Barrett esophagus, or Barrett metaplasia, describes the phenotypic change of normal esophageal squamous epithelium to a columnar and intestinal-type epithelium. This metaplastic change is important because patients with Barrett esophagus have an increased risk of esophageal adenocarcinoma. The main cause of Barrett metaplasia is gastroesophageal reflux (GER; 109350). The retrograde movement of acid and bile salts from the stomach into the esophagus in this disease causes prolonged injury to the esophageal epithelium and induces chronic esophagitis, which in turn is believed to trigger the pathologic changes (summary by Wong et al., 2005).

Cri-du-chat syndrome was first described by Lejeune et al. (1963) as a hereditary congenital syndrome associated with deletion of part of the short arm of chromosome 5. The deletions can vary in size from extremely small and involving only band 5p15.2 to the entire short arm. Although the majority of deletions arise as new mutations, approximately 12% result from unbalanced segregation of translocations or recombination involving a pericentric inversion in one of the parents.

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.

Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.

Gastroesophageal reflux (GER) is characterized by the retrograde movement of stomach contents into the esophagus. In its most severe form, GER results in extensive tissue damage caused by acid reflux. In adolescents and adults, and even infrequently in children, chronic GER is associated with the risk of developing Barrett metaplasia (614266), a premalignant lesion of the esophageal mucosa (Hu et al., 2000). In turn, Barrett metaplasia is correlated with the development of adenocarcinoma of the esophagus (see 614266), estimated as the fifth most prevalent neoplasia in the Western world (Lagergren et al., 1999).

Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.

Dubowitz syndrome (DS) is a rare multiple congenital syndrome characterized primarly by growth retardation, microcephaly, distinctive facial dysmorphism, cutaneous eczema, a mild to severe intellectual deficit and genital abnormalities.

Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described.

Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference =2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems (most notably autistic spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures.

Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones.

Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facies syndrome (FHUFS), is a rare and sporadic multiple congenital anomaly syndrome comprising bilateral femoral hypoplasia and characteristic facial features, such as long philtrum, thin upper lip, micrognathia with or without cleft palate, upward-slanting palpebral fissures, and a short nose with broad tip. Other features, such as renal anomalies, are more variable (summary by Nowaczyk et al., 2010).

Cerebrocostomandibular syndrome (CCMS) is characterized mainly by severe micrognathia, rib defects, and mental retardation. A spectrum of rib gap defects have been reported ranging from a few dorsal rib segments to complete absence of ossification. In about half of the 65 reported cases to date, there is cerebral involvement including mental retardation, microcephaly, and histologic anomalies. Both autosomal dominant and autosomal recessive forms of the disorder have been described (Zeevaert et al., 2009). See CDG2G (611209) for a cerebrocostomandibular-like syndrome.

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with thiamine treatment, but the red cells remain macrocytic and anemia can recur if treatment is withdrawn. Progressive sensorineural hearing loss often occurs early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence. Thiamine treatment may reduce insulin requirement and delay onset of diabetes in some individuals.

D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).

The branchiooculofacial syndrome (BOFS) is characterized by: branchial (cervical or infra- or supra-auricular) skin defects that range from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; ocular anomalies that can include microphthalmia, anophthalmia, coloboma, and nasolacrimal duct stenosis/atresia; and facial anomalies that can include ocular hypertelorism or telecanthus, broad nasal tip, upslanted palpebral fissures, cleft lip or prominent philtral pillars that give the appearance of a repaired cleft lip (formerly called "pseudocleft lip") with or without cleft palate, upper lip pits, and lower facial weakness (asymmetric crying face or partial 7th cranial nerve weakness). Malformed and prominent pinnae and hearing loss from inner ear and/or petrous bone anomalies are common. Intellect is usually normal.

The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996). Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (Kestila et al., 1998). Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature. Genetic Heterogeneity of Nephrotic Syndrome and Focal Segmental Glomerulosclerosis Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also NPHS2 (600995), caused by mutation in the podocin gene (604766); NPHS3 (610725), caused by mutation in the PLCE1 gene (608414); NPHS4 (256370), caused by mutation in the WT1 gene (607102); NPHS5 (614199), caused by mutation in the LAMB2 gene (150325); NPHS6 (614196), caused by mutation in the PTPRO gene (600579); NPHS7 (615008), caused by mutation in the DGKE gene (601440); NPHS8 (615244), caused by mutation in the ARHGDIA gene (601925); NPHS9 (615573), caused by mutation in the COQ8B gene (615567); NPHS10 (615861), caused by mutation in the EMP2 gene (602334); NPHS11 (616730), caused by mutation in the NUP107 gene (607617); NPHS12 (616892), caused by mutation in the NUP93 gene (614351); NPHS13 (616893), caused by mutation in the NUP205 gene (614352); NPHS14 (617575), caused by mutation in the SGPL1 gene (603729); NPHS15 (617609), caused by mutation in the MAGI2 gene (606382); NPHS16 (617783), caused by mutation in the KANK2 gene (614610), NPHS17 (618176), caused by mutation in the NUP85 gene (170285); NPHS18 (618177), caused by mutation in the NUP133 gene (607613); NPHS19 (618178), caused by mutation in the NUP160 gene (607614); NPHS20 (301028), caused by mutation in the TBC1D8B gene (301027); NPHS21 (618594) caused by mutation in the AVIL gene (613397); NPHS22 (619155), caused by mutation in the NOS1AP gene (605551); NPHS23 (619201), caused by mutation in the KIRREL1 gene (607428); NPHS24 (619263), caused by mutation in the DAAM2 gene (606627); and NPHS26 (620049), caused by mutation in the LAMA5 gene (601033). The symbol NPHS25 has been used as an alternative designation for NPHS21. See also FSGS1 (603278), caused by mutation in the ACTN4 gene (604638); FSGS2 (603965), caused by mutation in the TRPC6 gene (603652); FSGS3 (607832), associated with variation in the CD2AP gene (604241); FSGS4 (612551), mapped to chromosome 22q12; FSGS5 (613237), caused by mutation in the INF2 gene (610982); FSGS6 (614131), caused by mutation in the MYO1E gene (601479); FSGS7 (616002), caused by mutation in the PAX2 gene (167409); FSGS8 (616032), caused by mutation in the ANLN gene (616027); and FSGS9 (616220), caused by mutation in the CRB2 gene (609720).

Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. Males can present with a mild or severe phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant. The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.

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.

Bohring-Opitz syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia. The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

Aromatic L-amino acid decarboxylase deficiency (AADCD) is an autosomal recessive inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency (Abeling et al., 2000). The disorder is clinically characterized by vegetative symptoms, oculogyric crises, dystonia, and severe neurologic dysfunction, usually beginning in infancy or childhood (summary by Brun et al., 2010).

Transient neonatal hyperparathyroidism is characterized by interference with placental maternal-fetal calcium transport, causing fetal calcium deficiency resulting in hyperparathyroidism and metabolic bone disease. Because 80% of calcium is transferred during the third trimester, abnormalities may not be detected on second-trimester ultrasounds. Affected infants present at birth with prenatal fractures, shortened ribs, and bowing of long bones, as well as respiratory and feeding difficulties. Postnatal recovery or improvement is observed once calcium is provided orally, with most patients showing complete resolution of skeletal abnormalities by 2 years of age (Suzuki et al., 2018).

Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings.

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.

Leri pleonosteosis is an autosomal dominant skeletal disorder characterized by flexion contractures of the interphalangeal joints, limited movement of multiple joints, and short, broad metacarpals, metatarsals, and phalanges. Additional features may include chronic joint pain, short stature, bony overgrowths, spinal cord compression, scleroderma-like skin changes, and blepharophimosis. The clinical features overlap with several other musculoskeletal conditions, including Myhre syndrome (MYHRS; 139210) and geleophysic dysplasia (GPHYSD1; 231050) (summary by Banka et al., 2015).

Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males.

Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is characterized by sudden cardiac or respiratory arrest, disordered testicular development, and neurologic dysfunction, and is uniformly fatal before 1 year of age (Slater et al., 2020).

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).

Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.

The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400).

Congenital disorder of glycosylation type Ii (CDG1I) is a rare autosomal recessive disorder characterized by neurologic involvement, including a convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression (summary by Papazoglu et al., 2021). For a general discussion of CDGs, see CDG1A (212065).

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.

Craniolenticulosutural dysplasia is characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (summary by Boyadjiev et al., 2011).

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.

X-linked intellectual disability, Stocco Dos Santos type is characterised by severe intellectual deficit with hyperactivity, language delay, congenital hip luxation, short stature, kyphosis and recurrent respiratory infections. Aggressive behaviour and frequent epileptic seizures may also be present. The syndrome has been described in four boys from the same family. Transmission is X-linked and is caused by mutations in the <i>KIAA1202</i> gene, localised to the Xp11.2 region.

MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by early-onset hypotonia, feeding difficulty, gastrointestinal manifestations including gastroesophageal reflux and constipation, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in ~75% of affected individuals), and seizures (in ~50%). MECP2 duplication syndrome is 100% penetrant in males. Occasionally females have been described with a MECP2 duplication and a range of findings from mild intellectual disability to a phenotype similar to that seen in males. In addition to the core features, autistic behaviors, nonspecific neuroradiologic findings on brain MRI, mottled skin, and urogenital anomalies have been observed in several affected boys.

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.

Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.

For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included: Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B12-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy. Partially deficient or B12-responsive phenotypes (mut– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation. Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer.

Microcephalic osteodysplastic primordial dwarfism type I 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).

Stiff skin syndrome (SSKS) is characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness (Loeys et al., 2010). Patients with similar phenotypes involving stiff skin have been described; see, e.g., familial progressive scleroderma (181750), symmetric lipomatosis (151800), and congenital fascial dystrophy (228020).

Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by Young et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).

Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, and micrognathia), and a seizure disorder (Battaglia et al., 2008).

The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).

Pitt-Hopkins syndrome (PTHS) is characterized by significant developmental delays with moderate-to-severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.

SADDAN dysplasia (severe achondroplasia with developmental delay and acanthosis nigricans) is a very rare skeletal dysplasia characterized by the constellation of these features. Radiology reveals 'ram's horn' shaped clavicles and reverse bowing of lower limbs. Approximately half of patients die before the fourth week of life secondary to respiratory failure (summary by Zankl et al., 2008).

SLC25A24 Fontaine progeroid syndrome is a multisystem connective tissue disorder characterized by poor growth, abnormal skeletal features, and distinctive craniofacial features with sagging, thin skin, and decreased subcutaneous fat suggesting an aged appearance that is most pronounced in infancy and improves with time. Characteristic radiographic features include turribrachycephaly with widely open anterior fontanelle, craniosynostosis, and anomalies of the terminal phalanges. Cardiovascular, genitourinary, ocular, and gastrointestinal abnormalities may also occur. To date, 13 individuals with a molecularly confirmed diagnosis of SLC25A24 Fontaine progeroid syndrome have been described.

Temple-Baraitser syndrome is a rare developmental disorder characterized by severe mental retardation and anomalies of the first ray of the upper and lower limbs with absence/hypoplasia of the nails. Most patients also have seizures; various dysmorphic facial features have been reported (summary by Jacquinet et al., 2010).

SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by onset of the following features in infancy or childhood (median age of onset 2 months; range of onset birth to 6 years): psychomotor retardation, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, postnatal growth retardation, and feeding difficulties. Other less frequent features include distinctive facial features, contractures, kyphoscoliosis, gastroesophageal reflux, ptosis, choreoathetosis, ophthalmoplegia, and epilepsy (infantile spasms or generalized convulsions). The median survival is 20 years; approximately 30% of affected individuals succumb during childhood. Affected individuals may have hyperintensities in the basal ganglia, cerebral atrophy, and leukoencephalopathy on head MRI. Elevation of methylmalonic acid (MMA) in the urine and plasma is found in a vast majority of affected individuals, although at levels that are far below those typically seen in individuals with classic methylmalonic aciduria.

Omodysplasia-2 (OMOD2) is a rare autosomal dominant skeletal dysplasia characterized by shortened humeri, dislocated radial heads, shortened first metacarpals, craniofacial dysmorphism, and variable genitourinary anomalies (Saal et al., 2015). For a discussion of genetic heterogeneity of OMOD, see 258315.

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.

The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009). For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

An extremely rare, sporadic form of Orofaciodigital syndrome with only a few reported cases and characteristics of facial (blepharophimosis, bulbous nasal tip, broad nasal bridge, downslanting palpebral fissures and low set ears) and skeletal (post-axial polydactyly and fusion of vertebrae) malformations along with severe intellectual disability, deafness and congenital heart defects.

Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. 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).

X-linked Opitz G/BBB syndrome (X-OS) is a multiple-congenital-anomaly disorder characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations (present in <50% of individuals) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only.

Syndromic multisystem autoimmune disease due to Itch deficiency is a rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland.

The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005).

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

Developmental and epileptic encephalopathy-5 (DEE5) is a neurologic disorder characterized by global developmental delay and the onset of tonic seizures or infantile spasms in the first months of life. The seizures tend to be refractory to treatment, and EEG shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals have severely impaired psychomotor development with lack of visual attention, poor head control, feeding difficulties, microcephaly, and spastic quadriplegia. Brain imaging may show cerebral atrophy and hypomyelination (summary by Saitsu et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350.

The chromosome 16p12.2-p11.2 deletion syndrome is characterized phenotypically by dysmorphic facial features, feeding difficulties, recurrent ear infections, developmental delay, and cognitive impairment. Additional features, such as heart defects and short stature, are variable (Ballif et al., 2007; Battaglia et al., 2009). The pericentric region of chromosome 16, specifically involving 16p12-p11, is a structurally complex region enriched in repetitive sequence elements, rendering this region susceptible to deletion or rearrangement (Ballif et al., 2007). There are several phenotypes associated with variation in this region: see 611913 for a deletion or duplication at 16p11.2 associated with autism; see 136570 for discussion of a recurrent 520-kb deletion at 16p12.1 associated with developmental delay and craniofacial dysmorphism; and see 613444 for a 220-kb deletion at 16p11.2 associated with isolated severe early-onset obesity and obesity with developmental delay. Battaglia et al. (2009) emphasized that the region at chromosome 16p11.2 that confers susceptibility to autism (AUTS14; see 611913) is located more centromeric to and is distinct from the 16p12.2-p11.2 region involved in the multiple congenital anomalies and intellectual disability phenotype.

Meier-Gorlin syndrome is a condition primarily characterized by short stature. It is considered a form of primordial dwarfism because the growth problems begin before birth (intrauterine growth retardation). After birth, affected individuals continue to grow at a slow rate. Other characteristic features of this condition are underdeveloped or missing kneecaps (patellae), small ears, and, often, an abnormally small head (microcephaly). Despite a small head size, most people with Meier-Gorlin syndrome have normal intellect.\n\nSome people with Meier-Gorlin syndrome have other skeletal abnormalities, such as unusually narrow long bones in the arms and legs, a deformity of the knee joint that allows the knee to bend backwards (genu recurvatum), and slowed mineralization of bones (delayed bone age).\n\nAbnormalities in sexual development may also occur in Meier-Gorlin syndrome. In some males with this condition, the testes are small or undescended (cryptorchidism). Affected females may have unusually small external genital folds (hypoplasia of the labia majora) and small breasts. Both males and females with this condition can have sparse or absent underarm (axillary) hair.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\n\nMost people with Meier-Gorlin syndrome have distinctive facial features. In addition to being abnormally small, the ears may be low-set or rotated backward. Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge.

Most people with Meier-Gorlin syndrome have distinctive facial features. In addition to being abnormally small, the ears may be low-set or rotated backward. Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\n\nAbnormalities in sexual development may also occur in Meier-Gorlin syndrome. In some males with this condition, the testes are small or undescended (cryptorchidism). Affected females may have unusually small external genital folds (hypoplasia of the labia majora) and small breasts. Both males and females with this condition can have sparse or absent underarm (axillary) hair.\n\nSome people with Meier-Gorlin syndrome have other skeletal abnormalities, such as unusually narrow long bones in the arms and legs, a deformity of the knee joint that allows the knee to bend backwards (genu recurvatum), and slowed mineralization of bones (delayed bone age).\n\nMeier-Gorlin syndrome is a condition primarily characterized by short stature. It is considered a form of primordial dwarfism because the growth problems begin before birth (intrauterine growth retardation). After birth, affected individuals continue to grow at a slow rate. Other characteristic features of this condition are underdeveloped or missing kneecaps (patellae), small ears, and, often, an abnormally small head (microcephaly). Despite a small head size, most people with Meier-Gorlin syndrome have normal intellect.

Most people with Meier-Gorlin syndrome have distinctive facial features. In addition to being abnormally small, the ears may be low-set or rotated backward. Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\n\nAbnormalities in sexual development may also occur in Meier-Gorlin syndrome. In some males with this condition, the testes are small or undescended (cryptorchidism). Affected females may have unusually small external genital folds (hypoplasia of the labia majora) and small breasts. Both males and females with this condition can have sparse or absent underarm (axillary) hair.\n\nSome people with Meier-Gorlin syndrome have other skeletal abnormalities, such as unusually narrow long bones in the arms and legs, a deformity of the knee joint that allows the knee to bend backwards (genu recurvatum), and slowed mineralization of bones (delayed bone age).\n\nMeier-Gorlin syndrome is a condition primarily characterized by short stature. It is considered a form of primordial dwarfism because the growth problems begin before birth (intrauterine growth retardation). After birth, affected individuals continue to grow at a slow rate. Other characteristic features of this condition are underdeveloped or missing kneecaps (patellae), small ears, and, often, an abnormally small head (microcephaly). Despite a small head size, most people with Meier-Gorlin syndrome have normal intellect.

Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome MCAHS2 (300868) is caused by mutation in the PIGA gene (311770) on chromosome Xp22, MCAHS3 (615398) is caused by mutation in the PIGT gene (610272) on chromosome 20q13, and MCAHS4 (618548) is caused by mutation in the PIGQ gene (605754) on chromosome 16p13. Knaus et al. (2018) provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between MCAHS and HPMRS1 (239300), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).

Any Pitt-Hopkins-like syndrome in which the cause of the disease is a mutation in the NRXN1 gene.

Congenital myopathy-10A (CMYP10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011). Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYP10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYP10B) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Congenital disorder of glycosylation type Ir (CDG1R) is an autosomal recessive disorder characterized by developmental delay, failure to thrive, feeding difficulties, hypotonia, and strabismus. Transferrin analysis demonstrates underglycosylation (summary by Pi et al., 2022). For a discussion of the classification of CDGs, see CDG1A (212065).

Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).

