Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

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). Patients with a clinical diagnosis of Beemer-Langer syndrome have been found to carry mutations in the IFT80 gene (611177); see SRTD2, 611263. For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

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.

MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.

Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.

Transaldolase deficiency (TALDOD) is a rare inborn error of pentose metabolism. Typical features include intrauterine growth restriction, triangular face, loose wrinkly skin at birth, and development of progressive liver failure (summary by Lee-Barber et al., 2019).

The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes: Timothy syndrome with or without syndactyly. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval. These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C: QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current). Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current).

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.

CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015).

The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36. See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features.

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.

Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.

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).

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.

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.

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).

Yunis-Varon syndrome (YVS) is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013).

Microcephalic osteodysplastic primordial dwarfism type I (MOPD1) is a severe autosomal recessive skeletal dysplasia characterized by dwarfism, microcephaly, and neurologic abnormalities, including mental retardation, brain malformations, and ocular/auditory sensory deficits. Patients often die in early childhood (summary by Pierce and Morse, 2012).

Any arthrogryposis-renal dysfunction-cholestasis syndrome in which the cause of the disease is a mutation in the VPS33B gene.

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.

Any atrial heart septal defect in which the cause of the disease is a mutation in the TBX20 gene.

Any hypothyroidism, congenital, nongoitrous in which the cause of the disease is a mutation in the NKX2-5 gene.

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.

Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.

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.

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.

LTBP4-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective tissue disorder such as inguinal hernias and hollow visceral diverticula (e.g., intestine, bladder). Other manifestations can include pyloric stenosis, diaphragmatic hernia, rectal prolapse, gastrointestinal elongation/tortuosity, cardiovascular abnormality, pulmonary hypertension, hypotonia and frequent pulmonary infections. Bladder diverticula and hydronephrosis are common. Early demise has been associated with pulmonary emphysema.

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).

Potocki-Lupski syndrome (PTLS) is characterized by cognitive, behavioral, and medical manifestations. Cognitively, most individuals present with developmental delay, later meeting criteria for moderate intellectual disability. Behaviorally, issues with attention, hyperactivity, withdrawal, and anxiety may be seen. Some individuals meet criteria for autism spectrum disorder. Medically, hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, hypoglycemia associated with growth hormone deficiency, and mildly dysmorphic facial features are observed. Medical manifestations typically lead to identification of PTLS in infancy; however, those with only behavioral and cognitive manifestations may be identified in later childhood.

Cardiospondylocarpofacial syndrome (CSCF) is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion, extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations (summary by Le Goff et al., 2016).

Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (Boggs et al., 1994). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (Vassal et al., 1998). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (Sen et al., 2004).

14q11.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, hypotonia and facial dysmorphism.

Cranioectodermal dysplasia (CED) is a ciliopathy with skeletal involvement (narrow thorax, shortened proximal limbs, syndactyly, polydactyly, brachydactyly), ectodermal features (widely spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth deficiency, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus, epicanthal folds, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage kidney disease in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.

The chromosome 13q14 deletion syndrome is characterized by retinoblastoma (180200), variable degrees of mental impairment, and characteristic facial features, including high forehead, prominent philtrum, and anteverted earlobes (summary by Caselli et al., 2007).

Congenital myopathy-11 (CMYO11) is an autosomal recessive skeletal muscle disorder characterized clinically by severe hypotonia apparent at birth, resulting in early feeding problems, motor delay, and walking difficulties. However, the course of the disease is nonprogressive: most affected individuals achieve independent ambulation and tend to show improvement of muscle weakness throughout childhood and early adulthood. There is no respiratory or cardiac involvement; cognitive development is normal. Muscle biopsy may show rare centralized nuclei, type 1 fiber hypotrophy, and type 1 fiber predominance, suggestive of a pathologic diagnosis of congenital fiber-type disproportion (CFTD). However, the findings on skeletal muscle biopsy may be nonspecific (Muhammad et al., 2013). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015).

Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010). Genetic Heterogeneity of Fibrochondrogenesis Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3.

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.

The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and generalized cutaneous capillary malformations (a few to hundreds of oval/circular macules or patches varying in size from 1-2 mm to several cm), hypoplastic distal phalanges of the hands and/or feet, early-onset intractable epilepsy, and profound developmental delay. Seizures, which can be focal, tonic, and complex partial and can include infantile spasms, appear to stabilize after age two years. Myoclonus of the limbs and eyelids is common; other abnormal movements (dyskinetic, choreiform) may be seen. To date, the diagnosis has been confirmed in 18 individuals from 15 families.

