrome
MedGen UID:
230818
Concept ID:
C1319466
Disease or Syndrome
Barber-Say syndrome (BBRSAY) is a rare congenital condition characterized by severe hypertrichosis, especially of the back, skin abnormalities such as hyperlaxity and redundancy, and facial dysmorphism, including macrostomia, eyelid deformities, ocular telecanthus, abnormal and low-set ears, bulbous nasal tip with hypoplastic alae nasi, and low frontal hairline (summary by Roche et al., 2010).
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.
Autosomal dominant chondrodysplasia punctata
MedGen UID:
303176
Concept ID:
C1442935
Disease or Syndrome
Autosomal dominant form of chondrodysplasia punctata.
Renal hypodysplasia/aplasia 1
MedGen UID:
301437
Concept ID:
C1619700
Congenital Abnormality
Renal hypodysplasia/aplasia belongs to a group of perinatally lethal renal diseases, including bilateral renal aplasia, unilateral renal agenesis with contralateral dysplasia (URA/RD), and severe obstructive uropathy. Renal aplasia falls at the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT; 610805), and usually results in death in utero or in the perinatal period. Families have been documented in which bilateral renal agenesis or aplasia coexists with unilateral renal aplasia, renal dysplasia, or renal aplasia with renal dysplasia, suggesting that these conditions may belong to a pathogenic continuum or phenotypic spectrum (summary by Joss et al., 2003; Humbert et al., 2014). Genetic Heterogeneity of Renal Hypodysplasia/Aplasia See also RHDA2 (615721), caused by mutation in the FGF20 gene (605558) on chromosome 8p22; RHDA3 (617805), caused by mutation in the GREB1L gene (617782) on chromosome 18q11; and RHDA4 (619887), caused by mutation in the GFRA1 gene (601496) on chromosome 10q25.
Cervical ribs, Sprengel anomaly, anal atresia, and urethral obstruction
MedGen UID:
318617
Concept ID:
C1832391
Disease or Syndrome
Charcot-Marie-Tooth disease type 4B1
MedGen UID:
321947
Concept ID:
C1832399
Disease or Syndrome
Charcot-Marie-Tooth disease, type 4B1 (CMT4B1) is a severe early-onset demyelinating CMT peripheral sensorimotor polyneuropathy. It was initially described in an Italian family and around 10 additional families have been described so far. Onset occurs during early childhood with distal and proximal muscular weakness starting in the lower extremities, sensory loss and cranial nerve involvement. Foot deformities are frequent and diaphragmatic and facial involvement has been reported. CMT4B1 is caused by mutations in the gene encoding myotubularin-related protein 2 (MTMR2; 11q22), involved in polyphosphoinositide signaling. Transmitted in an autosomal recessive manner.
Aprosencephaly cerebellar dysgenesis
MedGen UID:
330459
Concept ID:
C1832412
Disease or Syndrome
A rare genetic non-syndromic central nervous system malformation with characteristics of absence of the telencephalon and absent or abnormal diencephalic structures, combined with severe abnormalities of the mesencephalon and cerebellum. Further malformations, for example of the hands and feet, have been described in addition.
Multiple synostoses syndrome 2
MedGen UID:
331348
Concept ID:
C1832708
Disease or Syndrome
Multiple synostoses syndrome-2 (SYNS2) is an autosomal dominant disorder characterized by progressive joint fusions of the fingers, wrists, ankles, and cervical spine; characteristic facies, including a broad hemicylindrical nose; and progressive conductive hearing loss (summary by Dawson et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of multiple synostoses syndrome, see SYNS1 (186500).
ALG3-congenital disorder of glycosylation
MedGen UID:
322026
Concept ID:
C1832736
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). CDG1D is a type I CDG that generally presents with severe neurologic involvement associated with dysmorphism and visual impairment. Liver involvement is sometimes present (summary by Marques-da-Silva et al., 2017). For a discussion of the classification of CDGs, see CDG1A (212065).
Van den Ende-Gupta syndrome
MedGen UID:
322127
Concept ID:
C1833136
Disease or Syndrome
Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by Patel et al., 2014).
Charcot-Marie-Tooth disease type 4H
MedGen UID:
324487
Concept ID:
C1836336
Disease or Syndrome
Charcot-Marie-Tooth disease, type 4H (CMT4H) is a demyelinating CMT peripheral sensorimotor polyneuropathy. It has been described in 10 individuals from two large consanguineous families from Lebanon and Algeria. Onset occurs within the first two years of life with slowly progressive muscle weakness in the distal extremities. Other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. CMT4H is caused by mutations in the FGD4 gene (12p11.1). Transmitted in an autosomal recessive manner.
Bruck syndrome 2
MedGen UID:
373129
Concept ID:
C1836602
Disease or Syndrome
Bruck syndrome-2 (BRKS2) is an autosomal recessive disorder characterized by osteoporosis, joint contractures at birth, fragile bones, and short stature (Van der Slot et al., 2003). For a discussion of genetic heterogeneity of Bruck syndrome, see Bruck syndrome-1 (BRKS1; 259450).
Arthrogryposis-severe scoliosis syndrome
MedGen UID:
373169
Concept ID:
C1836756
Disease or Syndrome
Distal arthrogryposis type 4 (DA4) is distinguished by the presence of scoliosis (summary by Bamshad et al., 2009). For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Spondyloepiphyseal dysplasia with congenital joint dislocations
MedGen UID:
373381
Concept ID:
C1837657
Disease or Syndrome
CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.
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.
Neuronopathy, distal hereditary motor, autosomal dominant 8
MedGen UID:
373984
Concept ID:
C1838492
Disease or Syndrome
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
TARP syndrome
MedGen UID:
333324
Concept ID:
C1839463
Disease or Syndrome
The classic features of TARP syndrome are talipes equinovarus, atrial septal defect, Robin sequence (micrognathia, cleft palate, and glossoptosis), and persistent left superior vena cava. Not all patients have all classic features. Some patients have the additional features of central nervous system dysfunction, renal abnormalities, variable cardiac anomalies including hypertrophic obstructive cardiomyopathy, and variable distal limb defects including syndactyly. Most patients die in late prenatal or early postnatal stages (summary by Kaeppler et al., 2018).
Prieto syndrome
MedGen UID:
374294
Concept ID:
C1839730
Disease or Syndrome
Prieto syndrome (PRS) is an X-linked intellectual developmental disorder characterized by mildly to severely impaired intellectual development, developmental delay, autism spectrum disorder, or neuropsychiatric symptoms, variably accompanied by speech delay, epilepsy, microcephaly, structural brain defects, and minor facial anomalies (summary by Kury et al., 2022).
Charcot-Marie-Tooth disease recessive intermediate A
MedGen UID:
334012
Concept ID:
C1842197
Disease or Syndrome
GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.
Diaphanospondylodysostosis
MedGen UID:
374993
Concept ID:
C1842691
Disease or Syndrome
Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (summary by Funari et al., 2010).
Charcot-Marie-Tooth disease axonal type 2K
MedGen UID:
375064
Concept ID:
C1842983
Disease or Syndrome
A severe early-onset form of axonal Charcot-Marie-Tooth peripheral sensorimotor polyneuropathy. Onset occurs in the neonatal period or early infancy with a clinical picture including hypotonia, scoliosis, a hoarse voice, vocal cord paralysis and respiratory insufficiency. However, nerve conduction velocities and pathological findings from sural nerve biopsies are indicative of a predominantly axonal neuropathy with some demyelinating features. Caused by mutations in the GDAP1 gene (8q13.3), encoding a protein required for mitochondrial fission.
Pontocerebellar hypoplasia type 1A
MedGen UID:
335969
Concept ID:
C1843504
Disease or Syndrome
Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early. Genetic Heterogeneity of Pontocerebellar Hypoplasia Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH1D (618065), caused by mutation in the EXOSC9 gene (606180); PCH1E (619303), caused by mutation in the SLC25A46 gene (610826); PCH1F (619304), caused by mutation in the EXOSC1 gene (606493); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH7 (614969), caused by mutation in the TOE1 gene (613931); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); PCH10 (615803), caused by mutation in the CLP1 gene (608757); PCH11 (617695), caused by mutation in the TBC1D23 gene (617687); PCH12 (618266), caused by mutation in the COASY gene (609855); PCH13 (618606), caused by mutation in the VPS51 gene (615738); PCH14 (619301), caused by mutation in the PPIL1 gene (601301); PCH15 (619302), caused by mutation in the CDC40 gene (605585); PCH16 (619527), caused by mutation in the MINPP1 gene (605391); and PCH17 (619909), caused by mutation in the PRDM13 gene (616741) on chromosome 6q16.
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).
Alpha thalassemia-X-linked intellectual disability syndrome
MedGen UID:
337145
Concept ID:
C1845055
Disease or Syndrome
Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.
Syndromic X-linked intellectual disability Claes-Jensen type
MedGen UID:
335139
Concept ID:
C1845243
Disease or Syndrome
Claes-Jensen type of X-linked syndromic intellectual developmental disorder (MRXSCJ) is characterized by impaired intellectual development with substantial clinical heterogeneity in affected males. However, males are usually reported to have short stature, microcephaly, hyperreflexia, and aggressive behavior. In rare cases, female carriers exhibit mildly impaired intellectual development or learning difficulties (summary by Guerra et al., 2020).
X-linked intellectual disability, Stocco dos Santos type
MedGen UID:
335202
Concept ID:
C1845530
Disease or Syndrome
X-linked intellectual disability, Stocco Dos Santos type is characterised by severe intellectual deficit with hyperactivity, language delay, congenital hip luxation, short stature, kyphosis and recurrent respiratory infections. Aggressive behaviour and frequent epileptic seizures may also be present. The syndrome has been described in four boys from the same family. Transmission is X-linked and is caused by mutations in the <i>KIAA1202</i> gene, localised to the Xp11.2 region.
Uruguay Faciocardiomusculoskeletal syndrome
MedGen UID:
335320
Concept ID:
C1846010
Disease or Syndrome
Uruguay faciocardiomusculoskeletal syndrome (FCMSU) is an X-linked disorder in which affected males have a distinctive facial appearance, muscular hypertrophy, and cardiac ventricular hypertrophy leading to premature death. Additional features include large, broad, and deformed hands and feet, congenital hip dislocation, and scoliosis (summary by Xue et al., 2016).
Oculofaciocardiodental syndrome
MedGen UID:
337547
Concept ID:
C1846265
Disease or Syndrome
Oculofaciocardiodental (OFCD) syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-) and teeth (dental). This condition occurs only in females.\n\nThe eye abnormalities associated with OFCD syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a higher risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.\n\nPeople with OFCD syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes and a broad nasal tip that is divided by a cleft. Some affected people have an opening in the roof of the mouth called a cleft palate.\n\nHeart defects are another common feature of OFCD syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).\n\nTeeth with very large roots (radiculomegaly) are characteristic of OFCD syndrome. Additional dental abnormalities can include delayed loss of primary (baby) teeth, missing or abnormally small teeth, misaligned teeth, and defective tooth enamel.
Multiple epiphyseal dysplasia type 4
MedGen UID:
376164
Concept ID:
C1847593
Disease or Syndrome
Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild.
Whistling face syndrome, recessive form
MedGen UID:
376364
Concept ID:
C1848470
Disease or Syndrome
Whistling face syndrome is characterized by an atypical facial appearance with anomalies of the hands and feet. Most cases show autosomal dominant inheritance: see distal arthrogryposis 2A (DA2A; 193700). There are rare reports of presumably autosomal recessive inheritance (summary by Altunhan et al., 2010).
Methylmalonic aciduria and homocystinuria type cblF
MedGen UID:
336373
Concept ID:
C1848578
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord.
Ulna hypoplasia-intellectual disability syndrome
MedGen UID:
341275
Concept ID:
C1848650
Disease or Syndrome
Ulna hypoplasia - intellectual deficit is a very rare syndrome characterized by mesomelic shortness of the forearms, bilateral clubfeet, aplasia or hypoplasia of all nails and severe psychomotor retardation.
Teebi-Shaltout syndrome
MedGen UID:
376472
Concept ID:
C1848912
Disease or Syndrome
Teebi-Shaltout syndrome is characterized by slow hair growth, scaphocephaly with prominent forehead, bitemporal depression, absence of primary teeth, camptodactyly, and caudal appendage with sacral dimple (summary by Aldemir et al., 2013).
Spondylocarpotarsal synostosis syndrome
MedGen UID:
341339
Concept ID:
C1848934
Disease or Syndrome
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Cold-induced sweating syndrome 1
MedGen UID:
338577
Concept ID:
C1848947
Disease or Syndrome
Cold-induced sweating syndrome (CISS) and its infantile presentation, Crisponi syndrome(CS) is characterized by dysmorphic features (distinctive facies, lower facial weakness, flexion deformity at the elbows, camptodactyly with fisted hands, misshapen feet, and overriding toes); intermittent contracture of facial and oropharyngeal muscles when crying or being handled with puckering of lips and drooling of foamy saliva often associated with laryngospasm and respiratory distress; excessive startling and opisthotonus-like posturing with unexpected tactile or auditory stimuli; poor suck reflex and severely impaired swallowing; and a scaly erythematous rash. During the first decade of life, children with CISS/CS develop profuse sweating of the face, arms, and chest with ambient temperatures below 18º to 22º C, and with other stimuli including nervousness or ingestion of sweets. Affected individuals sweat very little in hot environments and may feel overheated. Progressive thoracolumbar kyphoscoliosis occurs, requiring intervention in the second decade.