TECPR2-related hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID) is characterized by developmental delay and subsequent intellectual disability, behavioral abnormalities, neurologic manifestations (muscular hypotonia, sensory neuropathy with lower-limb hypo- or areflexia and ataxic gait), and autonomic dysfunction (including central hypoventilation and apnea, gastrointestinal dysmotility, dysphagia, and gastroesophageal reflux disease with recurrent aspiration). To date, more than 30 individuals with TECPR2-HSAN with ID have been identified.

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.

The signs and symptoms of hereditary hyperekplexia typically fade by age 1. However, older individuals with hereditary hyperekplexia may still startle easily and have periods of rigidity, which can cause them to fall down. They may also continue to have hypnagogic myoclonus or movements during sleep. As they get older, individuals with this condition may have a low tolerance for crowded places and loud noises. People with hereditary hyperekplexia who have epilepsy have the seizure disorder throughout their lives.\n\nHereditary hyperekplexia may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year.\n\nOther signs and symptoms of hereditary hyperekplexia can include muscle twitches when falling asleep (hypnagogic myoclonus) and movements of the arms or legs while asleep. Some infants, when tapped on the nose, extend their head forward and have spasms of the limb and neck muscles. Rarely, infants with hereditary hyperekplexia experience recurrent seizures (epilepsy).\n\nHereditary hyperekplexia is a condition in which affected infants have increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. During these rigid periods, some infants stop breathing, which, if prolonged, can be fatal. Infants with hereditary hyperekplexia have hypertonia at all times, except when they are sleeping.

Hereditary hyperekplexia is a condition in which affected infants have increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. During these rigid periods, some infants stop breathing, which, if prolonged, can be fatal. Infants with hereditary hyperekplexia have hypertonia at all times, except when they are sleeping.\n\nOther signs and symptoms of hereditary hyperekplexia can include muscle twitches when falling asleep (hypnagogic myoclonus) and movements of the arms or legs while asleep. Some infants, when tapped on the nose, extend their head forward and have spasms of the limb and neck muscles. Rarely, infants with hereditary hyperekplexia experience recurrent seizures (epilepsy).\n\nHereditary hyperekplexia may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year.\n\nThe signs and symptoms of hereditary hyperekplexia typically fade by age 1. However, older individuals with hereditary hyperekplexia may still startle easily and have periods of rigidity, which can cause them to fall down. They may also continue to have hypnagogic myoclonus or movements during sleep. As they get older, individuals with this condition may have a low tolerance for crowded places and loud noises. People with hereditary hyperekplexia who have epilepsy have the seizure disorder throughout their lives.

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.

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.

Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) is an autosomal dominant neurologic disorder with significant phenotypic heterogeneity, even within families. The disorder is most often diagnosed through genetic analysis with retrospective clinical phenotyping. Symptom onset is usually in early childhood, although later onset, even in adulthood, has been reported. Most affected individuals show global developmental delay from early childhood, particularly of motor and language skills. Many have mild intellectual disability; behavioral and psychiatric abnormalities such as autism and obsessive-compulsive disorder are also often observed. The movement disorder is prominent and may include cerebellar signs such as ataxia, tremor, dysmetria, poor coordination, and dysarthria. Other abnormal movements including spasticity, myoclonus, and dystonia have been reported, thus widening the phenotypic spectrum. Brain imaging is usually normal, but may show cerebellar atrophy or nonspecific white matter lesions. Variable dysmorphic facial features may also be present (summary by Thevenon et al., 2012; Jacobs et al., 2021; Wijnen et al., 2020).

Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (summary by Coelho 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).

Congenital disorder of glycosylation type IIm, or developmental and epileptic encephalopathy-22 (DEE22), is an X-linked dominant severe neurologic disorder characterized by infantile-onset seizures, hypsarrhythmia on EEG, hypotonia, and developmental delay associated with severe intellectual disability and lack of speech. These features are consistent with developmental and epileptic encephalopathy (DEE). Brain malformations usually include cerebral and cerebellar atrophy. Additionally, some patients may have dysmorphic features or coarse facies (Ng et al., 2013; Kodera et al., 2013). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

X-linked intellectual developmental disorder-98 (XLID98) is a neurodevelopmental disorder characterized by delayed psychomotor development, poor speech, behavioral abnormalities, poor overall growth, dysmorphic facial features, and often early-onset seizures. Some carrier females are unaffected, whereas other females with mutations are affected; males tend to be more severely affected than females. It is believed that the phenotypic variability and disease manifestations in female carriers results from skewed X-inactivation or cellular mosaicism (summary by de Lange et al., 2016).

Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the USP9X gene.

Immunodeficiency-8 with lymphoproliferation (IMD8) is an autosomal recessive primary immunodeficiency characterized by early-childhood onset of recurrent infections and lymphoproliferative disorders, often associated with EBV infection. Laboratory studies show defects in the numbers and function of certain lymphocyte subsets, particularly T cells (Moshous et al., 2013; Stray-Pedersen et al., 2014).

Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) is a severe autosomal recessive neurologic disorder with onset at birth or in early infancy. Affected individuals show very poor, if any, normal cognitive development. Some patients are never learn to sit or walk independently (summary by Al-Sayed et al., 2013). Genetic Heterogeneity of Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies See also IHPRF2 (616801), caused by mutation in the UNC80 gene (612636) on chromosome 2q34; and IHPRF3 (616900), caused by mutation in the TBCK gene (616899) on chromosome 4q24.

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.

Primary ciliary dyskinesia-25 is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have recurrent upper and lower airway disease, bronchiectasis, and decreased fertility. About half of patients show laterality defects, including situs inversus totalis. Respiratory cilia from patients show defects in the inner and outer dynein arms (summary by Tarkar et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400.

Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.

Any combined oxidative phosphorylation deficiency in which the cause of the disease is a mutation in the LYRM4 gene.

Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.

ADNP-related disorder is characterized by hypotonia, severe speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip) based on a cohort of 78 individuals. Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, brain abnormalities, seizures, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, endocrine issues including short stature and hormonal deficiencies, cardiac and urinary tract anomalies, and hearing loss.

Webb-Dattani syndrome is an autosomal recessive disorder characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency due to hypoplastic development of these brain regions. Patients present soon after birth with multiple pituitary hormonal deficiencies and subsequently develop microcephaly, seizures, and spasticity. Other features include postretinal blindness and renal abnormalities (summary by Webb et al., 2013).

