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).
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).
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).
Noonan syndrome 2- MedGen UID:
- 344290
- •Concept ID:
- C1854469
- •
- Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
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.
Greenberg dysplasia- MedGen UID:
- 418969
- •Concept ID:
- C2931048
- •
- Disease or Syndrome
Greenberg dysplasia (GRBGD), also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is a rare autosomal recessive osteochondrodysplasia characterized by gross fetal hydrops, severe shortening of all long bones with a moth-eaten radiographic appearance, platyspondyly, disorganization of chondroosseous calcification, and ectopic ossification centers. It is lethal in utero. Patient fibroblasts show increased levels of cholesta-8,14-dien-3-beta-ol, suggesting a defect of sterol metabolism (summary by Konstantinidou et al., 2008).
Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in postsqualene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis (607330), and HEM skeletal dysplasia.
Chromosome 5q12 deletion syndrome- MedGen UID:
- 816612
- •Concept ID:
- C3810282
- •
- Disease or Syndrome
PDE4D haploinsufficiency syndrome is a rare syndromic intellectual disability characterized by developmental delay, intellectual disability, low body mass index, long arms, fingers and toes, prominent nose and small chin.
Developmental and epileptic encephalopathy, 28- MedGen UID:
- 863956
- •Concept ID:
- C4015519
- •
- Disease or Syndrome
Developmental and epileptic encephalopathy-28 (DEE28) is an autosomal recessive severe neurologic disorder characterized by the onset of refractory seizures in the first months of life. Affected individuals have severe axial hypotonia and profoundly impaired psychomotor development. More severely affected patients have acquired microcephaly, poor or absent visual contact, and retinal degeneration; early death may occur (summary by Mignot et al., 2015).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Noonan syndrome 10- MedGen UID:
- 902892
- •Concept ID:
- C4225280
- •
- Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Lymphatic malformation 7- MedGen UID:
- 934596
- •Concept ID:
- C4310629
- •
- Disease or Syndrome
LMPHM7 is an autosomal dominant disorder with variable expressivity. Some patients may develop severe nonimmune lymphatic-related hydrops fetalis (LRHF) in utero, resulting in early death, whereas others may have milder manifestations, such as atrial septal defect (ASD) or varicose veins as adults. The hydrops and/or swelling improves spontaneously in those who survive the neonatal period (summary by Martin-Almedina et al., 2016).
For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.
Intellectual disability, autosomal dominant 47- MedGen UID:
- 1622196
- •Concept ID:
- C4539951
- •
- Mental or Behavioral Dysfunction
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, variable degrees of intellectual disability, and facial dysmorphism (including high nasal bridge, deep-set eyes, and wide mouth), often associated with feeding difficulties and/or gastroesophageal reflux. Additional reported manifestations are seizures, hypotonia, autistic features, and joint laxity. Brain imaging may show non-specific features (such as cerebral atrophy).
Neurodevelopmental disorder with seizures and speech and walking impairment- MedGen UID:
- 1672912
- •Concept ID:
- C5193119
- •
- Disease or Syndrome
Neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI) is an autosomal recessive disorder with onset in infancy. Patients show global developmental delay, particularly of speech acquisition, as well as walking difficulties due to hypotonia, hypertonia, spasticity, or poor coordination. Other features include seizures, mild dysmorphic features, and variable short stature. The pregnancies tend to be complicated by hyper- or hypotension (summary by Ganapathi et al., 2019).
Congenital hypotonia, epilepsy, developmental delay, and digital anomalies- MedGen UID:
- 1674629
- •Concept ID:
- C5193125
- •
- Disease or Syndrome
ATN1-related neurodevelopmental disorder (ATN1-NDD) is characterized by developmental delay / intellectual disability. Other neurologic findings can include infantile hypotonia, brain malformations, epilepsy, cortical visual impairment, and hearing loss. Feeding difficulties, present in some individuals, may require gastrostomy support when severe; similarly, respiratory issues, present in some, may require respiratory support after the neonatal period. Distinctive facial features and hand and foot differences are common. Other variable findings can include cardiac malformations and congenital anomalies of the kidney and urinary tract (CAKUT). To date, 18 individuals with ATN1-NDD have been identified.