Richieri Costa-Pereira syndrome
MedGen UID:
336581
Concept ID:
C1849348
Disease or Syndrome
Patients with Richieri-Costa-Pereira syndrome display a pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of the mandible, cleft palate/Robin sequence, absence of lower central incisors, minor ear anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability is also a common finding (summary by Favaro et al., 2011).
Bartsocas-Papas syndrome 1
MedGen UID:
337894
Concept ID:
C1849718
Disease or Syndrome
Bartsocas-Papas syndrome-1 (BPS1) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by Mitchell et al., 2012). Genetic Heterogeneity of Bartsocas-Papas Syndrome Bartsocas-Papas syndrome-2 (BPS2) is caused by mutation in the CHUK gene (600664). A less severe form of popliteal pterygium syndrome (PPS; 119500) is caused by mutation in the IRF6 gene (607199).
Pelviscapular dysplasia
MedGen UID:
342400
Concept ID:
C1850040
Disease or Syndrome
Syndrome with characteristics of pelviscapular dysplasia with epiphyseal abnormalities, congenital dwarfism and facial dysmorphism. The facial dysmorphism has manifestations of frontal bossing, hypertelorism, narrow palpebral fissures, deep-set eyes, strabismus, low-set posteriorly rotated and malformed ears, dysplasia of conchae, a small chin, a short neck with redundant skin folds, and a low hairline. Intelligence may vary from normal to moderately impaired. Radiographic features comprise aplasia of the body of the scapula, hypoplasia of the iliac bone, humeroradial synostosis, dislocation of the femoral heads, and moderate brachydactyly. Mutations in the TBX15 gene have been identified as potentially causative. Pelviscapular dysplasia is phenotypically similar to pelvis-shoulder dysplasia.
Parkinsonian-pyramidal syndrome
MedGen UID:
337969
Concept ID:
C1850100
Disease or Syndrome
Parkinson's disease is a progressive disorder of the nervous system. The disorder affects several regions of the brain, especially an area called the substantia nigra that controls balance and movement.\n\nOften the first symptom of Parkinson's disease is trembling or shaking (tremor) of a limb, especially when the body is at rest. Typically, the tremor begins on one side of the body, usually in one hand. Tremors can also affect the arms, legs, feet, and face. Other characteristic symptoms of Parkinson's disease include rigidity or stiffness of the limbs and torso, slow movement (bradykinesia) or an inability to move (akinesia), and impaired balance and coordination (postural instability). These symptoms worsen slowly over time.\n\nParkinson's disease can also affect emotions and thinking ability (cognition). Some affected individuals develop psychiatric conditions such as depression and visual hallucinations. People with Parkinson's disease also have an increased risk of developing dementia, which is a decline in intellectual functions including judgment and memory.\n\nGenerally, Parkinson's disease that begins after age 50 is called late-onset disease. The condition is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 are sometimes referred to as juvenile-onset Parkinson's disease.
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.
Exstrophy-epispadias complex
MedGen UID:
338020
Concept ID:
C1850321
Disease or Syndrome
Carey et al. (1978) gave the name OEIS complex to a combination of defects comprising omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. This rare complex is thought to represent the most severe end of a spectrum of birth defects, the exstrophy-epispadias sequence, which, in order of increasing severity, includes phallic separation with epispadias, pubic diastasis, exstrophy of the bladder (600057), cloacal exstrophy, and OEIS complex. Very few instances of recurrence of anomalies in this cluster have been reported.
Giant axonal neuropathy 1
MedGen UID:
376775
Concept ID:
C1850386
Disease or Syndrome
GAN-related neurodegeneration comprises a phenotypic continuum ranging from severe (sometimes called classic giant axonal neuropathy) to milder pure early-onset peripheral motor and sensory neuropathies. The classic giant axonal neuropathy phenotype typically manifests as an infantile-onset neurodegenerative disorder, starting as a severe peripheral motor and sensory neuropathy and evolving into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. At the milder end of the spectrum are predominantly motor and sensory neuropathies (with little to no CNS involvement) that overlap with the axonal form of Charcot-Marie-Tooth neuropathies.
Atelosteogenesis type II
MedGen UID:
338072
Concept ID:
C1850554
Disease or Syndrome
Clinical features of atelosteogenesis type 2 (AO2) include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. AO2 is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. However, it exists in a continuous phenotypic spectrum with diastrophic dysplasia, and long-term survivors have been reported.
Cerebrooculofacioskeletal syndrome 3
MedGen UID:
342008
Concept ID:
C1851443
Disease or Syndrome
Cerebrooculofacioskeletal syndrome is a severe, progressive neurologic disorder characterized by prenatal onset of arthrogryposis, microcephaly, and growth failure. Postnatal features include severe developmental delay, congenital cataracts (in some), and marked UV sensitivity of the skin. Survival beyond 6 years of age is rare. COFS represents the severe end of the spectrum of disorders caused by mutations in nucleotide excision repair (NER) genes, with Cockayne syndrome and xeroderma pigmentosum being milder NER-related phenotypes (summary by Drury et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see COFS1 (214150).
Ehlers-Danlos syndrome type 7B
MedGen UID:
342092
Concept ID:
C1851801
Disease or Syndrome
Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.\n\nThe various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.\n\nAn unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.\n\nMany people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.\n\nOther types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.\n\nBleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.
Dystonia 5
MedGen UID:
342121
Concept ID:
C1851920
Disease or Syndrome
GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur.
Arthrogryposis, distal, type 2E
MedGen UID:
343844
Concept ID:
C1852597
Disease or Syndrome
Hereditary spastic paraplegia 33
MedGen UID:
339943
Concept ID:
C1853251
Disease or Syndrome
Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the ZFYVE27 gene.
Genitopatellar syndrome
MedGen UID:
381208
Concept ID:
C1853566
Disease or Syndrome
KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype.
Microcephaly-micromelia syndrome
MedGen UID:
381553
Concept ID:
C1855079
Disease or Syndrome
Microcephaly-micromelia syndrome (MIMIS) is a severe autosomal recessive disorder that usually results in death in utero or in the perinatal period. Affected individuals have severe growth retardation with microcephaly and variable malformations of the limbs, particularly the upper limbs. Defects include radial ray anomalies, malformed digits, and clubfeet (summary by Evrony et al., 2017).
Spondylometaphyseal dysplasia, Sedaghatian type
MedGen UID:
340816
Concept ID:
C1855229
Disease or Syndrome
Sedaghatian-type spondylometaphyseal dysplasia (SMDS) is a rare lethal disorder characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, delayed epiphyseal ossification, irregular iliac crests, and pulmonary hemorrhage. Affected infants present with severe hypotonia and cardiorespiratory problems; most die within days of birth due to respiratory failure. Cardiac abnormalities include conduction defects, complete heart block, and structural anomalies. Half of infants with SMDS are reported to have central nervous system malformations consistent with abnormal neuronal migration, including agenesis of the corpus callosum, pronounced frontotemporal pachygyria, simplified gyral pattern, partial lissencephaly, and severe cerebellar hypoplasia (summary by Smith et al., 2014).
Frank-Ter Haar syndrome
MedGen UID:
383652
Concept ID:
C1855305
Disease or Syndrome
The primary characteristics of the Frank-ter Haar syndrome (FTHS) are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).
Lambert syndrome
MedGen UID:
343381
Concept ID:
C1855551
Disease or Syndrome
A very rare syndrome described in four siblings of one French family and with characteristics of branchial dysplasia (malar hypoplasia, macrostomia, preauricular tags and meatal atresia), club feet, inguinal hernia and cholestasis due to paucity of interlobular bile ducts and intellectual deficit.
Hydrolethalus syndrome 1
MedGen UID:
343455
Concept ID:
C1856016
Disease or Syndrome
Hydrolethalus-1 (HLS1) is an autosomal recessive lethal malformation syndrome characterized by hydrocephaly with absent upper midline structures of the brain, micrognathia, and polydactyly. Various other features such as cleft lip or palate, club feet, anomalies of the ears, eyes, and nose, keyhole-shaped defect in the occipital bone, abnormal genitalia, and congenital heart and respiratory organ defects have also been observed in affected individuals. Affected individuals are stillborn or die shortly after birth (summary by Mee et al., 2005). Genetic Heterogeneity of Hydrolethalus Syndrome See also HLS2 (614120), caused by mutation in the KIF7 gene (611254) on chromosome 15q26.
Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome
MedGen UID:
343465
Concept ID:
C1856053
Disease or Syndrome
MARCH is an autosomal recessive lethal congenital disorder characterized by severe hydranencephaly with almost complete absence of the cerebral hemispheres, which are replaced by fluid, relative preservation of the posterior fossa structures, and renal dysplasia or agenesis. Affected fetuses either die in utero or shortly after birth, and show arthrogryposis and features consistent with anhydramnios. Histologic examination of residual brain tissue shows multinucleated neurons resulting from impaired cytokinesis (summary by Frosk et al., 2017).
Fuhrmann syndrome
MedGen UID:
346429
Concept ID:
C1856728
Disease or Syndrome
This syndrome has main characteristics of bowing of the femora, aplasia or hypoplasia of the fibulae and poly, oligo and syndactyly. It has been reported in 11 patients. Most of the patients also had a hypoplastic pelvis and hypoplasia of the fingers and fingernails. Some had congenital dislocation of the hip, absence or fusion of tarsal bones, absence of various metatarsals and hypoplasia and aplasia of the toes. The syndrome is caused by a partial loss of WNT7A function (gene mapped to 3p25).
Erythema of acral regions
MedGen UID:
384009
Concept ID:
C1856900
Finding
Lethal Kniest-like syndrome
MedGen UID:
347372
Concept ID:
C1857100
Disease or Syndrome
Silverman-Handmaker dyssegmental dysplasia (DDSH) is a lethal autosomal recessive skeletal dysplasia with anisospondyly and micromelia. Individuals with DDSH also have a flat face, micrognathia, cleft palate and reduced joint mobility, and frequently have an encephalocele. The endochondral growth plate is short, the calcospherites (spherical calcium-phosphorus crystals produced by hypertrophic chondrocytes) are unfused, and there is mucoid degeneration of the resting cartilage (summary by Arikawa-Hirasawa et al., 2001).
Temtamy syndrome
MedGen UID:
347474
Concept ID:
C1857512
Disease or Syndrome
Temtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (summary by Akizu et al., 2013).
NDE1-related microhydranencephaly
MedGen UID:
341899
Concept ID:
C1857977
Disease or Syndrome
Microhydranencephaly (MHAC) is a severe neurodevelopmental defect characterized by extreme microcephaly, profound motor and mental retardation, spasticity, and incomplete cerebral formation. Radiologic studies show gross dilation of the ventricles resulting from the absence of cerebral hemispheres or severe delay in their development, as well as hypoplasia of the corpus callosum, cerebellum, and brainstem (summary by Guven et al., 2012).
Charcot-Marie-Tooth disease type 4B2
MedGen UID:
346869
Concept ID:
C1858278
Disease or Syndrome
Autosomal recessive Charcot-Marie-Tooth disease type 4B2 (CMT4B2) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. CMT4B1 (601382) is a clinically similar disorder caused by mutation in the MTMR2 gene (603557) on 11q22. For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating CMT, see CMT4A (214400).
Autosomal recessive distal spinal muscular atrophy 1
MedGen UID:
388083
Concept ID:
C1858517
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-1 (HMNR1) is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, most infants with the severe form of the disease die before 2 years of age. Affected individuals present in infancy with inspiratory stridor, weak cry, recurrent bronchopneumonia, and swallowing difficulties. The disorder is caused by distal and progressive motor neuronopathy resulting in muscle weakness (summary by Perego et al., 2020). Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy See also HMNR2 (605726), caused by mutation in the SIGMAR1 gene (601978); HMNR3 (607088) (encompassing Harding HMN types III and IV), which maps to chromosome 11q13; HMNR4 (611067), caused by mutation in the PLEKHG5 gene (611101); HMNR5 (614881), caused by mutation in the DNAJB2 gene (604139); HMNR6 (620011), caused by mutation in the REEP1 gene (609139); HMNR7 (619216), caused by mutation in the VWA1 gene (611901); HMNR8 (618912), caused by mutation in the SORD gene (182500); HMNR9 (620402), caused by mutation in the COQ7 gene (601683); and HMRN10 (620542), caused by mutation in the VRK1 gene (602168).
Blepharophimosis - intellectual disability syndrome, Verloes type
MedGen UID:
347661
Concept ID:
C1858538
Disease or Syndrome
Blepharophimosis-intellectual disability syndrome, Verloes type is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly, severe epilepsy with hypsarrhythmia, adducted thumbs, abnormal genitalia, and normal thyroid function. Hypotonia, moderate to severe psychomotor delay, and characteristic facial dysmorphism (including round face with prominent cheeks, blepharophimosis, large, bulbous nose with wide alae nasi, posteriorly rotated ears with dysplastic conchae, narrow mouth, cleft palate, and mild micrognathia) are additional characteristic features.