Tenorio syndrome (TNORS) is characterized by overgrowth, macrocephaly, and impaired intellectual development. Some patients may have mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjogren syndrome (270150) (summary by Tenorio et al., 2014).

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).

Lymphatic malformation-6 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPHM6, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema, but childhood onset of lymphedema with or without systemic involvement also occurs. Mild facial edema is often present. Patients have normal intelligence and no seizures (summary by Fotiou et al., 2015). For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

Any Meier-Gorlin syndrome in which the cause of the disease is a mutation in the GMNN gene.

Congenital myasthenic syndrome-19 (CMS19) is an autosomal recessive disorder resulting from a defect in the neuromuscular junction, causing generalized muscle weakness, exercise intolerance, and respiratory insufficiency. Patients present with hypotonia, feeding difficulties, and respiratory problems soon after birth, but the severity of the weakness and disease course is variable (summary by Logan et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by Gentile et al., 2019).

Au-Kline syndrome is characterized by developmental delay and hypotonia with moderate-to-severe intellectual disability, and typical facial features that include long palpebral fissures, ptosis, shallow orbits, large and deeply grooved tongue, broad nose with a wide nasal bridge, and downturned mouth. There is frequently variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating). Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are also reported in the majority of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, osteopenia, and other skeletal anomalies.

Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB) is an autosomal recessive disorder characterized by severe neurologic impairment including impaired intellectual development, epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. Most affected individuals are nonambulatory, cannot sit unassisted, and have no speech development. More variable features include feeding difficulties, poor growth, cortical visual impairment, spasticity, scoliosis, immunodeficiency, and thrombocytopenia (Tanaka et al., 2015).

Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities (summary by Basel-Vanagaite et al., 2015).

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.

Arboleda-Tham syndrome (ARTHS) is an autosomal dominant disorder with the core features of impaired intellectual development, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications (summary by Kennedy et al., 2019).

CLIFAHDD is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo (summary by Chong et al., 2015).

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).

X-linked syndromic intellectual developmental disorder-33 (MRXS33) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by O'Rawe et al., 2015).

MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported.

EBF3 neurodevelopmental disorder (EBF3-NDD) is associated with developmental delay (DD) / intellectual disability (ID), speech delay, gait or truncal ataxia, hypotonia, behavioral problems, and facial dysmorphism. Variability between individuals with EBF3-NDD is significant. Although all affected children have DD noted in early infancy, intellect generally ranges from mild to severe ID, with two individuals functioning in the low normal range. Less common issues can include genitourinary abnormalities and gastrointestinal and/or musculoskeletal involvement. To date, 42 symptomatic individuals from 39 families have been reported.

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.

The core features of short stature-micrognathia syndrome (SSMG) are intrauterine growth restriction (IUGR), postnatal short stature that is often rhizomelic, and micrognathia. Other common features include preterm birth, microcephaly, developmental delay, and genitourinary malformations in males. Transient liver dysfunction and glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, and cataracts have also been observed. Inter- and intrafamilial phenotypic severity varies greatly, from a relatively mild disorder to intrauterine death or stillbirth (Ritter et al., 2022).

A rare genetic, multiple congenital anomalies syndrome characterized by short stature, hand brachydactyly with hypoplastic distal phalanges, global development delay, intellectual disability, and more variably seizures, obesity, and craniofacial dysmorphism that includes microcephaly, high forehead, flat face, hypertelorism, deep set eyes, flat nasal bridge, averted nostrils, long philtrum, thin lip vermilion, and short neck.

Distal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (summary by Chesler et al., 2016 and Delle Vedove et al., 2016).

Frontometaphyseal dysplasia (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).

Developmental and epileptic encephalopathy-44 (DEE44) is an autosomal recessive neurologic disorder characterized by the onset of refractory infantile spasms or myoclonus usually in the first weeks or months of life, up to about 12 months of age. Affected infants may have normal or mildly delayed development before the onset of seizures, but thereafter show developmental stagnation and severe neurologic impairment. EEG in some patients shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Additional features include poor feeding and poor overall growth with microcephaly, axial hypotonia with peripheral hypertonia or spasticity, abnormal movements, limited eye contact, and profoundly impaired intellectual development with absent language. Many patients require tube feeding, and some die in childhood (summary by Muona et al., 2016; Colin et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Developmental and epileptic encephalopathy-38 (DEE38) is an autosomal recessive neurologic and neurodegenerative disorder characterized by the onset of various type of seizures usually between about 4 and 7 months of age. Prior to the onset of seizures, most infants show severely impaired global development, hypotonia with poor head control, and visual inattention with roving eye movements and nystagmus. Seizures are usually refractory to treatment and associated with status epilepticus. Patients have little or no development with inability to walk or speak, spasticity or abnormal movements, and often cortical blindness. There is failure to thrive, and many require tube-feeding. Death in early childhood due to aspiration or intractable epilepsy may occur. The disorder is associated with a defect in GPI-anchoring of membrane-bound proteins (summary by Palmer et al., 2016; Davids et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

HIVEP2-related intellectual disability is a neurological disorder characterized by moderate to severe developmental delay and intellectual disability and mild physical abnormalities (dysmorphic features). Early symptoms of the condition include weak muscle tone (hypotonia) and delayed development of motor skills, such as sitting, standing, and walking. After learning to walk, many affected individuals continue to have difficulty with this activity; their walking style (gait) is often unbalanced and wide-based. Speech is also delayed, and some people with this condition never learn to talk. Most people with HIVEP2-related intellectual disability also have unusual physical features, such as widely spaced eyes (hypertelorism), a broad nasal bridge, or fingers with tapered ends, although there is no characteristic pattern of such features among affected individuals. Many people with the condition exhibit neurodevelopmental disorders, such as hyperactivity, attention deficit disorder, aggression, anxiety, and autism spectrum disorder, which is a group of developmental disorders characterized by impaired communication and social interaction.\n\nOther features of HIVEP2-related intellectual disability include mild abnormalities in the structure of the brain and an abnormally small brain and head size (microcephaly). Less common health problems include seizures; recurrent ear infections; and eye disorders, such as eyes that do not look in the same direction (strabismus), "lazy eye" (amblyopia), and farsightedness (hyperopia). Some people with HIVEP2-related intellectual disability have gastrointestinal problems, which can include backflow of acidic stomach contents into the esophagus (gastroesophageal reflux) and constipation.