Any aortic valve disease in which the cause of the disease is a mutation in the SMAD6 gene.

Immunodeficiency-110 (IMD110) is an autosomal recessive primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, and autoimmune manifestations. Patients are at risk for developing lymphoproliferative disorders or lymphoma, particularly associated with EBV. Some patients may show cardiac malformations, including atrial septal defect (Abdollahpour et al., 2012; Nehme et al., 2012).

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).

PACS1 neurodevelopmental disorder (PACS1-NDD) is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Hypotonia is reported in about a third of individuals and is noted to improve over time. Approximately 60% of individuals are ambulatory. Feeding difficulty is common, with 25% requiring gastrostomy tube to maintain appropriate caloric intake. Other common features include constipation, seizures, behavioral issues, congenital heart anomalies, short stature, and microcephaly. Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth. To date approximately 35 individuals with PACS1-NDD have been reported.

Autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) is characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA (mtDNA) deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression (summary by Ronchi et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).

A rare, genetic, neurologic disease characterized by primary hyperaldosteronism presenting with early-onset, severe hypertension, hypokalemia and neurological manifestations (including seizures, severe hypotonia, spasticity, cerebral palsy and profound developmental delay/intellectual disability).

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).

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.

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.

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.

CHOPS syndrome is a disorder involving multiple abnormalities that are present from birth (congenital). The name "CHOPS" is an abbreviation for a list of features of the disorder including cognitive impairment, coarse facial features, heart defects, obesity, lung (pulmonary) involvement, short stature, and skeletal abnormalities.\n\nChildren with CHOPS syndrome have intellectual disability and delayed development of skills such as sitting and walking. Characteristic facial features include a round face; thick hair; thick eyebrows that grow together in the middle (synophrys); wide-set, bulging eyes with long eyelashes; a short nose; and down-turned corners of the mouth.\n\nMost affected individuals are born with a heart defect called patent ductus arteriosus (PDA). The ductus arteriosus is a connection between two major arteries, the aorta and the pulmonary artery. This connection is open during fetal development and normally closes shortly after birth. However, the ductus arteriosus remains open, or patent, in babies with PDA. If untreated, this heart defect causes infants to breathe rapidly, feed poorly, and gain weight slowly; in severe cases, it can lead to heart failure. Multiple heart abnormalities have sometimes been found in children with CHOPS syndrome. In addition to PDA, affected individuals may have ventricular septal defect, which is a defect in the muscular wall (septum) that separates the right and left sides of the heart's lower chamber.\n\nPeople with CHOPS syndrome have abnormalities of the throat and airways that cause momentary cessation of breathing while asleep (obstructive sleep apnea). These abnormalities can also cause affected individuals to breathe food or fluids into the lungs accidentally, which can lead to a potentially life-threatening bacterial lung infection (aspiration pneumonia) and chronic lung disease. Affected individuals are shorter than more than 97 percent of their peers and are overweight for their height. They also have skeletal differences including unusually short fingers and toes (brachydactyly) and abnormally-shaped spinal bones (vertebrae).\n\nOther features that can occur in CHOPS syndrome include a small head size (microcephaly); hearing loss; clouding of the lens of the eye (cataract); a single, horseshoe-shaped kidney; and, in affected males, undescended testes (cryptorchidism).

Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above.

Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). For a discussion of genetic heterogeneity of spinal muscular atrophy with congenital bone fractures, see SMABF1 (616866).

Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). Genetic Heterogeneity of Spinal Muscular Atrophy With Congenital Bone Fractures See also SMABF2 (616867), caused by mutation in the ASCC1 gene (614215) on chromosome 10q22.

EVEN-plus syndrome (EVPLS) is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (600373; Royer-Bertrand et al., 2015).

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).

The Cincinnati type of acrofacial dysostosis is a ribosomopathy characterized by a spectrum of mandibulofacial dysostosis phenotypes, with or without extrafacial skeletal defects (Weaver et al., 2015). In addition, a significant number of neurologic abnormalities have been reported, ranging from mild delays to refractory epilepsy, as well as an increased incidence of congenital heart defects, primarily septal in nature (Smallwood et al., 2023).

White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females.

X-linked syndromic intellectual developmental disorder-34 (MRXS34) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by Mircsof et al., 2015).

GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.

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).

RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.

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).

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).