Congenital cataracts-facial dysmorphism-neuropathy syndrome
MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality
CTDP1-related congenital cataracts, facial dysmorphism, and neuropathy (CTDP1-CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), mildly dysmorphic facial features apparent in late childhood, and a hypo-/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade of life. Secondary foot deformities and scoliosis are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild nonprogressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and most have subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Romani population.
Tel Hashomer camptodactyly syndrome
MedGen UID:
347860
Concept ID:
C1859356
Disease or Syndrome
A rare syndrome with characteristics of camptodactyly, muscle hypoplasia and weakness, skeletal anomalies, facial dysmorphism and abnormal dermatoglyphics. Dysmorphic features include facial asymmetry, hypertelorism, broad nasal bridge, long philtrum and a small mouth. Winging scapulae, scoliosis, syndactyly and clinodactyly are commonly observed. The affected patients usually have normal mental development. The molecular basis of the syndrome has not yet been elucidated.
Cooper-Jabs syndrome
MedGen UID:
347912
Concept ID:
C1859591
Disease or Syndrome
A rare multiple congenital anomalies/dysmorphic syndrome characterized by auditory canal atresia (resulting in moderate conductive hearing loss) associated with intellectual disability, ventricular septal defect, umbilical hernia, anteriorly displaced anus, various skeletal anomalies (such as mild clubfoot, long fifth fingers, proximally placed thumbs), and craniofacial dysmorphism which includes brachycephaly, prominent forehead, flattened occiput, midface hypoplasia, anteverted nares, and low set, posteriorly rotated ears with overlapping superior helix. There have been no further descriptions in the literature since 1987.
Acrofacial dysostosis Rodriguez type
MedGen UID:
349730
Concept ID:
C1860119
Disease or Syndrome
A multiple malformation syndrome in which mandibulofacial dysostosis and severe limb reduction defects are associated with complex malformations of different organs and systems especially the central nervous system, urogenital tract, heart, and lungs. The mandibulofacial defect causes death by respiratory distress. Limb reduction is severe and includes shoulder and pelvis hypoplasia, phocomelia with humerus hypoplasia, absent radius and ulna, complete absence of long bones of the legs, and various hand anomalies, predominantly preaxial reduction. These infants also show facial dysmorphism and ear anomalies. The condition is a rare with an autosomal recessive mode of inheritance. The prognosis is poor and this condition leads to death in utero or shortly after birth.
Ablepharon macrostomia syndrome
MedGen UID:
395439
Concept ID:
C1860224
Disease or Syndrome
Ablepharon-macrostomia syndrome (AMS) is a congenital ectodermal dysplasia characterized by absent eyelids, macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and ears, variable abnormalities of the nipples, genitalia, fingers, and hands, largely normal intellectual and motor development, and poor growth (summary by Marchegiani et al., 2015).
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.
Brachydactyly type C
MedGen UID:
350590
Concept ID:
C1862103
Congenital Abnormality
The brachydactyly type C (BDC) phenotype includes brachymesophalangy of fingers 2, 3, and 5. The fourth finger is usually unaffected and thus appears as the longest finger of the hand. Shortening of metacarpal 1 and hyperphalangy in fingers 2 and 3 may occur and can be considered relatively characteristic signs. BDC can be highly variable, ranging from severely affected hands with very short fingers to mildly affected cases with only moderate brachydactyly, most often affecting the middle and proximal phalanges of fingers 2 and 3 (summary by Lehmann et al., 2006).
Acromelic frontonasal dysostosis
MedGen UID:
350933
Concept ID:
C1863616
Disease or Syndrome
Verloes et al. (1992) described a rare variant of frontonasal dysplasia (see FND1, 136760), designated acromelic frontonasal dysplasia (AFND), in which similar craniofacial anomalies are associated with variable central nervous system malformations and limb defects including tibial hypoplasia/aplasia, talipes equinovarus, and preaxial polydactyly of the feet.
Brachyphalangy, polydactyly, and tibial aplasia/hypoplasia
MedGen UID:
355340
Concept ID:
C1864965
Disease or Syndrome
Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome
MedGen UID:
355971
Concept ID:
C1865361
Disease or Syndrome
Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is an autosomal recessive multiple congenital anomaly syndrome with features of a first and second branchial arch syndrome. Craniofacial abnormalities can lead to conductive hearing loss, respiratory insufficiency, and feeding difficulties. Additional features include rhizomelic skeletal anomalies as well as abnormalities of the shoulder and pelvic joints. Affected individuals may also have some features of a neurocristopathy or abnormal mesoderm development, such as urogenital anomalies, that are distinct from other branchial arch syndromes (summary by Parry et al., 2013).
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.
Charcot-Marie-Tooth disease type 4C
MedGen UID:
356581
Concept ID:
C1866636
Disease or Syndrome
SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems.
Neurogenic scapuloperoneal syndrome, Kaeser type
MedGen UID:
356670
Concept ID:
C1867005
Disease or Syndrome
A rare genetic neuromuscular disease with characteristics of adult-onset muscle weakness and atrophy in a scapuloperoneal distribution, mild involvement of the facial muscles, dysphagia, and gynaecomastia. Elevated serum CK levels and mixed myopathic and neurogenic abnormalities are associated clinical findings. Caused by heterozygous mutation in the DES gene on chromosome 2q35.
Short stature-craniofacial anomalies-genital hypoplasia syndrome
MedGen UID:
357988
Concept ID:
C1867443
Disease or Syndrome
Pterygia, impaired intellectual development, and distinctive craniofacial features is a chromosomal disorder characterized by these cardinal features. Craniofacial features include trigonocephaly and retrognathia. Intellectual development may be severely impaired (summary by Devriendt et al., 2000).
4p partial monosomy syndrome
MedGen UID:
408255
Concept ID:
C1956097
Disease or Syndrome
Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, and micrognathia), and a seizure disorder (Battaglia et al., 2008).
Autosomal recessive limb-girdle muscular dystrophy type 2M
MedGen UID:
370585
Concept ID:
C1969040
Disease or Syndrome
MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (Godfrey et al., 2006). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009).
COG8-congenital disorder of glycosylation
MedGen UID:
409971
Concept ID:
C1970021
Disease or Syndrome
Syndrome with characteristics of severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products. So far, only two cases have been described. The disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus.
Neuronopathy, distal hereditary motor, autosomal recessive 4
MedGen UID:
369682
Concept ID:
C1970211
Disease or Syndrome
A rare genetic neuromuscular disease characterized by proximal muscle weakness with an early involvement of foot and hand muscles following normal motor development in early childhood, a rapidly progressive disease course leading to generalized areflexic tetraplegia with contractures, severe scoliosis, hyperlordosis, and progressive respiratory insufficiency leading to assisted ventilation. Cranial nerve functions are normal and tongue wasting and fasciculations are absent. Milder phenotype with a moderate generalized weakness and slower disease progress was reported. There is evidence the disease is caused by homozygous mutation in the gene encoding pleckstrin homology domain-containing protein, family G member 5 (PLEKHG5) on chromosome 1p36.
Mucolipidosis type II
MedGen UID:
435914
Concept ID:
C2673377
Disease or Syndrome
GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.
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.
Endocrine-cerebro-osteodysplasia syndrome
MedGen UID:
390740
Concept ID:
C2675227
Disease or Syndrome
Endocrine-cerebro-osteodysplasia (ECO) syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.
Chromosome 15q26-qter deletion syndrome
MedGen UID:
390804
Concept ID:
C2675463
Disease or Syndrome
Distal monosomy 15q is a rare chromosomal anomaly syndrome characterized by pre- and postnatal growth restriction, developmental delay, variable degrees of intellectual disability, hand and foot anomalies (e.g. brachy-/clinodactyly, talipes equinovarus, nail hypoplasia, proximally placed digits) and mild craniofacial dysmorphism (incl. microcephaly, triangular face, broad nasal bridge, micrognathia). Neonatal lymphedema, heart malformations, aplasia cutis congenita, aortic root dilatation, and autistic spectrum disorder have also been reported.
Chromosome 17P13.3, telomeric, duplication syndrome
MedGen UID:
390813
Concept ID:
C2675492
Disease or Syndrome
Chromosome 1q41-q42 deletion syndrome
MedGen UID:
382704
Concept ID:
C2675857
Disease or Syndrome
1q41q42 microdeletion syndrome is a chromosomal anomaly characterized by a severe developmental delay and/or intellectual disability, typical facial dysmorphic features, brain anomalies, seizures, cleft palate, clubfeet, nail hypoplasia and congenital heart disease.
Chromosome 2q32-q33 deletion syndrome
MedGen UID:
436765
Concept ID:
C2676739
Disease or Syndrome
SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited to absent speech, behavioral issues, and craniofacial anomalies. All individuals described to date have manifest developmental delay / intellectual disability, with severe speech delay. Affected individuals often have hypotonia and feeding difficulties in infancy. Behavioral issues may include autistic features, hyperactivity, and aggressiveness. Craniofacial anomalies may include palatal abnormalities (cleft palate, high-arched palate, and bifid uvula), micrognathia, and abnormal shape or size of the upper central incisors. Less common features include skeletal anomalies (osteopenia, pectus deformities, kyphosis/lordosis, and scoliosis), growth restriction, strabismus/refractive errors, congenital heart defects, genitourinary anomalies, and epilepsy. While dysmorphic features have been described in individuals with this condition, these features are not typically distinctive enough to allow for a clinical diagnosis of SAS.
Meckel syndrome, type 6
MedGen UID:
382942
Concept ID:
C2676790
Disease or Syndrome
Because of their serious health problems, most individuals with Meckel syndrome die before or shortly after birth. Most often, affected infants die of respiratory problems or kidney failure.\n\nOther signs and symptoms of Meckel syndrome vary widely among affected individuals. Numerous abnormalities of the brain and spinal cord (central nervous system) have been reported in people with Meckel syndrome, including a group of birth defects known as neural tube defects. These defects occur when a structure called the neural tube, a layer of cells that ultimately develops into the brain and spinal cord, fails to close completely during the first few weeks of embryonic development. Meckel syndrome can also cause problems with development of the eyes and other facial features, heart, bones, urinary system, and genitalia.\n\nMeckel syndrome is a disorder with severe signs and symptoms that affect many parts of the body. The most common features are enlarged kidneys with numerous fluid-filled cysts; an occipital encephalocele, which is a sac-like protrusion of the brain through an opening at the back of the skull; and the presence of extra fingers and toes (polydactyly). Most affected individuals also have a buildup of scar tissue (fibrosis) in the liver.
Spondyloepiphyseal dysplasia congenita
MedGen UID:
412530
Concept ID:
C2745959
Congenital Abnormality
Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990).
Spondylo-megaepiphyseal-metaphyseal dysplasia
MedGen UID:
412869
Concept ID:
C2750066
Disease or Syndrome
Spondylo-megaepiphyseal-metaphyseal dysplasia is a rare autosomal recessive skeletal dysplasia characterized by disproportionate short stature with a short and stiff neck and trunk; relatively long limbs that may show flexion contractures of the distal joints; delayed and impaired ossification of the vertebral bodies and the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones; and numerous pseudoepiphyses of the short tubular bones in hands and feet (summary by Hellemans et al., 2009).
Santos syndrome
MedGen UID:
414444
Concept ID:
C2751698
Disease or Syndrome
Hereditary spastic paraplegia 50
MedGen UID:
442869
Concept ID:
C2752008
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
ALG12-congenital disorder of glycosylation
MedGen UID:
443954
Concept ID:
C2931001
Disease or Syndrome
Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. CDG1G is a multisystem disorder characterized by impaired psychomotor development, dysmorphic features, failure to thrive, male genital hypoplasia, coagulation abnormalities, and immune deficiency. More variable features include skeletal dysplasia, cardiac anomalies, ocular abnormalities, and sensorineural hearing loss. Some patients die in the early neonatal or infantile period, whereas others are mildly affected and live to adulthood (summary by Tahata et al., 2019). For a general discussion of CDGs, see CDG1A (212065).
ALG8 congenital disorder of glycosylation
MedGen UID:
419692
Concept ID:
C2931002
Disease or Syndrome
CDGs, previously called carbohydrate-deficient glycoprotein syndromes, grew from hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. For a general discussion of CDGs, see CDG1A (212065). CDG1H is a severe form of CDG. The majority of patients have brain involvement, liver pathology, gastrointestinal symptoms, dysmorphism (including brachydactyly), eye involvement (especially cataract), and skin symptoms. Most patients die within the first year of life (summary by Marques-da-Silva et al., 2017).