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.

Heart and brain malformation syndrome (HBMS) is a severe autosomal recessive multiple congenital anomaly syndrome characterized by profoundly delayed psychomotor development, dysmorphic facial features, microphthalmia, cardiac malformations, mainly septal defects, and brain malformations, including Dandy-Walker malformation (summary by Shaheen et al., 2016). Homozygous mutation in the SMG9 gene can also cause neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies (NEDITPDO; 619995), a less severe neurodevelopmental disorder.

Witteveen-Kolk syndrome (WITKOS) is an autosomal dominant disorder with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging (summary by Balasubramanian et al., 2021).

Most individuals with HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) have symptoms early in life, before age 12 months. The major features of HNRNPH2-NDD are developmental delay / intellectual disability, motor and language delays, behavioral and psychiatric disorders, and growth and musculoskeletal abnormalities. Minor features include dysmorphic facies, gastrointestinal disturbances, epilepsy, and visual defects. Although HNRNPH2-NDD is an X-linked condition, there is not enough information on affected females versus affected males to make any generalizations about phenotypic differences between the two sexes.

CDK13-related disorder, reported in 43 individuals to date, is characterized in all individuals by developmental delay / intellectual disability (DD/ID); nearly all individuals older than age one year display impaired verbal language skills (either absent or restricted speech). Other common findings are recognizable facial features in some individuals, behavioral problems (autism spectrum disorder or autistic traits/stereotypies, attention-deficit/hyperactivity disorder), feeding difficulties in infancy, structural cardiac defects, and seizures.

Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination is a syndromic form of severe to profound intellectual disability with onset of delayed psychomotor development and seizures in infancy. Affected children have hypotonia, feeding difficulties resulting in failure to thrive, and inability to speak or walk, and they tend to show repetitive stereotypic behaviors. Brain imaging shows cerebral atrophy and delayed myelination (summary by Schoch et al., 2017).

Jansen-de Vries syndrome (JDVS) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with speech delay, and behavioral abnormalities. Most patients have variable additional features, including feeding and gastrointestinal difficulties, high pain threshold and/or hypersensitivity to sound, and dysmorphic features, including mild facial abnormalities, strabismus, and small hands and feet (summary by Jansen et al., 2017).

SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported.

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, variable degrees of intellectual disability, and facial dysmorphism (including high nasal bridge, deep-set eyes, and wide mouth), often associated with feeding difficulties and/or gastroesophageal reflux. Additional reported manifestations are seizures, hypotonia, autistic features, and joint laxity. Brain imaging may show non-specific features (such as cerebral atrophy).

Combined oxidative phosphorylation deficiency-32 is an autosomal recessive neurodegenerative disorder characterized by onset of delayed psychomotor development and developmental regression in infancy. Affected individuals have multiple variable symptoms, including poor or absent speech, inability to walk, and abnormal movements. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem consistent with Leigh syndrome (256000). Patient cells showed decreased activities of mitochondrial respiratory chain complexes, I, III, and IV, as well as impaired mitochondrial translation (summary by Lake et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

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).

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.

Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (84%), dysplastic ears (87%; overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment [65%]), and thumb malformations (89%; triphalangeal thumbs, duplication of the thumb [preaxial polydactyly], and rarely hypoplasia of the thumbs). Renal impairment (42%), including end-stage renal disease (ESRD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%; flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of individuals. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.

Zimmermann-Laband syndrome is a rare disorder characterized by gingival fibromatosis, dysplastic or absent nails, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, hirsutism, and abnormalities of the cartilage of the nose and/or ears (summary by Balasubramanian and Parker, 2010). Genetic Heterogeneity of Zimmermann-Laband Syndrome ZLS2 (616455) is caused by mutation in the ATP6V1B2 gene (606939) on chromosome 8p21. ZLS3 (618658) is caused by mutation in the KCNN3 gene (602983) on chromosome 1q21.

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.

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.

The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011). Genetic Heterogeneity of Meier-Gorlin Syndrome Most forms of Meier-Gorlin syndrome are autosomal recessive disorders, including Meier-Gorlin syndrome-1; Meier-Gorlin syndrome-2 (613800), caused by mutation in the ORC4 gene (603056) on chromosome 2q23; Meier-Gorlin syndrome-3 (613803), caused by mutation in the ORC6 gene (607213) on chromosome 16q11; Meier-Gorlin syndrome-4 (613804), caused by mutation in the CDT1 gene (605525) on chromosome 16q24; Meier-Gorlin syndrome-5 (613805), caused by mutation in the CDC6 gene (602627) on chromosome 17q21; Meier-Gorlin syndrome-7 (617063), caused by mutation in the CDC45L gene (603465) on chromosome 22q11; and Meier-Gorlin syndrome-8 (617564), caused by mutation in the MCM5 gene (602696) on chromosome 22q12. An autosomal dominant form of the disorder, Meier-Gorlin syndrome-6 (616835), is caused by mutation in the GMNN gene (602842) on chromosome 6p22.

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA) is characterized by infantile-onset global developmental delay with severe to profound intellectual disability, mildly delayed walking with broad-based and unsteady gait, and absence of meaningful language. Patients have features of autism, with repetitive behaviors and poor communication, but usually are socially reactive and have a happy demeanor. More variable neurologic features include mild seizures, spasticity, and peripheral neuropathy (summary by Palmer et al., 2017).

Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features. Although intellectual deficits are almost invariably associated with cytogenetically visible 3p deletions, rare patients with a 3p26-p25 deletion and normal intelligence or only mild abnormalities have been described (summary by Shuib et al., 2009).

STAT3 hyper IgE syndrome (STAT3-HIES) is a primary immune deficiency syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency.

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).

MGRISCE2 is an autosomal recessive disorder characterized by intrauterine growth restriction, poor postnatal growth with short stature and microcephaly, and increased sister chromatid exchange on cell studies. The disorder results from defective DNA decatenation. The pathogenesis of the disorder is similar to that of Bloom syndrome (BLM; 210900), but patients with mutations in the TOP3A gene do not have a malar rash (summary by Martin et al., 2018). For a discussion of genetic heterogeneity of MGRISCE, see Bloom syndrome (BLM; MGRISCE1; 210900)

IDDMSSD is a neurodevelopmental disorder characterized by impaired intellectual development, poor speech, postnatal macrocephaly, and seizures (Harms et al., 2018).