An inherited condition caused by autosomal dominant mutation(s) in the PPP1CB gene, encoding serine/threonine-protein phosphatase PP1-beta catalytic subunit. The condition is characterized by facial features similar to those seen in Noonan syndrome but may also include short stature, cognitive deficits, relative macrocephaly, small posterior fossa resulting in Chiari I malformation, hypernasal voice, cardiac defects, and ectodermal abnormalities, which typically presents as slow-growing, sparse, and/or unruly hair.

Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals and a wide spectrum of functional and morphologic abnormalities. Intrauterine growth restriction or low birth weight and feeding difficulties are common. Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported. About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities. Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.

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).

Any Neu-Laxova syndrome in which the cause of the disease is a mutation in the PHGDH gene.

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.

A rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by initially normal growth and development followed by the infantile-onset of failure to thrive, psychomotor delay, poor feeding, dyspnea, severe hypertrophic cardiomyopathy and hepatomegaly. Laboratory studies report increased plasma lactate and alanine, abnormal liver enzymes and decreased activity of mitochondrial respiratory chain complexes I, III, IV, and V. Caused by compound heterozygous mutation in the MRPL3 gene on chromosome 3q22.

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

Neurodevelopmental disorder with spasticity and poor growth (NEDSG) is an autosomal recessive disorder characterized by severe early-onset encephalopathy with progressive microcephaly (Nahorski et al., 2018).

IDDCDF is an autosomal recessive syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Additional features, such as distal skeletal anomalies, may also be observed (Stephen et al., 2018).

Developmental delay with or without dysmorphic facies and autism (DEDDFA) is a complex neurodevelopmental disorder apparent from infancy or early childhood and associated with variably impaired intellectual development. Some patients may be severely affected with no speech and inability to walk, whereas others may be able to attend special schools or have normal intellectual function associated with autism spectrum disorder and mild speech delay. Genetic analysis has suggested that the phenotype can be broadly categorized into 2 main groups. Patients with TRRAP mutations affecting residues 1031-1159 have a more severe disorder, often with multisystem involvement, including renal, cardiac, and genitourinary systems, as well as structural brain abnormalities. Patients with mutations outside of that region tend to have a less severe phenotype with a higher incidence of autism and usually no systemic involvement. Patients in both groups usually have somewhat similar dysmorphic facial features, such as upslanting palpebral fissures, hypertelorism, low-set ears, and broad or depressed nasal bridge, although these features are highly variable (summary by Cogne et al., 2019).

Khan-Khan-Katsanis syndrome (3KS) is an autosomal recessive neurodevelopmental disorder with variable involvement of the ocular, renal, skeletal, and sometimes cardiac systems. Affected individuals present at birth with multiple congenital anomalies, defects in urogenital and limb morphogenesis, poor overall growth with microcephaly, and global developmental delay (summary by Khan et al., 2019).

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.

Neurooculocardiogenitourinary syndrome (NOCGUS) is a multisystem disorder characterized by poor growth and anomalies of the ocular, craniofacial, neurologic, cardiovascular, genitourinary, skeletal, and gastrointestinal systems. Lethality before 2 years of age has been observed (Reis et al., 2019).

Intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF) is an autosomal dominant disorder characterized by global developmental delay apparent from infancy, impaired language development, and dysmorphic facial features, including hypertelorism, epicanthal folds, and abnormal palpebral fissures. Some patients may have additional findings, including feeding difficulties, mild cardiac or genitourinary defects, and distal skeletal anomalies (summary by Balak et al., 2019).

Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) is a neurodevelopmental disorder characterized by onset of hypotonia and variably impaired global developmental delay in infancy. Affected individuals tend to have learning disability, usually requiring special schooling, as well as behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder (ADHD). Additional more variable features may include nonspecific dysmorphic facial features, congenital heart defects, visual or ocular movement anomalies, and poor feeding and/or gastroesophageal reflux (summary by Calpena et al., 2019).

X-linked holoprosencephaly-13 (HPE13) is a neurologic disorder characterized by midline developmental defects that mainly affect the brain and craniofacial structure. The severity and manifestations are variable: some patients may have full alobar HPE with cyclopia, whereas others have semilobar HPE or septooptic dysplasia. Dysmorphic features include microcephaly, hypotelorism, low-set ears, micrognathia, and cleft lip/palate. Patients with a more severe phenotype may die in the newborn period, whereas those with a less severe phenotype show global developmental delay. Additional variable features include congenital heart defects and vertebral anomalies. Phenotypic variability may be related to the type of mutation, X-inactivation status, and possible incomplete penetrance. The STAG2 protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; HPE13 can thus be classified as a 'cohesinopathy' (summary by Kruszka et al., 2019). For a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Rhizomelic limb shortening with dysmorphic features (RLSDF) is characterized by rhizomelic shortening of the extremities, predominantly of the upper limbs, and variable dysmorphic features, including macrocephaly, prominent forehead, hypertelorism, depressed or broad nasal bridge, and micrognathia. Hearing loss has also been observed (Sajan et al., 2019; Pagnamenta et al., 2023).