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures- MedGen UID:
- 1710110
- •Concept ID:
- C5394312
- •
- Disease or Syndrome
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures (NEDHYMS) is an autosomal recessive disorder characterized by global developmental delay with axial hypotonia, inability to sit or walk, and severely impaired intellectual development with absent language. Most patients develop early-onset intractable seizures that prevent normal development. Additional features include feeding difficulties with poor overall growth and microcephaly. Some patients may have spastic quadriplegia, poor eye contact due to cortical blindness, variable dysmorphic features, and nonspecific abnormalities on brain imaging (summary by Tan et al., 2020).
Skeletal dysplasia, mild, with joint laxity and advanced bone age- MedGen UID:
- 1711043
- •Concept ID:
- C5394341
- •
- Disease or Syndrome
CSGALNACT1 deficiency is characterized by mild skeletal dysplasia, joint hypermobility, and advanced bone age. Shortness of long bones is evident prenatally, and patients exhibit short stature and relative macrocephaly. Advanced carpotarsal bone age and monkey-wrench appearance of the femur observed in infancy may disappear with age (Mizumoto et al., 2020).
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).
Meckel syndrome 14- MedGen UID:
- 1809650
- •Concept ID:
- C5676989
- •
- Disease or Syndrome
Meckel syndrome-14 (MKS14) is a lethal disorder characterized by occipital encephalocele, postaxial polydactyly of the hands and feet, and polycystic kidneys. Stillbirth has been reported, as well as death within hours in a live-born affected individual (Shaheen et al., 2016; Ridnoi et al., 2019).
For a general phenotypic description and discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).
Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment- MedGen UID:
- 1823998
- •Concept ID:
- C5774225
- •
- Disease or Syndrome
Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment (NEDMVIC) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, facial dysmorphism, and microcephaly (Ziegler et al., 2022).
Microcephaly 30, primary, autosomal recessive- MedGen UID:
- 1824053
- •Concept ID:
- C5774280
- •
- Disease or Syndrome
Autosomal recessive primary microcephaly-30 (MCPH30) is characterized by small head circumference, poor overall growth, and global developmental delay with variably impaired intellectual development. Affected individuals have been reported to have variable additional congenital anomalies, including atrial septal defect, dysmorphic facial features, tracheal stenosis, and anomalies of the skin and teeth (Carvalhal et al., 2022).
For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies- MedGen UID:
- 1846947
- •Concept ID:
- C5882734
- •
- Disease or Syndrome
Thrombocytopenia-11 with multiple congenital anomalies and dysmorphic facies (THC11) is a syndromic disorder characterized by dysmorphic facial features, multiple congenital anomalies that may involve the heart, brain, genitourinary, endocrine, and/or skeletal systems, chronic and persistent thrombocytopenia, sometimes with leukopenia or anemia, poor growth with microcephaly, hypotonia, and mildly impaired intellectual development or learning disabilities. The disorder results from constitutive activation of the RAS signaling pathway and can be considered a RASopathy (Niemann et al., 2020; Miller et al., 2022).
For a discussion of genetic heterogeneity of thrombocytopenia, see 313900.
Orofaciodigital syndrome 20- MedGen UID:
- 1854813
- •Concept ID:
- C5935578
- •
- Disease or Syndrome
Orofaciodigital syndrome-20 (OFD20) is characterized by bilateral oral clefting, polydactyly/syndactyly, cerebral malformations, cardiac defects, anorectal anomalies, and shortening of the long bones (Bruel et al., 2023).
For a general phenotypic description and discussion of genetic heterogeneity of OFD, see OFD1 (311200).