COG1 congenital disorder of glycosylation
MedGen UID:
443957
Concept ID:
C2931011
Disease or Syndrome
An extremely rare form of carbohydrate deficient glycoprotein syndrome with, in the few cases reported to date, variable signs including microcephaly, growth retardation, psychomotor retardation and facial dysmorphism.
Chromosome 17q23.1-q23.2 deletion syndrome
MedGen UID:
461957
Concept ID:
C3150607
Disease or Syndrome
17q23.1q23.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, short stature, heart defects and limb abnormalities.
Rett syndrome, congenital variant
MedGen UID:
462055
Concept ID:
C3150705
Disease or Syndrome
The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005).
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).
Chromosome 4Q32.1-q32.2 triplication syndrome
MedGen UID:
462207
Concept ID:
C3150857
Disease or Syndrome
Familial clubfoot due to 17q23.1q23.2 microduplication
MedGen UID:
462230
Concept ID:
C3150880
Disease or Syndrome
17q23.1-q23.2 microduplication is a newly described cause of familial isolated clubfoot.
Chromosome 2q31.1 duplication syndrome
MedGen UID:
462290
Concept ID:
C3150940
Disease or Syndrome
A rare, genetic, chromosomal anomaly syndrome resulting from partial duplication of the long arm of chromosome 2 characterized by congenital pendular nystagmus associated with bilateral cutaneous syndactyly between the third and fourth fingers.
Progressive demyelinating neuropathy with bilateral striatal necrosis
MedGen UID:
462323
Concept ID:
C3150973
Disease or Syndrome
Thiamine metabolism dysfunction syndrome-4 (THMD4) is an autosomal recessive metabolic disorder characterized by childhood onset of episodic encephalopathy, often associated with a febrile illness, and causing transient neurologic dysfunction. Most patients recover fully, but some may have mild residual weakness. Affected individuals also develop a slowly progressive axonal polyneuropathy beginning in childhood. Brain imaging during the acute episodes shows lesions consistent with bilateral striatal degeneration or necrosis (summary by Spiegel et al., 2009). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Hereditary spastic paraplegia 51
MedGen UID:
462406
Concept ID:
C3151056
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
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 3
MedGen UID:
462463
Concept ID:
C3151113
Disease or Syndrome
Abnormalities 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.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\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\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\nMost 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.
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.
Hereditary spastic paraplegia 47
MedGen UID:
481368
Concept ID:
C3279738
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Spastic paraplegia 52, autosomal recessive
MedGen UID:
481373
Concept ID:
C3279743
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Meckel syndrome, type 9
MedGen UID:
481785
Concept ID:
C3280155
Disease or Syndrome
Meckel syndrome is a severe autosomal recessive ciliopathy classically defined by the triad of encephalocele, polydactyly, and renal and biliary ductal dysplasia (summary by Hopp et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).
Arthrogryposis, distal, type 1B
MedGen UID:
482156
Concept ID:
C3280526
Disease or Syndrome
MEGF10-related myopathy
MedGen UID:
482309
Concept ID:
C3280679
Disease or Syndrome
Congenital myopathy-10A (CMYP10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011). Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYP10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYP10B) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Psychomotor retardation, epilepsy, and craniofacial dysmorphism
MedGen UID:
482685
Concept ID:
C3281055
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures (NEDHCS) is an autosomal recessive syndrome characterized primarily by hypotonia and poor feeding apparent in early infancy. Affected individuals have severe global developmental delay, early-onset intractable seizures, and recognizable craniofacial dysmorphism with skull abnormalities. The disorder is believed to be unique to the Amish population, where it exhibits a founder effect (summary by Ammous et al., 2021).
Ehlers-Danlos syndrome, kyphoscoliotic and deafness type
MedGen UID:
482790
Concept ID:
C3281160
Disease or Syndrome
FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment. Most affected children achieve independent walking between ages two and four years. A decline of motor function in adulthood may be seen, but affected individuals are likely to be able to participate in activities of daily living in adulthood and maintain independent walking. Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy. Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse.
Hereditary sensory and autonomic neuropathy type 6
MedGen UID:
761278
Concept ID:
C3539003
Disease or Syndrome
Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).
Hereditary spastic paraplegia 55
MedGen UID:
761342
Concept ID:
C3539506
Disease or Syndrome
A rare complex type of hereditary spastic paraplegia with characteristics of childhood onset of progressive spastic paraplegia associated with optic atrophy (with reduced visual acuity and central scotoma), ophthalmoplegia, reduced upper-extremity strength and dexterity, muscular atrophy in the lower extremities and sensorimotor neuropathy. Caused by mutations in the C12ORF65 gene (12q24.31) encoding probable peptide chain release factor C12ORF65, mitochondrial.
Peroxisome biogenesis disorder 2A (Zellweger)
MedGen UID:
763187
Concept ID:
C3550273
Disease or Syndrome
The peroxisome biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 2 (CG2) have mutations in the PEX5 gene. For information on the history of PBD complementation groups, see 214100.
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.
Peroxisome biogenesis disorder 5A (Zellweger)
MedGen UID:
766854
Concept ID:
C3553940
Disease or Syndrome
The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 5 (CG5, equivalent to CG10 and CGF) have mutations in the PEX2 gene. For information on the history of PBD complementation groups, see 214100.
Pontocerebellar hypoplasia type 8
MedGen UID:
767123
Concept ID:
C3554209
Disease or Syndrome
Pontocerebellar hypoplasia type 8 is an autosomal recessive neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum (summary by Mochida et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
MEGF8-related Carpenter syndrome
MedGen UID:
767161
Concept ID:
C3554247
Disease or Syndrome
Carpenter syndrome-2 (CRPT2) is an autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease (summary by Twigg et al., 2012). For a discussion of genetic heterogeneity of Carpenter syndrome, see 201000.
Distal arthrogryposis type 5D
MedGen UID:
767329
Concept ID:
C3554415
Disease or Syndrome
This autosomal recessive form of distal arthrogryposis, designated DA5D by McMillin et al. (2013), is characterized by severe camptodactyly of the hands, including adducted thumbs and wrists; mild camptodactyly of the toes; clubfoot and/or a calcaneovalgus deformity; extension contractures of the knee; unilateral ptosis or ptosis that is more severe on one side; a round-shaped face; arched eyebrows; a bulbous, upturned nose; and micrognathia. Notably, these patients do not have ophthalmoplegia. For a general phenotypic description and discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120). For discussion of genetic heterogeneity of distal arthrogryposis type 5, see DA5 (108145).
Atelosteogenesis type III
MedGen UID:
777149
Concept ID:
C3668942
Congenital Abnormality
The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
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.
Renal-hepatic-pancreatic dysplasia 2
MedGen UID:
815764
Concept ID:
C3809434
Disease or Syndrome
RHPD2 is an autosomal recessive multisystemic disorder with severe abnormalities apparent in utero and often resulting in fetal death or death in infancy. The main organs affected include the kidney, liver, and pancreas, although other abnormalities, including cardiac, skeletal, and lung defects, may also be present. Affected individuals often have situs inversus. The disorder results from a defect in ciliogenesis and ciliary function, as well as in cell proliferation and epithelial morphogenesis; thus, the clinical manifestations are highly variable (summary by Grampa et al., 2016). For a discussion of genetic heterogeneity of renal-hepatic-pancreatic dysplasia, see RHPD1 (208540).
Charcot-Marie-Tooth disease type 2R
MedGen UID:
815985
Concept ID:
C3809655
Disease or Syndrome
A rare subtype of axonal hereditary motor and sensory neuropathy characterised by early-onset axial hypotonia, generalised muscle weakness, absent deep tendon reflexes and decreased muscle mass. Electromyography reveals decreased motor nerve conduction velocities with markedly reduced sensory and motor amplitudes. There is evidence the disease is caused by homozygous or compound heterozygous mutation in the TRIM2 gene on chromosome 4q.
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.
Hereditary spastic paraplegia 64
MedGen UID:
816619
Concept ID:
C3810289
Disease or Syndrome
Spastic paraplegia-64 (SPG64) is a neurologic disorder characterized by childhood onset of progressive spastic paraplegia with impaired intellectual development, gait impairment, dysarthria, and white matter abnormalities on brain imaging. Some individuals show neurocognitive regression (Calame et al., 2022). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Meckel syndrome, type 8
MedGen UID:
854220
Concept ID:
C3836857
Disease or Syndrome
Meckel-Gruber syndrome is a severe autosomal recessive ciliopathy classically defined by the triad of encephalocele, polydactyly, and renal and biliary ductal dysplasia. Clinical heterogeneity exists even within families (summary by Shaheen et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).
Hereditary spastic paraplegia 45
MedGen UID:
854816
Concept ID:
C3888209
Disease or Syndrome
A rare pure or complex form of hereditary spastic paraplegia with characteristics of onset in infancy of progressive lower limb spasticity, abnormal gait, increased deep tendon reflexes and extensor plantar responses that may be associated with intellectual disability. Additional signs such as contractures in the lower limbs, amyotrophy, clubfoot and optic atrophy, have also been reported. Caused by homozygous mutation in the NT5C2 gene on chromosome 10q24.
Peroxisome biogenesis disorder 7A (Zellweger)
MedGen UID:
854881
Concept ID:
C3888385
Disease or Syndrome
Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 8 (CG8, equivalent to CGA) have mutations in the PEX26 gene. For information on the history of PBD complementation groups, see 214100.
Hennekam lymphangiectasia-lymphedema syndrome 1
MedGen UID:
860487
Concept ID:
C4012050
Disease or Syndrome
Hennekam lymphangiectasia-lymphedema syndrome (HKLLS1) is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (summary by Alders et al., 2014). Genetic Heterogeneity of Hennekam Lymphangiectasia-Lymphedema Syndrome See also HKLLS2 (616006), caused by mutation in the FAT4 gene (612411) on chromosome 4q28, and HKLLS3 (618154), caused by mutation in the ADAMTS3 gene (605011) on chromosome 4q13.
Desbuquois dysplasia 1
MedGen UID:
860583
Concept ID:
C4012146
Disease or Syndrome
Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (summary by Huber et al., 2009). Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011). Genetic Heterogeneity of Desbuquois Dysplasia DBQD2 (615777) is caused by mutation in the XYLT1 gene (608124) on chromosome 16p12. Two unrelated patients with immunodeficiency-23 (IMD23; 615816), due to mutation in the PGM3 gene (172100), were reported to have skeletal features reminiscent of DBQD.
Short stature with microcephaly and distinctive facies
MedGen UID:
862776
Concept ID:
C4014339
Disease or Syndrome
Short stature with microcephaly and distinctive facies (SSMCF) is characterized by pre- or postnatal growth retardation, frontal bossing, high forehead, sparse hair and eyebrows, and telecanthus. Patients also show skin dyspigmentation, with hyper- and/or hypopigmented areas (Leduc et al., 2016).
Charcot-Marie-Tooth disease axonal type 2S
MedGen UID:
863786
Concept ID:
C4015349
Disease or Syndrome
Charcot-Marie-Tooth disease type 2S is a relatively pure form of autosomal recessive axonal neuropathy characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy affecting the lower and upper limbs. Patients have decreased reflexes and variable distal sensory impairment (summary by Cottenie et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Microcephaly and chorioretinopathy 2
MedGen UID:
863825
Concept ID:
C4015388
Disease or Syndrome
Microcephaly and chorioretinopathy-2 is an autosomal recessive developmental disorder characterized by delayed psychomotor development, visual impairment, and short stature (summary by Martin et al., 2014). For a discussion of genetic heterogeneity of microcephaly and chorioretinopathy, see MCCRP1 (251270).
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1
MedGen UID:
864165
Concept ID:
C4015728
Disease or Syndrome
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-1 (IMNEPD1) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. However, some patients may not display all features (summary by Picker-Minh et al., 2016, Sharkia et al., 2017). Genetic Heterogeneity of Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease See also IMNEPD2 (619418), caused by mutation in the YARS1 gene (603623) on chromosome 1p35.
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.
Joubert syndrome 24
MedGen UID:
905319
Concept ID:
C4084841
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.
Autosomal recessive limb-girdle muscular dystrophy type 2W
MedGen UID:
897675
Concept ID:
C4225192
Disease or Syndrome