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).

Neurodevelopmental, jaw, eye, and digital syndrome (NEDJED) is characterized by phenotypic diversity, with patients exhibiting a range of overlapping phenotypes. Most patients show developmental delay ranging from mild to severe, and often have behavioral disorders as well. Brain imaging shows hypoplasia of the corpus callosum, prominence of lateral ventricles, and/or white matter abnormalities. Many patients have retro- or micrognathia, but mild prognathism has also been observed. Ocular anomalies are variably present, and may be severe and complex; however, some patients show only mild myopia. Abnormalities of fingers and toes include brachydactyly, clinodactyly, syndactyly, and contractures; polydactyly is rarely seen (Holt et al., 2019).

Suleiman-El-Hattab syndrome (SULEHS) is an autosomal recessive multisystem developmental disorder characterized by hypotonia and feeding difficulties soon after birth, global developmental delay with impaired intellectual development and poor expressive speech, and a general happy demeanor. There is a distinctive facial appearance with microcephaly, thick arched eyebrows with synophrys, hypertelorism, epicanthal folds, low-set ears, broad nasal bridge, and thin upper lip. Additional more variable features include recurrent respiratory infections, cardiovascular malformations, cryptorchidism, seizures, and distal anomalies of the hands and feet (summary by Suleiman et al., 2019).

Mandibuloacral dysplasia progeroid syndrome (MDPS) is an autosomal recessive severe laminopathy-like disorder characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis, and hypertension (Elouej et al., 2020).

Lessel-Kreienkamp syndrome (LESKRES) is a neurodevelopmental disorder characterized by global developmental delay with intellectual disability and speech and language delay apparent from infancy or early childhood. The severity of the disorder is highly variable: some patients have mildly delayed walking and mild cognitive deficits, whereas others are nonambulatory and nonverbal. Most have behavioral disorders. Additional features, including seizures, hypotonia, gait abnormalities, visual defects, cardiac defects, and nonspecific dysmorphic facial features, may also be present (summary by Lessel et al., 2020).

Mitochondrial complex II deficiency nuclear type 3 (MC2DN3) is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients may have an encephalomyopathic picture with episodic developmental regression, loss of motor skills, hypotonia, ataxia, dystonia, and seizures or myoclonus. Other patients present in infancy with hypertrophic cardiomyopathy, which may be fatal. Laboratory studies show increased serum lactate and mitochondrial complex II deficiency in muscle and fibroblasts (summary by Jackson et al., 2014 and Alston et al., 2015). For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (252011).

Coffin-Siris syndrome-12 (CSS12) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, speech and language delay, and behavioral abnormalities, such as autism or hyperactivity. Affected individuals may have hypotonia and poor feeding in infancy. There are variable dysmorphic facial features, although most patients do not have the classic hypoplastic fifth digit/nail abnormalities that are often observed in other forms of CSS (Barish et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

Autosomal dominant primary microcephaly-26 (MCPH26) is characterized by progressive microcephaly beginning at birth and associated with global developmental delay with variably impaired intellectual development. Some patients may have only mild learning difficulties or speech delay, whereas other are more severely affected with the inability to walk or speak. Additional features may include short stature, spasticity, feeding difficulties requiring tube feeding, and nonspecific dysmorphic facial features. Brain imaging in some patients shows a simplified gyral pattern or dysgenesis of the corpus callosum, suggesting abnormal neuronal migration (summary by Cristofoli et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies-2 (SSFSC2) is characterized by thin and short long bones, distinctive facial dysmorphism, and dental and skeletal abnormalities, in the absence of developmental delay or intellectual disability. Cardiac anomalies have been reported in some patients (Lin et al., 2021). For a discussion of genetic heterogeneity of SSFSC, see SSFSC1 (617877).

Li-Campeau syndrome (LICAS) is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, dysmorphic facial features, hypothyroidism, and variable abnormalities of the cardiac and genital systems. Additional features may include seizures, short stature, hypotonia, and brain imaging anomalies, such as cortical atrophy (summary by Li et al., 2021).