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).

Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder characterized by infantile hypotonia, ophthalmic abnormalities, moderate to profound global developmental delay, poor or absent speech, behavioral abnormalities, hyperkinetic movements, and EEG abnormalities in the absence of overt seizures (summary by Baker et al., 2018).

Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).

Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but DEE2 is considered to be a distinct entity (summary by Fehr et al., 2013). For a discussion of genetic heterogeneity of DEE, see 308350.

ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies.

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.

Pontocerebellar hypoplasia type 10 is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination. Some patients have dysmorphic features and an axonal sensorimotor neuropathy (summary by Karaca et al., 2014 and Schaffer et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

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).

Menke-Hennekam syndrome-1 (MKHK1) is a congenital disorder characterized by variable impairment of intellectual development and facial dysmorphisms. Feeding difficulties, autistic behavior, recurrent upper airway infections, hearing impairment, short stature, and microcephaly are also frequently seen. Although mutations in the same gene cause Rubinstein-Taybi syndrome-1 (RSTS1; 180849), patients with MKHK1 do not resemble the striking phenotype of RSTS1. Genetic Heterogeneity of Menke-Hennekam Syndrome Menke-Hennekam syndrome-2 (MKHK2; 618333) is caused by heterozygous mutation in exons 30 or 31 of the EP300 gene (602700). Mutation elsewhere in that gene results in RSTS2 (613684).

Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (Turnpenny et al., 2018).

Susceptibility to acute infection-induced encephalopathy-9 (IIAE9) is an autosomal recessive disorder characterized by episodic acute neurodegeneration and developmental regression associated with infections and febrile illness. Patients present in the first months or years of life, often after normal or only mildly delayed early development. Some patients may have partial recovery between episodes, such as transient ataxia, but the overall disease course is progressive, resulting in global developmental delay, abnormal movements, refractory seizures, microcephaly, and cerebellar atrophy (summary by Fichtman et al., 2019). For a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.

Neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) is characterized by global developmental delay apparent from infancy or early childhood, resulting in mildly delayed walking, variably impaired intellectual development, and poor or absent speech. Additional features may include hypotonia, spasticity, or ataxia. About half of patients have abnormal findings on brain imaging, including cerebral or cerebellar atrophy, loss of white matter volume, thin corpus callosum, and perisylvian polymicrogyria. Seizures are not a prominent finding, and although some patients may have nonspecific dysmorphic facial features, there is no common or consistent gestalt (summary by Platzer 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.

Neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements (NEDNEH) is an autosomal recessive severe neurologic disorder characterized by delayed psychomotor development with inability to walk or speak, early-onset refractory seizures, and nonepileptic hyperkinetic movement disorders, including myoclonus dystonia and dyskinesias. Patients require tube feeding and may die of respiratory failure in childhood or in the second decade (summary by Gorman et al., 2019).

Autonomic bladder dysfunction with impaired pupillary reflex and secondary CAKUT (congenital anomalies of the kidney and urinary tract) is an autosomal recessive neurogenic disorder with onset in utero or early childhood. Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension (summary by Mann et al., 2019).

Basilicata-Akhtar syndrome (MRXSBA) is characterized by global developmental delay apparent from infancy, feeding difficulties, hypotonia, and poor or absent speech. Most patients are able to walk, although they may have an unsteady gait or spasticity. Additional findings include dysmorphic facial features and mild distal skeletal anomalies. Males and females are similarly affected (summary by Basilicata et al., 2018).

Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB) is characterized by early-onset hypotonia, delayed walking, poor speech, and impaired intellectual development. Additional features may include feeding difficulties, dysmorphic features, and visual defects. Brain imaging tends to show delayed myelination, thin corpus callosum, and/or enlarged ventricles. The severity of the disorder is highly variable; initial evidence suggests that the severity may depend on the type of mutation (summary by Haijes et al., 2019).

Halperin-Birk syndrome (HLBKS) is an autosomal recessive neurodevelopmental disorder characterized by structural brain defects, spastic quadriplegia with multiple contractures, profound developmental delay, seizures, dysmorphism, cataract, and optic nerve atrophy. Death occurs in early childhood (Halperin et al., 2019).

Short stature and microcephaly with genital anomalies (SSMGA) is characterized by severe growth failure, with extreme short stature, microcephaly, and delayed and dissociated bone age. Global psychomotor developmental delay may be present, although the brain appears structurally normal. Pubertal delay and genital anomalies have been observed (Hung et al., 2017).

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).

Developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is an X-linked neurologic disorder characterized by onset of severe refractory seizures in the first year of life, global developmental delay with impaired intellectual development and poor or absent speech, and dysmorphic facial features. The seizures tend to show a cyclic pattern with clustering. Many patients have midline brain defects on brain imaging, including thin corpus callosum and/or variable forms of holoprosencephaly (HPE). The severity and clinical manifestations are variable. Almost all reported patients are females with de novo mutations predicted to result in a loss of function (LOF). However, some patients may show skewed X inactivation, and the pathogenic mechanism may be due to a dominant-negative effect. The SMC1A protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; DEE85 can thus be classified as a 'cohesinopathy' (summary by Symonds et al., 2017 and Kruszka et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Nabais Sa-de Vries syndrome type 2 (NSDVS2) is characterized by global developmental delay apparent from birth and distinctive dysmorphic facial features. Most patients have additional anomalies, including congenital heart defects, sleep disturbances, hypotonia, and variable endocrine abnormalities, such as hypothyroidism (summary by Nabais Sa et al., 2020).

Anauxetic dysplasia-3 (ANXD3) is characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. Radiographs show short metacarpals, broad middle phalanges, and metaphyseal irregularities. Most patients also exhibit motor and cognitive delays (Narayanan et al., 2019). For a discussion of genetic heterogeneity of anauxetic dysplasia, see ANXD1 (607095).

Nizon-Isidor syndrome (NIZIDS) is a neurodevelopmental disorder characterized by global developmental delay, mildly delayed walking, poor speech and language, variably impaired intellectual development, and behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD). Some patients may have additional features, including nonspecific facial dysmorphism, gastrointestinal difficulties, distal hand anomalies, and thin corpus callosum on brain imaging (summary by Nizon et al., 2019).

