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).

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.

CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.

The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of live-born individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy scaling ichthyosis in the newborn; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; and cataracts.

Schneckenbecken dysplasia (SHNKND) is a perinatally lethal skeletal dysplasia. The German term 'Schneckenbecken' refers to the distinctive, snail-like appearance of the ilia that results from a medial bone projection from the inner iliac margin. Other hallmarks of the disorder include thoracic hypoplasia, severe flattening of the vertebral bodies, and short, thick long bones (summary by Hiraoka et al., 2007).

Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality (summary by Ben-Mahmoud et al., 2018).

Sacral defect with anterior meningocele (SDAM) is a form of caudal dysgenesis. It is present at birth and becomes symptomatic later in life, usually because of obstructive labor in females, chronic constipation, or meningitis. Inheritance is autosomal dominant (Chatkupt et al., 1994). Welch and Aterman (1984) gave a population frequency of 0.14%. Caudal dysgenesis syndrome and caudal regression syndrome are broad terms that refer to a heterogeneous constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. Approximately 15 to 25% of mothers of children with caudal dysgenesis have insulin-dependent diabetes mellitus (222100) (Lynch et al., 2000). See also Currarino syndrome (176450), a similar disorder caused by mutation in the HLXB9 gene (142994) on chromosome 7q36. Currarino syndrome classically comprises the triad of hemisacrum, anorectal malformation, and presacral mass. However, Currarino syndrome also shows phenotypic variability: Lynch et al. (2000) stated that there is variable expressivity of clinical features and that some patients with Currarino syndrome are asymptomatic. Kochling et al. (2001) found the complete triad of Currarino syndrome in only 8 of 23 patients with mutations in the HLXB9 gene, These reports suggest that some patients previously reported as having forms of sacral agenesis, including SDAM, may have had Currarino syndrome and vice versa. See also spina bifida (182940), which can be seen in some patients with sacral agenesis or caudal regression syndrome and may be etiologically related.

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).

Heterotaxy Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. Multiple Types of Congenital Heart Defects Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011). Reviews Obler et al. (2008) reviewed published cases of double-outlet right ventricle and discussed etiology and associations. Genetic Heterogeneity of Visceral Heterotaxy See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22; HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q21; HTX7 (616749), caused by mutation in the MMP21 gene (608416) on chromosome 10q26; HTX8 (617205), caused by mutation in the PKD1L1 gene (609721) on chromosome 7p12; HTX9 (618948), caused by mutation in the MNS1 gene (610766) on chromosome 15q21; HTX10 (619607), caused by mutation in the CFAP52 gene (609804) on chromosome 17p13; HTX11 (619608), caused by mutation in the CFAP45 gene (605152) on chromosome 1q23; and HTX12 (619702), caused by mutation in the CIROP gene (619703) on chromosome 14q11. Genetic Heterogeneity of Multiple Types of Congenital Heart Defects An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26. CHTD2 (614980) is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q31. CHTD4 (615779) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26. CHTD5 (617912) is caused by mutation in the GATA5 gene (611496) on chromosome 20q13. CHTD6 (613854) is caused by mutation in the GDF1 gene (602880) on chromosome 19p13. CHTD7 (618780) is caused by mutation in the FLT4 gene (136352) on chromosome 5q35. CHTD8 (619657) is caused by mutation in the SMAD2 gene (601366) on chromosome 18q21. CHTD9 (620294) is caused by mutation in the PLXND1 gene (604282) on chromosome 3q22.

CHIME syndrome, also known as Zunich neuroectodermal syndrome, is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (summary by Ng et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.

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).

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.

Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles. Some cases have been reported to have pulmonary hypertension as a result of restrictive lung disease (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA5 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of cleft palate and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders might represent variable expressivity of the same condition. For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120). Genetic Heterogeneity of Distal Arthrogryposis 5 A subtype of DA5 due to mutation in the ECEL1 gene (605896) on chromosome 2q36 has been designated DA5D (615065). See NOMENCLATURE.

Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by Waterham et al., 2001).

BCARD syndrome is an autosomal recessive connective tissue disorder characterized by bone abnormalities, including low bone mineral density, scoliosis, contractures of the fingers and other joints, prominent knees, and rare pathologic fractures; cataract and other ocular abnormalities, including high myopia, optically empty vitreous, and risk for retinal detachment; risk of arterial rupture due to vascular aneurysm or dissection; and sensorineural deafness. Affected individuals also exhibit recognizable craniofacial dysmorphisms, and variable skin features have been observed, including reduced palmar creases, soft skin with easy bruising, and blistering. Developmental delay, which is present in most patients, may be attributable to sensory deficits or medical complications (Ewans et al., 2019).

Syndrome with the association of toe syndactyly, facial dysmorphism including telecanthus and a broad nasal tip, urogenital malformations and anal atresia. Around ten cases have been reported so far. The syndrome is caused by mutations in the FAM58A gene (located on the X chromosome) encoding a protein of unknown function.

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.

Any brachydactyly type A1 in which the cause of the disease is a mutation in the GDF5 gene.

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).

An autosomal dominant condition caused by mutation(s) in the MYT1L gene, encoding myelin transcription factor 1-like protein. It is characterized by intellectual disability and mild dysmorphic facial features.