Autosomal recessive muscular dystrophy with cardiomyopathy and triangular tongue (MDRCMTT) is an autosomal recessive muscle disorder characterized by onset of severe and progressive muscle weakness and atrophy in childhood, resulting in loss of independent ambulation. Patients may also have dilated cardiomyopathy and have macroglossia with a small tip, resulting in a triangular appearance of the tongue (summary by Warman Chardon et al., 2015).
Cardiac anomalies - developmental delay - facial dysmorphism syndrome
MedGen UID:
900924
Concept ID:
C4225208
Disease or Syndrome
Impaired intellectual development and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by Adegbola et al., 2015).
Seckel syndrome 9
MedGen UID:
907155
Concept ID:
C4225212
Disease or Syndrome
Any Seckel syndrome in which the cause of the disease is a mutation in the TRAIP gene.
Spastic paraplegia-severe developmental delay-epilepsy syndrome
MedGen UID:
897828
Concept ID:
C4225215
Disease or Syndrome
Spastic paraplegia and psychomotor retardation with or without seizures is an autosomal recessive complex neurodevelopmental disorder with onset in infancy. Affected children show hypotonia followed by severely impaired global development and significant motor disability. Most develop seizures in childhood and have speech delay. Other features, such as ocular abnormalities, foot deformities, hypoplasia of the corpus callosum, and decreased white matter, are more variable (summary by Hollstein et al., 2015).
Rhizomelic chondrodysplasia punctata type 5
MedGen UID:
900333
Concept ID:
C4225237
Disease or Syndrome
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life (summary by Wanders and Waterham, 2005). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
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).
Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
MedGen UID:
899982
Concept ID:
C4225295
Disease or Syndrome
PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria.
Lethal congenital contracture syndrome 9
MedGen UID:
903881
Concept ID:
C4225303
Disease or Syndrome
Any lethal congenital contracture syndrome in which the cause of the disease is a mutation in the ADGRG6 gene.
Intellectual disability, autosomal dominant 38
MedGen UID:
895359
Concept ID:
C4225343
Mental or Behavioral Dysfunction
Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the EEF1A2 gene.
Congenital contractures of the limbs and face, hypotonia, and developmental delay
MedGen UID:
907234
Concept ID:
C4225398
Disease or Syndrome
CLIFAHDD is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo (summary by Chong et al., 2015).
Acromesomelic dysplasia 3
MedGen UID:
904735
Concept ID:
C4225404
Disease or Syndrome
Singleton-Merten syndrome 1
MedGen UID:
899946
Concept ID:
C4225427
Disease or Syndrome
Singleton-Merten syndrome (SGMRT) is an uncommon autosomal dominant disorder characterized by abnormalities of blood vessels, teeth, and bone. Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty and can lead to early death. Dental findings include delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization, leading to tooth loss. Osseous features consist of osteoporosis, either generalized or limited to distal extremities, distal limb osteolysis, widened medullary cavities, and easy tearing of tendons from bone. Less common features are mild facial dysmorphism (high anterior hair line, broad forehead, smooth philtrum, thin upper vermilion border), generalized muscle weakness, psoriasis, early-onset glaucoma, and recurrent infections. The disorder manifests with variable inter- and intrafamilial phenotypes (summary by Rutsch et al., 2015). Genetic Heterogeneity of Singleton-Merten Syndrome An atypical form of Singleton-Merten syndrome (SGMRT2; 616298) is caused by mutation in the DDX58 gene (609631) on chromosome 9p21.
MIRAGE syndrome
MedGen UID:
924576
Concept ID:
C4284088
Disease or Syndrome
MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported.
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).
Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies
MedGen UID:
934611
Concept ID:
C4310644
Disease or Syndrome
GDACCF is an intellectual disability syndrome apparent soon after birth with neonatal hypotonia, poor feeding, and respiratory insufficiency followed by delayed psychomotor development and intellectual disability with poor speech. Brain imaging shows aplasia or hypoplasia of the corpus callosum. Affected individuals have variable dysmorphic facial features, and some may have dysplastic, cystic kidneys or mild cardiac defects (summary by Stevens et al., 2016).
Lissencephaly 8
MedGen UID:
934613
Concept ID:
C4310646
Disease or Syndrome
Lissencephaly-8 (LIS8) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development, intellectual disability with poor or absent speech, early-onset refractory seizures, and hypotonia. Brain imaging shows variable features, including cortical gyral abnormalities and hypoplasia of the corpus callosum, brainstem, and cerebellum (Jerber et al., 2016). For a general description and a discussion of genetic heterogeneity lissencephaly, see LIS1 (607432).
Periventricular nodular heterotopia 7
MedGen UID:
934636
Concept ID:
C4310669
Disease or Syndrome
Periventricular nodular heterotopia-7 (PVNH7) is a neurologic disorder characterized by abnormal neuronal migration during brain development resulting in delayed psychomotor development and intellectual disability; some patients develop seizures. Other features include cleft palate and 2-3 toe syndactyly (summary by Broix et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049.
Arthrogryposis, distal, with impaired proprioception and touch
MedGen UID:
934659
Concept ID:
C4310692
Disease or Syndrome
Distal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (summary by Chesler et al., 2016 and Delle Vedove et al., 2016).
Frontometaphyseal dysplasia 2
MedGen UID:
934664
Concept ID:
C4310697
Disease or Syndrome
Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia characterized by supraorbital hyperostosis, undermodeling of the small bones, and small and large joint contractures, as well as extraskeletal developmental abnormalities, primarily of the cardiorespiratory system and genitourinary tract. Patients with FMD2 appear to have a propensity for keloid formation (summary by Wade et al., 2016). For a discussion of genetic heterogeneity of frontometaphyseal dysplasia, see FMD1 (305620).
Myofibrillar myopathy 7
MedGen UID:
934678
Concept ID:
C4310711
Disease or Syndrome
Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures (summary by Straussberg et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;
MedGen UID:
934692
Concept ID:
C4310725
Disease or Syndrome
MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.
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).
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.
Chromosome 19q13.11 deletion syndrome, proximal
MedGen UID:
935013
Concept ID:
C4311046
Disease or Syndrome
Proximal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed development, intellectual disability with poor speech, feeding difficulties, and autistic features. Some patients may have additional features, including renal tract anomalies (summary by Caubit et al., 2016).
MYPN-related myopathy
MedGen UID:
1384302
Concept ID:
C4479186
Disease or Syndrome
Congenital myopathy-24 (CMYP24) is an autosomal recessive congenital myopathy characterized by onset of slowly progressive muscle weakness in the first decade. Affected individuals present with gait difficulties due to proximal muscle weakness and atrophy mainly affecting the lower limbs and neck. Muscle biopsy shows nemaline bodies. Some patients may have mild cardiac or respiratory involvement, but they do not have respiratory failure (summary by Miyatake et al., 2017). For a discussion of genetic heterogeneity of congenital myopathy, see 117000. For a discussion of genetic heterogeneity of nemaline myopathy, see 256030.
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).
Autosomal recessive cutis laxa type 2D
MedGen UID:
1376619
Concept ID:
C4479409
Disease or Syndrome
Autosomal recessive cutis laxa type IID (ARCL2D) 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 and neurologic 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).
Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies
MedGen UID:
1375601
Concept ID:
C4479520
Disease or Syndrome
IDDFSDA is an autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early-onset seizures, intellectual disability, and dysmorphic features. There is phenotypic variability. The most severely affected patients have a neurodevelopmental disorder with microcephaly, absent speech, and inability to walk, and they require feeding tubes. Some patients have congenital heart defects or nonspecific abnormalities on brain imaging. Less severely affected individuals have mild to moderate intellectual disability with normal speech and motor development (summary by Santiago-Sim et al., 2017).
Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect
MedGen UID:
1373185
Concept ID:
C4479539
Disease or Syndrome
AMC1 is an autosomal recessive severe neurologic disorder with onset in utero. Most affected individuals die in utero or are subject to pregnancy termination because of lack of fetal movements and prenatal evidence of contractures of virtually all joints. Those who survive have generalized contractures and hypotonia. The disorder is caused by a neurogenic defect and poor or absent myelin formation around peripheral nerves rather than by a muscular defect (summary by Xue et al., 2017). <Genetic Heterogeneity of Arthrogryposis Multiplex Congenita Also see AMC2 (208100), caused by mutation in the ERGIC1 gene (617946); AMC3 (618484), caused by mutation in the SYNE1 gene (608441); AMC4 (618776), caused by mutation in the SCYL2 gene (616365); AMC5 (618947), caused by mutation in the TOR1A gene (605204), and AMC6 (619334), caused by mutation in the NEB gene (161650)
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
MedGen UID:
1380860
Concept ID:
C4479566
Disease or Syndrome
NMIHBA is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay apparent from infancy and profoundly impaired intellectual development. Affected individuals have microcephaly with accompanying dysmorphic features, truncal hypotonia, peripheral spasticity, and lack of independent ambulation or speech acquisition. Brain imaging shows variable abnormalities, including cortical atrophy, thin corpus callosum, cerebellar hypoplasia, and delayed myelination (summary by Zollo et al., 2017).
Rahman syndrome
MedGen UID:
1388282
Concept ID:
C4479637
Disease or Syndrome
The name HIST1H1E syndrome has been proposed as a mnemonic for the characteristic features of this emerging, recognizable phenotype: hypotonia; intellectual disability with behavioral issues; skeletal; testes (undescended) and thyroid; heart anomalies (most commonly atrial septal defect); and ectodermal issues (including sparse hair, thin nails, and abnormal dentition). In the 47 affected individuals reported to date, predominant findings were intellectual disability (ranging from mild to profound) and behavioral problems (combinations of anxiety/phobias, obsessive behaviors, attention-deficit/hyperactivity disorder, and autistic spectrum disorder/traits among others). Skeletal involvement can include scoliosis and decreased bone mineral density. Other findings in some include seizures, craniosynostosis, and hearing loss. Life expectancy does not appear to be reduced in HIST1H1E syndrome.
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.
Pontocerebellar hypoplasia, type 11
MedGen UID:
1627627
Concept ID:
C4540164
Congenital Abnormality
Pontocerebellar hypoplasia type 11 (PCH11) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with impaired intellectual development and poor speech, microcephaly, dysmorphic features, and pontocerebellar hypoplasia on brain imaging. Additional features are more variable (summary by Marin-Valencia et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Epileptic encephalopathy, infantile or early childhood, 1
MedGen UID:
1626137
Concept ID:
C4540199
Disease or Syndrome
Developmental and epileptic encephalopathy-91 (DEE91) is characterized by delayed psychomotor development apparent in infancy and resulting in severely to profoundly impaired intellectual development with poor or absent speech. Most patients never achieve independent walking. Patients typically have onset of refractory multifocal seizures between the first weeks and years of life, and some may show developmental regression. Additional features, such as hypotonia and cortical visual impairment, are more variable (summary by Myers et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350.
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 51
MedGen UID:
1625009
Concept ID:
C4540474
Mental or Behavioral Dysfunction
Schwartz-Jampel syndrome type 1
MedGen UID:
1647990
Concept ID:
C4551479
Disease or Syndrome
Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive disorder characterized by muscle stiffness (myotonia) and chondrodysplasia. Affected individuals usually present in childhood with permanent muscle stiffness or bone deformities. Common clinical features include mask-like facies (narrow palpebral fissures, blepharospasm, and pursed lips); permanent muscle stiffness with continuous skeletal muscle activity recorded on electromyography; dwarfism; pectus carinatum; kyphoscoliosis; bowing of long bones; and epiphyseal, metaphyseal, and hip dysplasia. The disorder is slowly progressive but does not appear to alter life span (summary by Stum et al., 2006).
Adams-Oliver syndrome 1
MedGen UID:
1635567
Concept ID:
C4551482
Disease or Syndrome
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Perrault syndrome 1
MedGen UID:
1640257
Concept ID:
C4551721
Disease or Syndrome
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Galloway-Mowat syndrome 1
MedGen UID:
1634188
Concept ID:
C4551772
Disease or Syndrome
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.
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).
Alkuraya-Kucinskas syndrome
MedGen UID:
1634304
Concept ID:
C4693347
Disease or Syndrome
ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures (summary by Gueneau et al., 2018).
Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features
MedGen UID:
1647077
Concept ID:
C4693405