Alzahrani-Kuwahara syndrome (ALKUS) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay with severely impaired intellectual function and poor or absent speech. Patients have poor overall growth and dysmorphic facial features. More variable findings include early-onset cataracts, hypotonia, congenital heart defects, lower limb spasticity, and hypospadias (summary by Alzahrani et al., 2020).

Dilated cardiomyopathy-2D (CMD2D) is characterized by neonatal onset of severe cardiomyopathy, with rapid progression to cardiac decompensation and death unless the patient undergoes heart transplantation (Ganapathi et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200.

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).

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).

Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by Shaheen et al., 2020 and David et al., 2020).

Zaki syndrome (ZKS) is characterized by developmental delay, progressive microcephaly, and short stature, as well as dysmorphic features including sparse scalp hair, cupped ears, wide nose and mouth, short philtrum, and high-arched palate. Other variable features have been observed, including ocular, skeletal, cardiac, and renal anomalies (Chai et al., 2021).

Ferguson-Bonni neurodevelopmental syndrome (FERBON) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, and hypotonia with early motor delay. Additional features may include dysmorphic facies, mild skeletal abnormalities, and hearing loss (summary by Ferguson et al., 2022).

Proximal 1p36 deletion syndrome is a multisystem developmental disorder characterized by global developmental delay with impaired intellectual development, poor overall growth with microcephaly, axial hypotonia, and dysmorphic facial features. Most patients have congenital cardiac malformations or cardiac dysfunction. Additional more variable features may include distal skeletal anomalies, seizures, and cleft palate. The phenotype shows some overlap with distal chromosome 1p36 deletion syndrome (summary by Kang et al., 2007).

Visceral heterotaxy-12 (HTX12) is an embryonic developmental disorder characterized by defects in the asymmetric positioning of visceral organs across the left-right axis, known as laterality defects. The phenotype is highly variable, ranging from complete organ reversal (situs inversus totalis) to selective misarrangement of organs (situs ambiguus) such as the liver, spleen, and pancreas. The disorder is often associated with dextrocardia or variable complex congenital heart defects. Early death may occur in the most severe cases (summary by Szenker-Ravi et al., 2022). For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (Chilton et al., 2020).

A rare disorder of pentose phosphate metabolism with characteristics of developmental delay and intellectual disability, delayed or absent speech, short stature and congenital heart defects (such as ventricular septal defect, atrial septal defect and patent foramen ovale). Additional reported features include hypotonia, hyperactivity, stereotypic behaviour, ophthalmologic abnormalities (bilateral cataract, uveitis, strabismus), hearing impairment and variable facial dysmorphism among others. Laboratory analysis shows elevated plasma and urinary polyols (erythritol, arabitol and ribitol) and urinary sugar-phosphates (ribose-5-phosphate and xylulose/ribulose-5-phosphate).

Cardiac valvular dysplasia-1 (CVDP1) is characterized by congenital malformations of the pulmonic, tricuspid, and mitral valves. Structural cardiac defects, including atrial and ventricular septal defects, single left ventricle, and hypoplastic right ventricle have also been observed in affected individuals (Ta-Shma et al., 2017). Genetic Heterogeneity of Cardiac Valvular Dysplasia CVDP2 (620067) is caused by mutation in the ADAMTS19 gene (607513) on chromosome 5q23.

Severe congenital liver disease (SCOLIV) is an autosomal recessive disorder characterized by the onset of progressive hepatic dysfunction usually in the first years of life. Affected individuals show feeding difficulties with failure to thrive and features such as jaundice, hepatomegaly, and abdominal distension. Laboratory workup is consistent with hepatic insufficiency and may also show coagulation defects, anemia, or metabolic disturbances. Cirrhosis and hypernodularity are commonly observed on liver biopsy. Many patients die of liver failure in early childhood (Moreno Traspas et al., 2022).

Primordial dwarfism-immunodeficiency-lipodystrophy syndrome (PDIL) is characterized by pre- and postnatal growth restriction, with extreme microcephaly, short stature, and absence of subcutaneous fat. There is also significant hematologic/immune dysfunction, with hypo- or agammaglobulinemia, as well as lymphopenia, anemia, and thrombocytopenia, and most affected individuals succumb to infection in early childhood (Parry et al., 2020).

Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly (NEDFLPH) is an autosomal recessive disorder characterized by global developmental delay with severely impaired intellectual development. Affected individuals often have behavioral abnormalities and may have variable findings on brain imaging, such as thin corpus callosum. Laboratory studies show nuclear lobulation defects in a subset of neutrophils, indicating a pseudo-Pelger-Huet anomaly (see 169400) and suggesting defects in the integrity of the nuclear envelope, where TMEM147 localizes (Thomas et al., 2022).

Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC) is an autosomal recessive disorder characterized by these cardinal features apparent from infancy. There is phenotypic variability both in disease manifestations and severity. More severely affected individuals are unable to walk independently, are nonverbal, and may have other anomalies, including congenital heart defects, feeding difficulties, or skeletal defects, whereas others show mildly delayed motor and speech acquisition with mild or borderline intellectual disability (summary by von Elsner et al., 2022).

Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH) is an autosomal dominant disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. Additional features may include developmental delay, impaired intellectual development, and growth failure/retardation (summary by Cuvertino et al., 2020 and Baldridge et al., 2020).

Lymphatic malformation-13 (LMPHM13) is characterized by the presence of nonimmune hydrops fetalis which often resolves with age. Capillary or cavernous hemangiomas are present in most patients, as are cardiac defects, often mild (Abdelrahman et al., 2018). For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

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 with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities (NDDRSB) is a severe autosomal recessive disorder characterized by onset of these features in infancy. Affected individuals present with respiratory failure requiring intubation soon after birth; some die due to cardiorespiratory insufficiency. Those that survive show severe global developmental delay, refractory myoclonic seizures, hyperkinetic movements with exaggerated startle response, and microcephaly with dysmorphic features. Additional findings may include sensorineural hearing loss and ocular defects. Brain imaging shows variable abnormalities consistent with progressive neurodegeneration (Cali et al., 2022).

Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity (NEDIHSS) is an autosomal recessive disorder characterized by prenatal or neonatal onset of intracranial hemorrhage, usually with ventriculomegaly and calcifications, resulting in parenchymal brain damage. Some affected individuals have symptoms incompatible with life and die in utero. Those that survive show profound global developmental delay with almost no motor or cognitive skills, hypotonia, spasticity, and seizures. Other features may include facial dysmorphism, retinal vascular abnormalities, and poor overall growth. The pathogenesis of the disease likely results from dysfunction of vascular endothelial cells in the brain (Lecca et al., 2023).

Early-onset epilepsy-2 with or without developmental delay (EPEO2) is an autosomal dominant neurologic disorder characterized by the onset of generalized tonic-clonic seizures in the first days, months, or years of life. The severity is highly variable: some patients have normal psychomotor development and normal brain imaging, whereas others may show developmental delay associated with abnormalities on brain imaging (summary by Yu et al., 2019). For a discussion of genetic heterogeneity of EPEO, see 617290.

Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities (ARCME) is characterized by severe dilated cardiomyopathy resulting in death or cardiac transplantation in childhood. Ventricular tachycardia, sustained or nonsustained, has been reported. In addition, some patients exhibit ectodermal manifestations including woolly or wiry hair, dental anomalies, dry skin, and/or dystrophic nails. Cleft lip and palate and corneal abnormalities have also been observed (Robinson et al., 2020; Henry et al., 2022).

Primary ciliary dyskinesia-52 (CILD52) is an autosomal recessive disorder characterized by laterality defects and mild respiratory symptoms due to subtle ciliary beating defects (summary by Leslie et al., 2022). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Primary ciliary dyskinesia-53 (CILD53) is an autosomal recessive disorder characterized by randomization of the left-right body asymmetry and respiratory symptoms (Hjeij et al., 2023). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Polydactyly-macrocephaly syndrome (PDMCS) is characterized by postaxial polydactyly and progressive macrocephaly. Variable ocular anomalies have been observed, including microphthalmia and coloboma as well as delayed visual maturation. Neurodevelopmental anomalies are also present, including global developmental delay and autism or autistic traits, with prominent perivascular spaces on brain imaging (Harris et al., 2024).

Neuroocular syndrome-1 (NOC1) encompasses a broad spectrum of overlapping anomalies, with developmental delay or impaired intellectual development as a consistent finding. Eye abnormalities show marked variability in the type and severity of defects, and include anophthalmia, microphthalmia, and coloboma. Other common systemic features include congenital heart and kidney defects, hypotonia, failure to thrive, and microcephaly (summary by Chowdhury et al., 2021). Genetic Heterogeneity of Neuroocular Syndrome See also NOC2 (168885), caused by mutation in the DAGLA gene (614015) on chromosome 11q12.