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities (NEDMISBA) is an autosomal recessive disorder characterized by a spectrum of neurologic abnormalities apparent from early infancy. Affected individuals have impaired intellectual development with poor speech, progressive microcephaly, and appendicular spasticity. Brain imaging usually shows abnormalities, including enlarged ventricles, white matter defects, and atrophy or hypoplasia of brain tissue. Some patients have a more severe phenotype with seizures, lack of developmental milestones, and early death (summary by Harel et al., 2018).

Optic atrophy-11 (OPA11) is an autosomal recessive disorder characterized by delayed psychomotor development, intellectual disability, ataxia, optic atrophy, and leukoencephalopathy on brain imaging. Laboratory studies are consistent with mitochondrial dysfunction (summary by Hartmann et al., 2016). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

Any lethal congenital contracture syndrome in which the cause of the disease is a mutation in the GLDN gene.

Sweeney-Cox syndrome (SWCOS) is characterized by striking facial dysostosis, including hypertelorism, deficiencies of the eyelids and facial bones, cleft palate/velopharyngeal insufficiency, and low-set cupped ears (Kim et al., 2017).

NDAGSCW is a neurodevelopmental disorder characterized by severely delayed psychomotor development apparent from infancy. Affected individuals have delayed and difficulty walking, intellectual disability, absent speech, and variable additional features, including hip dysplasia, tapering fingers, and seizures. Brain imaging shows decreased cortical white matter, often with decreased cerebellar white matter, thin corpus callosum, and thin brainstem (summary by Lamers et al., 2017).

Humerofemoral hypoplasia with radiotibial ray deficiency (HHRRD) is a severe dysostosis characterized by reduction of all 4 limbs as well as hypoplasia of the upper limb girdle and pelvis. Rudimentary finger- or toe-like appendages may be present (Szenker-Ravi et al., 2018).

MFRG is an autosomal recessive syndrome in which microcephaly, unilateral renal agenesis, ambiguous genitalia, and facial dysmorphisms, including severe micrognathia, are observed in most patients. Variable brain, cardiac, and skeletal anomalies are present, including corpus callosum agenesis or dysgenesis, lissencephaly, atrial and ventricular septal defects, patent ductus arteriosus, hypoplastic right ventricle, and joint contractures (Shaheen et al., 2016).

Complex cortical dysplasia with other brain malformations-9 is a severe autosomal recessive disorder characterized by profoundly impaired motor and cognitive development apparent from early infancy. Affected individuals develop intractable seizures and are unable to speak or ambulate. Brain imaging shows pachygyria as well as hypogenesis of the corpus callosum and other variable brain abnormalities. The phenotype results from impaired cortical neuronal migration (summary by Schaffer et al., 2018). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).

Congenital hypomyelinating neuropathy-3 is an autosomal recessive neurologic disorder characterized by onset of neurogenic muscle impairment in utero. Affected individuals present at birth with severe hypotonia, often causing respiratory insufficiency or failure and inability to swallow or feed properly. They have profoundly impaired psychomotor development and may die in infancy or early childhood. Those that survive are unable to sit or walk. Sural nerve biopsy shows hypomyelination of the nerve fibers, and brain imaging often shows impaired myelination and cerebral and cerebellar atrophy. Nerve conduction velocities are severely decreased (about 10 m/s) or absent due to improper myelination (summary by Vallat et al., 2016 and Low et al., 2018). For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).

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).

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).

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.

Neurodevelopmental disorder with hypotonia and brain abnormalities (NEDHYBA) is characterized by impaired development of motor skills, cognitive function, and speech acquisition beginning in infancy or early childhood. Some affected individuals may have feeding difficulties, seizures, behavioral abnormalities, and nonspecific dysmorphic facial features. Brain imaging shows variable abnormalities, including corpus callosum defects, cerebellar defects, and decreased white matter volume. There is significant phenotypic variability (summary by Duncan et al., 2021).

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.

Autosomal recessive spastic paraplegia-86 (SPG86) is a complex neurologic disorder characterized by global developmental delay apparent from early childhood combined with early-onset progressive spasticity mainly affecting the lower limbs, but also affecting the upper limbs. Affected individuals have hyperreflexia, extensor plantar responses, pyramidal signs, and difficulty walking or inability to walk. Some may have joint contractures and foot or ankle deformities. Patients with SPG86 have impaired intellectual development with poor or absent speech, often with behavioral abnormalities. Brain imaging shows thin corpus callosum and white matter abnormalities. Rare patients may have seizures. The disorder is thus a complicated form of SPG (summary by Yahia et al., 2021, Miyake et al., 2022). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Congenital disorder of deglycosylation-2 (CDDG2) is an autosomal recessive disorder with variable associated features such as dysmorphic facies, impaired intellectual development, and brain anomalies, including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis (Maia et al., 2022). For a discussion of genetic heterogeneity of congenital disorder of deglycosylation, see CDGG1 (615273).

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures (NEDFSS), is characterized by these features and global developmental delay with delayed or absent walking, moderate to severely impaired intellectual development, and poor or absent speech acquisition. Affected individuals may also have behavioral abnormalities. About half of patients develop various types of seizures that are usually well-controlled with medication. Rare patients are noted to have heat intolerance or insensitivity to pain (Lines et al., 2022).

Congenital disorder of glycosylation type IIaa (CDG2AA) is an autosomal recessive disorder characterized by infantile mortality due to liver disease, skeletal abnormalities, and protein glycosylation defects (Linders et al., 2021). For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).