Disease or Syndrome
Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA) is characterized by infantile-onset global developmental delay with severe to profound intellectual disability, mildly delayed walking with broad-based and unsteady gait, and absence of meaningful language. Patients have features of autism, with repetitive behaviors and poor communication, but usually are socially reactive and have a happy demeanor. More variable neurologic features include mild seizures, spasticity, and peripheral neuropathy (summary by Palmer et al., 2017).
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).
Hyperekplexia 4
MedGen UID:
1642659
Concept ID:
C4693933
Disease or Syndrome
Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures, and many have inguinal or umbilical hernia. Most patients die in the first months of life due to respiratory failure or other complications (summary by Piard et al., 2018). For a general description and a discussion of genetic heterogeneity of hyperekplexia, see HKPX1 (149400).
Peroxisome biogenesis disorder 1A (Zellweger)
MedGen UID:
1648474
Concept ID:
C4721541
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
MedGen UID:
1669929
Concept ID:
C4747715
Disease or Syndrome
SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013). For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).
Myasthenic syndrome, congenital, 24, presynaptic
MedGen UID:
1648337
Concept ID:
C4748684
Disease or Syndrome
Pontocerebellar hypoplasia, type 12
MedGen UID:
1648343
Concept ID:
C4748873
Disease or Syndrome
Trichohepatoneurodevelopmental syndrome
MedGen UID:
1648322
Concept ID:
C4748898
Disease or Syndrome
Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).
Spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant
MedGen UID:
1648362
Concept ID:
C4749003
Disease or Syndrome
SMALED2B is a severe neuromuscular disorder with onset in utero. Affected individuals show decreased fetal movements and are usually born with congenital contractures consistent with arthrogryposis multiplex congenita (AMC). After birth, they have severe hypotonia and muscle atrophy as well as respiratory insufficiency due to muscle weakness. Some patients may have dysmorphic facial features and/or abnormalities on brain imaging. Many patients die in early childhood (summary by Storbeck et al., 2017) For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).
Intellectual disability-hypotonic facies syndrome, X-linked, 1
MedGen UID:
1676827
Concept ID:
C4759781
Disease or Syndrome
Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.
Autosomal recessive spinocerebellar ataxia 20
MedGen UID:
1684324
Concept ID:
C5190595
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by Thomas et al., 2014).
Distal arthrogryposis type 2B1
MedGen UID:
1676961
Concept ID:
C5193014
Disease or Syndrome
Distal arthrogryposis is a clinically and genetically heterogeneous disorder characterized by clenched fist, overlapping fingers, camptodactyly, ulnar deviation, and positional foot deformities from birth. It is a disorder of primary limb malformation without primary neurologic or muscle disease. DA1 is not associated with other abnormalities, whereas other forms of DA have additional phenotypic features (Bamshad et al., 1996). The congenital contractures in DA2B (Sheldon-Hall syndrome, SHS) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Lethal arthrogryposis-anterior horn cell disease syndrome
MedGen UID:
1677784
Concept ID:
C5193016
Disease or Syndrome
Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by Smith et al., 2017 and Tan et al., 2017). Distinction from Lethal Congenital Contracture Syndrome 1 Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. Smith et al. (2017) suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, Said et al. (2017) concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements. Vuopala et al. (1995) differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1.
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).
Arthrogryposis, distal, type 2B2
MedGen UID:
1674500
Concept ID:
C5193097
Disease or Syndrome
Distal arthrogryposis type 2B2 (DA2B2) is characterized by congenital contractures of the distal limb joints and facial dysmorphism. Marked inter- and intrafamilial variability has been reported (summary by Daly et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see 108120.
Arthrogryposis, distal, type 2B3
MedGen UID:
1676839
Concept ID:
C5193098
Disease or Syndrome
Distal arthrogryposis type 2B3 (DA2B3) is characterized by facial dysmorphism and congenital joint contractures with predominantly distal involvement. Some patients exhibit muscle weakness (Tajsharghi et al., 2008). Considerable inter- and intrafamilial variability has been reported (Xu et al., 2018).
Contractures, pterygia, and variable skeletal fusions syndrome 1B
MedGen UID:
1676457
Concept ID:
C5193114
Disease or Syndrome
Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1B (CPSFS1B) is characterized by contractures of proximal and distal joints, pterygia involving the neck, elbows, fingers, and/or knees, and variable vertebral, carpal, and tarsal fusions. Inter- and intrafamilial variability has been observed (Cameron-Christie et al., 2018). An autosomal dominant form of contractures, pterygia, and spondylocarpotarsal fusion syndrome (CPSFS1A; 178110) is caused by heterozygous mutation in the MYH3 gene.
Arthrogryposis multiplex congenita 3, myogenic type
MedGen UID:
1680655
Concept ID:
C5193121
Disease or Syndrome
Myogenic-type arthrogryposis multiplex congenita-3 (AMC3) is an autosomal recessive disorder characterized by decreased fetal movements, hypotonia, variable skeletal defects, including clubfoot and scoliosis, and delayed motor milestones with difficulty walking (summary by Baumann et al., 2017).
Rothmund-Thomson syndrome type 2
MedGen UID:
1684753
Concept ID:
C5203410
Disease or Syndrome
Rothmund-Thomson syndrome (RTS) is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; skeletal and dental abnormalities; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age two years) as erythema, swelling, and blistering on the face, subsequently spreading to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, telangiectasias, and punctate atrophy (collectively known as poikiloderma) that persist throughout life. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities can include radial ray defects, ulnar defects, absent or hypoplastic patella, and osteopenia.
Developmental and epileptic encephalopathy, 80
MedGen UID:
1684779
Concept ID:
C5231418
Disease or Syndrome
Developmental and epileptic encephalopathy-80 (DEE80) is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019). For a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Infantile liver failure syndrome 3
MedGen UID:
1684678
Concept ID:
C5231437
Disease or Syndrome
Infantile liver failure syndrome-3 is an autosomal recessive disorder characterized by recurrent episodes of acute liver failure during intercurrent febrile illness. Patients first present in infancy or early childhood, and there usually is complete recovery between episodes with conservative treatment. Affected individuals also have skeletal anomalies of the vertebral bodies and femoral heads (summary by Cousin et al., 2019). For a discussion of genetic heterogeneity of infantile liver failure syndrome, see ILFS1 (615438).
Neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies
MedGen UID:
1684884
Concept ID:
C5231442
Disease or Syndrome
Halperin-Birk syndrome (HLBKS) is an autosomal recessive neurodevelopmental disorder characterized by structural brain defects, spastic quadriplegia with multiple contractures, profound developmental delay, seizures, dysmorphism, cataract, and optic nerve atrophy. Death occurs in early childhood (Halperin et al., 2019).
Neuromuscular disease and ocular or auditory anomalies with or without seizures
MedGen UID:
1684689
Concept ID:
C5231483
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).
Wieacker-Wolff syndrome, female-restricted
MedGen UID:
1715791
Concept ID:
C5393303
Disease or Syndrome
Female-restricted Wieacker-Wolff syndrome (WRWFFR) is an X-linked dominant syndromic form of neurogenic arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Affected individuals have decreased fetal movements causing the development of contractures in utero and resulting in AMC and diffuse contractures involving the large and small joints apparent at birth. There is global developmental delay with difficulty walking or inability to walk, hypotonia that often evolves to spasticity, and variably impaired intellectual development with poor or absent speech and language. Dysmorphic facial features, including hypotonic facies, ptosis, microretrognathia, and small mouth, are seen in most patients. Seizures are uncommon; some patients have evidence of a peripheral motor neuropathy with distal muscle weakness. The level of X inactivation in lymphocytes and fibroblasts is often skewed, but may not predict the severity of the phenotype. Most cases occur sporadically; rare X-linked dominant inheritance has been reported in families (summary by Frints et al., 2019).
Intellectual disability, autosomal dominant 9
MedGen UID:
1714250
Concept ID:
C5393830
Disease or Syndrome
NESCAV syndrome (NESCAVS) is a neurodegenerative disorder characterized by onset of features in infancy or early childhood. Affected individuals show global developmental delay with delayed walking or difficulty walking due to progressive spasticity mainly affecting the lower limbs and often leading to loss of independent ambulation. There is variably impaired intellectual development, speech delay, and learning disabilities and/or behavioral abnormalities. Additional features may include cortical visual impairment, often associated with optic atrophy, axonal peripheral neuropathy, seizures, dysautonomia, ataxia, and dystonia. Brain imaging often shows progressive cerebellar atrophy and thin corpus callosum. Some patients may show developmental regression, particularly of motor skills. The phenotype and presentation are highly variable (summary by Nemani et al., 2020).
Vertebral, cardiac, renal, and limb defects syndrome 3
MedGen UID:
1709064
Concept ID:
C5394250
Disease or Syndrome
Vertebral, cardiac, renal, and limb defects syndrome-3 (VCRL3) is an autosomal recessive disorder characterized by severe cardiac and renal anomalies that are lethal in infancy, including hypoplastic or absent left ventricle, transposition of the great arteries, absent pulmonary trunk, and hypoplastic or absent kidneys. Patients also exhibit vertebral segmentation defects and shortening of the proximal long bones or micromelia (Szot et al., 2020). For a discussion of genetic heterogeneity of VCRL, see VCRL1 (617660).
Neurodevelopmental disorder with language impairment and behavioral abnormalities
MedGen UID:
1708389
Concept ID:
C5394502
Disease or Syndrome
Neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB) is characterized by impaired intellectual development or developmental delay, behavioral abnormalities including autistic features, and language impairment. Other features include seizures and developmental regression (Salpietro et al., 2019).
Arthrogryposis multiplex congenita 2, neurogenic type
MedGen UID:
1725686
Concept ID:
C5435650
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.
Arthrogryposis multiplex congenita 5
MedGen UID:
1731112
Concept ID:
C5436453
Disease or Syndrome
Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by Kariminejad et al., 2017).
Myopathy, epilepsy, and progressive cerebral atrophy
MedGen UID:
1759100
Concept ID:
C5436652
Disease or Syndrome
Myopathy, epilepsy, and progressive cerebral atrophy (MEPCA) is a severe autosomal recessive disorder with onset in utero or at birth. Affected individuals have hypotonia with respiratory or feeding difficulties apparent from birth and often associated with contractures of the large joints. There is little spontaneous movement: skeletal muscle biopsy and electrophysiologic studies are consistent with a myopathy or myasthenic disorder. Patients also develop refractory seizures with burst-suppression pattern or hypsarrhythmia on EEG. Brain imaging shows progressive cerebral atrophy and myelination defects. All patients reported to date died within the first year of life (summary by Schorling et al., 2017).
Arthrogryposis, distal, type 1C
MedGen UID:
1722257
Concept ID:
C5436834
Disease or Syndrome
Distal arthrogryposis type 1C (DA1C) is characterized by multiple congenital contractures, scoliosis, and short stature. Contractures involving the proximal joints appear to be more common in MYLPF-associated DA than in other forms of DA, and segmental amyoplasia has been observed (Chong et al., 2020).
Developmental and epileptic encephalopathy 89
MedGen UID:
1761611
Concept ID:
C5436853
Disease or Syndrome
Developmental and epileptic encephalopathy-89 (DEE89) is a severe autosomal recessive disorder characterized by profound global developmental delay with impaired intellectual development, absent speech, inability to sit or walk due to axial hypotonia and spastic quadriparesis, and onset of seizures in the first days or months of life. EEG shows suppression-burst pattern or hypsarrhythmia, consistent with DEE or a clinical diagnosis of West syndrome. More variable features include joint contractures with foot deformities, dysmorphic facial features with cleft palate, and omphalocele. Affected individuals have poor motor skills, poor eye contact, and lack of language development; some die in infancy or early childhood. Brain imaging may be normal or show nonspecific abnormalities (summary by Chatron et al., 2020).
Chromosome 13q33-q34 deletion syndrome
MedGen UID:
1744234
Concept ID:
C5436890
Disease or Syndrome
Chromosome 13q33-q34 deletion syndrome is associated with developmental delay and/or impaired intellectual development, facial dysmorphism, and an increased risk for epilepsy, cardiac defects and additional anatomic anomalies (summary by Sagi-Dain et al., 2019).
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).
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.
Multiple congenital anomalies-neurodevelopmental syndrome, X-linked
MedGen UID:
1788942
Concept ID:
C5542341
Disease or Syndrome
X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade. Pathogenetically, the disorder results from disrupted gene expression and signaling during embryogenesis, thus affecting multiple systems (summary by Tripolszki et al., 2021 and Beck et al., 2021). Beck et al. (2021) referred to the disorder as LINKED syndrome (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects).
Neuronopathy, distal hereditary motor, autosomal recessive 7
MedGen UID:
1786836
Concept ID:
C5543119
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-7 (HMNR7) is characterized by onset of lower leg weakness in the first decade. Affected individuals have difficulty climbing stairs and problems standing on the heels. Some patients have later onset well into the adult years. Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs. Muscle biopsy and electrophysiologic studies are consistent with both a myopathic process and an axonal motor neuropathy. Sensory abnormalities are not typically present, and patients remain ambulatory. The phenotype shows phenotypic overlap with distal hereditary motor neuropathy, but can distinguished by the presence of myopathic features (summary by Deschauer et al., 2021 and Pagnamenta et al., 2021). For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).
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).
Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies
MedGen UID:
1794140
Concept ID:
C5561930
Disease or Syndrome
X-linked syndromic intellectual developmental disorder with pigmentary mosaicism and coarse facies (MRXSPF) is characterized by a phenotypic triad of severe developmental delay, coarse facial dysmorphisms, and Blaschkoid pigmentary mosaicism. Additional clinical features may include epilepsy, orthopedic abnormalities, hypotonia, and growth abnormalities. The disorder affects both males and females (Villegas et al., 2019; Diaz et al., 2020).
Visceral neuropathy, familial, 2, autosomal recessive
MedGen UID:
1794160
Concept ID:
C5561950
Disease or Syndrome
Autosomal recessive visceral neuropathy-2 (VSCN2) is characterized by intestinal dysmotility due to aganglionosis or hypoganglionosis of the colon. Patients also exhibit peripheral axonal neuropathy, ptosis, and sensorineural hearing loss (Le et al., 2021). For a discussion of genetic heterogeneity of VSCN, see VSCN1 (243180).
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).
DEGCAGS syndrome
MedGen UID:
1794177
Concept ID:
C5561967
Disease or Syndrome
DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections. Death in childhood may occur (summary by Bertoli-Avella et al., 2021).
Congenital disorder of glycosylation, type 2v
MedGen UID:
1794181
Concept ID:
C5561971
Disease or Syndrome
Congenital disorder of glycosylation type 2v (CDG2V) is an autosomal recessive disorder characterized by neurodevelopmental delay and variable facial dysmorphisms (Polla et al., 2021).
Ventriculomegaly and arthrogryposis
MedGen UID:
1794183
Concept ID:
C5561973
Disease or Syndrome
Ventriculomegaly and arthrogryposis (VENARG) is a severe autosomal recessive congenital disorder characterized by the onset of features in utero that are not compatible with life. Affected pregnancies are terminated spontaneously or by plan due to the severity of the defects. Prenatal ultrasound and autopsy show limb contractures consistent with arthrogryposis and enlarged brain ventricles that may be associated with hydrocephalus, abnormalities of the corpus callosum, and cerebellar hypoplasia. Some affected fetuses may also have congenital heart disease and hydrops fetalis (summary by Mero et al., 2017 and El-Dessouky et al., 2020).
NEK9-related lethal skeletal dysplasia
MedGen UID:
1799564
Concept ID:
C5568141
Disease or Syndrome
A rare lethal primary bone dysplasia with characteristics of fetal akinesia, multiple contractures, shortening of all long bones, short, broad ribs, narrow chest and thorax, pulmonary hypoplasia and a protruding abdomen. Short bowed femurs may also be associated.
Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome
MedGen UID:
1800507
Concept ID:
C5569084
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-21 (SCAR21) is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by Schmidt et al., 2015). The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by Lenz et al., 2018).
Carey-Fineman-Ziter syndrome 1
MedGen UID:
1804638
Concept ID:
C5676876
Disease or Syndrome
Carey-Fineman-Ziter syndrome-1 (CFZS1) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS1 may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016). Di Gioia et al. (2017) determined that CFZS1 represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion. Genetic Heterogeneity of Carey-Fineman-Ziter Syndrome Carey-Fineman-Ziter syndrome-2 (CFZS2) is caused by mutation in the MYMX gene (619912) on chromosome 6p21.
Combined oxidative phosphorylation deficiency 55
MedGen UID:
1806598
Concept ID:
C5676915
Disease or Syndrome
Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by Olahova et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
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).
Kury-Isidor syndrome
MedGen UID:
1807460
Concept ID:
C5676925
Disease or Syndrome
Kury-Isidor syndrome (KURIS) is a neurodevelopmental disorder with a highly variable phenotype. It is characterized mainly by mild global developmental delay apparent from infancy or early childhood with walking delayed by a few years and speech delay, often with language deficits. Intellectual development may be mildly delayed, borderline, or even normal; most patients have behavioral problems, including autism. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and nonspecific dysmorphic facial features (summary by Kury et al., 2022).
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.
Chromosome Xq13 duplication syndrome
MedGen UID:
1809227
Concept ID:
C5677057
Disease or Syndrome
Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy
MedGen UID:
1823958
Concept ID:
C5774185
Disease or Syndrome
Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy (NEDMLHB) is characterized by the onset of these features soon after birth or in early infancy. Affected individuals make almost no developmental progress, are unable to sit or walk, do not acquire speech, have poor visual fixation, and show poor overall growth associated with feeding problems. Some may have a progressive disease course, suggesting neurodegeneration. Additional more variable features include seizures, spasticity, and joint contractures. Brain imaging shows hypomyelination, thin corpus callosum, and cerebral and cerebellar atrophy (Wong et al., 2022).
Braddock-carey syndrome 1
MedGen UID:
1823961
Concept ID:
C5774188
Disease or Syndrome
Braddock-Carey syndrome (BRDCS) is characterized by Pierre-Robin sequence, persistent congenital thrombocytopenia, agenesis of the corpus callosum, severe developmental delay, microcephaly, high forehead, sparse curly hair, downslanting palpebral fissures, telecanthus, inverted U-shaped upper vermilion, enamel hypoplasia, large posteriorly rotated ears, clinodactyly, and camptodactyly (Braddock et al., 2016). Genetic Heterogeneity of Braddock-Carey Syndrome BRDCS2 (619981) is caused by mutation in the KIF15 gene (617569) on chromosome 3p21.
Keratoderma-ichthyosis-deafness syndrome, autosomal recessive
MedGen UID:
1823973
Concept ID:
C5774200
Disease or Syndrome
Autosomal recessive keratoderma-ichthyosis-deafness syndrome (KDIDAR) is characterized by severe palmoplantar keratoderma, mild generalized ichthyosis, and progressive sensorineural deafness. Other variable features include contractures, mild bleeding diathesis, and psychomotor retardation (Gruber et al., 2017).
Spinal muscular atrophy, distal, autosomal recessive, 6
MedGen UID:
1823974
Concept ID:
C5774201
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6) is a neuromuscular disorder characterized by onset of distal muscle weakness in early infancy. Affected individuals often present at birth with distal joint contractures or foot deformities and show delayed motor development, often with inability to walk or frequent falls. Hypo- or hyperreflexia may be observed; limb muscle atrophy may also be present. Patients often show respiratory distress or diaphragmatic palsy. Electrophysiologic studies are consistent with a peripheral motor neuropathy without sensory involvement (Maroofian et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive distal HMN, see HMNR1 (604320).
Arthrogryposis, distal, IIa 11
MedGen UID:
1823978
Concept ID:
C5774205
Disease or Syndrome
Distal arthrogryposis type 11 (DA11) is an autosomal dominant disorder characterized mainly by camptodactyly. Other features include absent flexion creases and limited forearm supination (Zhou et al., 2019).
Diaphragmatic hernia 4, with cardiovascular defects
MedGen UID:
1823983
Concept ID:
C5774210
Disease or Syndrome
Diaphragmatic hernia-4 with cardiovascular defects (DIH4) is an autosomal recessive congenital anomaly syndrome characterized by the presence of diaphragmatic hernia or eventration apparent at birth. Affected infants have associated pulmonary hypoplasia and respiratory insufficiency resulting in death in infancy. Most also have variable cardiovascular defects, including aortopulmonary window or conotruncal anomalies. Dysmorphic facial features and mild distal limb anomalies are sometimes observed (Beecroft et al., 2021). For a discussion of genetic heterogeneity of congenital diaphragmatic hernia (CDH), see DIH1 (142340).
Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
MedGen UID:
1823986
Concept ID:
C5774213
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (NEDHLSS) is characterized by global developmental delay apparent from infancy. Affected individuals show severe hypotonia with delayed walking or inability to walk, poor or absent speech, and impaired intellectual development with behavioral abnormalities. Most patients have early-onset seizures, mild skeletal defects that are usually distal, and nonspecific dysmorphic features. More severely affected individuals have additional congenital abnormalities; however, cardiac involvement is rare (summary by Rodan et al., 2021).
Bent bone dysplasia syndrome 2
MedGen UID:
1824006
Concept ID:
C5774233
Disease or Syndrome
Bent bone dysplasia syndrome-2 (BBDS2) is characterized by defects in both the axial and appendicular skeleton, with radiographic findings of undermineralized bone and a distinct angulation of the mid femoral shaft. Extraskeletal features include facial dysmorphisms, abnormally formed ears with tags, widely spaced nipples, and atrial septal defects. Abnormalities of muscle function are suggested by the presence of elbow fusions, ulnar flexion contractions at the wrist, and bilateral talipes equinovarus, as well as failure to mount a respiratory effort at birth (Barad et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of bent bone dysplasia syndrome, see BBDS1 (614592).
Neurooculorenal syndrome
MedGen UID:
1841013
Concept ID:
C5830377
Disease or Syndrome
Neurooculorenal syndrome (NORS) is an autosomal recessive developmental disorder with highly variable clinical manifestations involving several organ systems. Some affected individuals present in utero with renal agenesis and structural brain abnormalities incompatible with life, whereas others present in infancy with a neurodevelopmental disorder characterized by global developmental delay and dysmorphic facial features that may be associated with congenital anomalies of the kidney and urinary tract (CAKUT). Additional more variable features may include ocular anomalies, most commonly strabismus, congenital heart defects, and pituitary hormone deficiency. Brain imaging usually shows structural midline defects, including dysgenesis of the corpus callosum and hindbrain. There is variation in the severity, manifestations, and expressivity of the phenotype, even within families (Rasmussen et al., 2018; Munch et al., 2022).
Neurodegeneration and seizures due to copper transport defect
MedGen UID:
1841021
Concept ID:
C5830385
Disease or Syndrome
Neurodegeneration and seizures due to copper transport defect (NSCT) is an autosomal recessive disorder of copper transport characterized by hypotonia, global developmental delay, seizures, and rapid brain atrophy (summary by Dame et al., 2023).
Congenital myopathy 20
MedGen UID:
1841029
Concept ID:
C5830393
Disease or Syndrome
Congenital myopathy-20 (CMYP20) is an autosomal recessive neuromuscular disorder that shows wide phenotypic variability. Some patients present in early childhood with proximal muscle weakness affecting the lower and upper limbs resulting in difficulties running and climbing, whereas others present soon after birth with congenital limb or distal contractures. Additional features may include dysmorphic facial features and global developmental delay. Skeletal muscle biopsy may show nemaline rods (Nilipour et al., 2018; Pehlivan et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Autosomal dominant popliteal pterygium syndrome
MedGen UID:
979785
Concept ID:
CN296406
Disease or Syndrome
Most commonly, IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. In rare instances, IRF6 pathogenic variants have also been reported in individuals with nonsyndromic orofacial cleft (18/3,811; 0.47%) and in individuals with spina bifida (2/192). Individuals with VWS show one or more of the following anomalies: Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip. Cleft lip (CL). Cleft palate (CP). Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP). The PPS phenotype includes the following: CL±P. Fistulae of the lower lip. Webbing of the skin extending from the ischial tuberosities to the heels. In males: bifid scrotum and cryptorchidism. In females: hypoplasia of the labia majora. Syndactyly of fingers and/or toes. Anomalies of the skin around the nails. A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic). In some nonclassic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). Other musculoskeletal anomalies may include spina bifida occulta, talipes equinovarus, digital reduction, bifid ribs, and short sternum. In VWS, PPS, IRF6-related neural tube defect, and IRF6-related orofacial cleft, growth and intelligence are typical.

Professional guidelines

PubMed

Cady R, Hennessey TA, Schwend RM
Pediatrics 2022 Feb 1;149(2) doi: 10.1542/peds.2021-055555. PMID: 35104362Free PMC Article
Hordyjewska-Kowalczyk E, Nowosad K, Jamsheer A, Tylzanowski P
J Med Genet 2022 Mar;59(3):209-219. Epub 2021 Nov 15 doi: 10.1136/jmedgenet-2021-108040. PMID: 34782442
Ponseti IV
J Pediatr Orthop 2000 Nov-Dec;20(6):699-700. doi: 10.1097/00004694-200011000-00001. PMID: 11097239

Recent clinical studies

Etiology

Radler C
Foot Ankle Clin 2021 Dec;26(4):619-637. Epub 2021 Aug 8 doi: 10.1016/j.fcl.2021.07.001. PMID: 34752231
Yau A, Doyle SM
Curr Opin Pediatr 2020 Feb;32(1):100-106. doi: 10.1097/MOP.0000000000000860. PMID: 31815780
Chen C, Kaushal N, Scher DM, Doyle SM, Blanco JS, Dodwell ER
J Pediatr Orthop 2018 Sep;38(8):e462-e469. doi: 10.1097/BPO.0000000000001191. PMID: 29917009
Dobbs MB
Clin Orthop Relat Res 2009 May;467(5):1119-20. Epub 2009 Feb 25 doi: 10.1007/s11999-009-0761-6. PMID: 19241114Free PMC Article
Dobbs MB, Gurnett CA
Clin Orthop Relat Res 2009 May;467(5):1146-53. Epub 2009 Feb 18 doi: 10.1007/s11999-009-0734-9. PMID: 19224303Free PMC Article

Diagnosis

Cady R, Hennessey TA, Schwend RM
Pediatrics 2022 Feb 1;149(2) doi: 10.1542/peds.2021-055555. PMID: 35104362Free PMC Article
Yau A, Doyle SM
Curr Opin Pediatr 2020 Feb;32(1):100-106. doi: 10.1097/MOP.0000000000000860. PMID: 31815780
Bernstein RM
J Am Acad Orthop Surg 2002 Nov-Dec;10(6):417-24. doi: 10.5435/00124635-200211000-00006. PMID: 12470044
Cummings RJ, Davidson RS, Armstrong PF, Lehman WB
Instr Course Lect 2002;51:385-400. PMID: 12064128
Ponseti IV
J Pediatr Orthop 2000 Nov-Dec;20(6):699-700. doi: 10.1097/00004694-200011000-00001. PMID: 11097239

Therapy

Cohen JM, Alvestad S, Cesta CE, Bjørk MH, Leinonen MK, Nørgaard M, Einarsdóttir K, Engeland A, Gissler M, Karlstad Ø, Klungsøyr K, Odsbu I, Reutfors J, Selmer RM, Tomson T, Ulrichsen SP, Zoega H, Furu K
Ann Neurol 2023 Mar;93(3):551-562. Epub 2022 Dec 12 doi: 10.1002/ana.26561. PMID: 36433783
Bina S, Pacey V, Barnes EH, Burns J, Gray K
Cochrane Database Syst Rev 2020 May 15;5(5):CD008602. doi: 10.1002/14651858.CD008602.pub4. PMID: 32412098Free PMC Article
Parnell Prevost C, Gleberzon B, Carleo B, Anderson K, Cark M, Pohlman KA
BMC Complement Altern Med 2019 Mar 13;19(1):60. doi: 10.1186/s12906-019-2447-2. PMID: 30866915Free PMC Article
Giesberts RB, Hekman EEG, Verkerke GJ, Maathuis PGM
Acta Orthop 2018 Oct;89(5):565-569. Epub 2018 Jul 9 doi: 10.1080/17453674.2018.1493046. PMID: 29985745Free PMC Article
Chen C, Kaushal N, Scher DM, Doyle SM, Blanco JS, Dodwell ER
J Pediatr Orthop 2018 Sep;38(8):e462-e469. doi: 10.1097/BPO.0000000000001191. PMID: 29917009

Prognosis

Panza R, Albano F, Casto A, Del Vecchio C, Laforgia N, Dibello D
Ital J Pediatr 2023 Nov 14;49(1):151. doi: 10.1186/s13052-023-01559-9. PMID: 37964341Free PMC Article
Radler C
Foot Ankle Clin 2021 Dec;26(4):619-637. Epub 2021 Aug 8 doi: 10.1016/j.fcl.2021.07.001. PMID: 34752231
Rastogi A, Agarwal A
Int Orthop 2021 Oct;45(10):2599-2608. Epub 2021 Aug 20 doi: 10.1007/s00264-021-05189-w. PMID: 34415418
Oleas-Santillán G, Reid Nichols L, Rogers KJ, Richard Bowen J
J Pediatr Orthop B 2019 Sep;28(5):446-451. doi: 10.1097/BPB.0000000000000618. PMID: 31246178
Pirani S, Naddumba E, Mathias R, Konde-Lule J, Penny JN, Beyeza T, Mbonye B, Amone J, Franceschi F
Clin Orthop Relat Res 2009 May;467(5):1154-63. Epub 2009 Mar 24 doi: 10.1007/s11999-009-0759-0. PMID: 19308648Free PMC Article

Clinical prediction guides

Grin L, Wijnands S, Besselaar A, van Oorschot L, Vanwanseele B, van der Steen M
Gait Posture 2022 Sep;97:210-215. Epub 2022 Aug 1 doi: 10.1016/j.gaitpost.2022.07.261. PMID: 35995000
El-Banna G, Baskar D, Segovia N, Frick S
J Pediatr Orthop 2022 Jan 1;42(1):e91-e96. doi: 10.1097/BPO.0000000000001973. PMID: 34889836
Bina S, Pacey V, Barnes EH, Burns J, Gray K
Cochrane Database Syst Rev 2020 May 15;5(5):CD008602. doi: 10.1002/14651858.CD008602.pub4. PMID: 32412098Free PMC Article
Chen C, Kaushal N, Scher DM, Doyle SM, Blanco JS, Dodwell ER
J Pediatr Orthop 2018 Sep;38(8):e462-e469. doi: 10.1097/BPO.0000000000001191. PMID: 29917009
Ganesan B, Luximon A, Al-Jumaily A, Balasankar SK, Naik GR
PLoS One 2017;12(6):e0178299. Epub 2017 Jun 20 doi: 10.1371/journal.pone.0178299. PMID: 28632733Free PMC Article

Recent systematic reviews

Al-Mohrej OA, Alshaalan FN, Alhussainan TS
Int Orthop 2021 Oct;45(10):2589-2597. Epub 2021 Jun 10 doi: 10.1007/s00264-021-05092-4. PMID: 34114108
Bina S, Pacey V, Barnes EH, Burns J, Gray K
Cochrane Database Syst Rev 2020 May 15;5(5):CD008602. doi: 10.1002/14651858.CD008602.pub4. PMID: 32412098Free PMC Article
Parnell Prevost C, Gleberzon B, Carleo B, Anderson K, Cark M, Pohlman KA
BMC Complement Altern Med 2019 Mar 13;19(1):60. doi: 10.1186/s12906-019-2447-2. PMID: 30866915Free PMC Article
Chen C, Kaushal N, Scher DM, Doyle SM, Blanco JS, Dodwell ER
J Pediatr Orthop 2018 Sep;38(8):e462-e469. doi: 10.1097/BPO.0000000000001191. PMID: 29917009
Ganesan B, Luximon A, Al-Jumaily A, Balasankar SK, Naik GR
PLoS One 2017;12(6):e0178299. Epub 2017 Jun 20 doi: 10.1371/journal.pone.0178299. PMID: 28632733Free PMC Article

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