Rajab interstitial lung disease with brain calcifications-1 (RILCBC1) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by Xu et al., 2018). Genetic Heterogeneity of Rajab Interstitial Lung Disease with Brain Calcifications Also see Rajab interstitial disease with brain calcifications-2 (RILDBC2; 619013), caused by mutation in the FARSA gene (602918).

Kilquist syndrome (KILQS) is an autosomal recessive multisystem disorder characterized by neurologic, gastrointestinal, and secretory dysfunction. Affected individuals present at birth with hypotonia, feeding difficulties, mild dysmorphic features, and sensorineural hearing loss. They show poor overall growth associated with gastrointestinal anomalies such as gastroesophageal reflux or midgut malrotation, as well as profound global developmental delay with inability to sit or speak. Tear, sweat, and saliva production is also impaired, causing dry mouth and recurrent bronchial mucus plugging. Some of the clinical features are reminiscent of cystic fibrosis (CF; 219700) (summary by Stodberg et al., 2020).

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.

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).

Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity (summary by Cappuccio et al., 2020).

Coffin-Siris syndrome-12 (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).

Den Hoed-de Boer-Voisin syndrome (DHDBV) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; 226750). More variable features of DHDBV include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by den Hoed et al., 2021).

KINSSHIP syndrome (KINS) is an autosomal dominant disorder characterized by a recognizable pattern of anomalies including developmental delay, impaired intellectual development, seizures, mesomelic dysplasia, dysmorphic facial features, horseshoe or hypoplastic kidney, and failure to thrive (summary by Voisin et al., 2021).

Radio-Tartaglia syndrome (RATARS) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, speech delay, and variable behavioral abnormalities. Affected individuals show hypotonia, mild motor difficulties, and craniofacial dysmorphism. Brain imaging may show nonspecific defects; rare patients have seizures or pyramidal signs. A subset of individuals may have congenital heart defects, precocious puberty, and obesity in females. Some of the features are similar to those observed in patients with chromosome 1p36 deletion syndrome (607872) (summary by Radio et al., 2021).

Buratti-Harel syndrome (BURHAS) is a neurodevelopmental disorder characterized by infantile hypotonia, global developmental delay, mild motor and speech delay, and mild to moderately impaired intellectual development. Some patients are able to attend special schools and show learning difficulties, whereas others are more severely affected. Patients have prominent dysmorphic facial features, including hypertelorism, downslanting palpebral fissures, strabismus, and small low-set ears. Additional features may include laryngomalacia with feeding difficulties and distal skeletal anomalies (summary by Buratti et al., 2021).

Visceral myopathy-2 (VSCM2) is characterized by gastrointestinal symptoms resulting from intestinal dysmotility and paresis, including abdominal distention, pain, nausea, and vomiting. Some patients exhibit predominantly esophageal symptoms, with hiatal hernia and severe reflux resulting in esophagitis and stricture, whereas others experience chronic intestinal pseudoobstruction. Bladder involvement resulting in megacystis and megaureter has also been observed and may be evident at birth (Dong et al., 2019; Gilbert et al. (2020)).

Faundes-Banka syndrome (FABAS) is an autosomal dominant disorder characterized by variable combinations of developmental delay and microcephaly, as well as micrognathia and other dysmorphic features (Faundes et al., 2021).

White-Kernohan syndrome (WHIKERS) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, hypotonia, and characteristic facial features. Some patients may have abnormalities of other systems, including genitourinary and skeletal (summary by White et al., 2021).

Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum (NEDDFAC) is characterized by global developmental delay, impaired intellectual development with poor or absent speech and language, and dysmorphic facial features. Brain imaging tends to show thin corpus callosum and decreased white matter volume. Additional features such as seizures, cardiac defects, and behavioral abnormalities may also occur. The phenotype is variable (summary by Bina et al., 2020).

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).

Congenital central hypoventilation syndrome-2 and autonomic dysfunction (CCHS2) is an autosomal recessive disorder characterized by shallow breathing and apneic spells apparent in the neonatal period. Affected infants require mechanical ventilation due to impaired ventilatory response to hypercapnia, as well as tube feeding due to poor swallowing, aspiration, and gastrointestinal dysmotility. Some patients have other features of autonomic dysfunction, including bladder dysfunction, sinus bradycardia, and temperature dysregulation. Although mild global developmental delay with learning difficulties and seizures were present in the single family reported, it was unclear if these features were related to the hypoventilation phenotype (Spielmann et al., 2017). For a discussion of genetic heterogeneity of CCHS, see CCHS1 (209880).

DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections. Death in childhood may occur (summary by Bertoli-Avella et al., 2021).

Congenital disorder of glycosylation type 2v (CDG2V) is an autosomal recessive disorder characterized by neurodevelopmental delay and variable facial dysmorphisms (Polla et al., 2021).

Congenital disorder of glycosylation type IIw (CDG2W) is an autosomal dominant metabolic disorder characterized by liver dysfunction, coagulation deficiencies, and profound abnormalities in N-glycosylation of serum specific proteins. All reported patients carry the same mutation (602671.0017) (summary by Ng et al., 2021). For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).

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).

Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) is an early-onset neurodevelopmental disorder characterized by these features. Affected individuals also have nonspecific and variable dysmorphic facial features that do not constitute a recognizable gestalt. Although the disorder is caused by truncating mutations in the SRCAP gene as is FLHS, the DEHMBA phenotype is clinically distinguishable from FLHS by the lack of short stature, brachydactyly, and delayed bone age, as well as absence of a specific facial appearance. There are some overlapping features between the 2 disorders, mainly impaired intellectual development and speech delay (summary by Rots et al., 2021).

Galloway-Mowat syndrome-9 (GAMOS9) is an autosomal recessive disorder characterized by onset of nephrotic syndrome with proteinuria in infancy or early childhood. The renal disease is slowly progressive, but some affected individuals may develop end-stage renal disease in the first decade. Renal biopsy shows focal segmental glomerulosclerosis (FSGS) or diffuse mesangial sclerosis (DMS). Affected individuals also have developmental delay and secondary microcephaly. Additional features may include facial dysmorphism and gastroesophageal reflux. Early death may occur (Arrondel et al., 2019). For a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

A rare mitochondrial oxidative phosphorylation disorder with characteristics of neonatal onset of hypotonia, feeding difficulties, deafness, and early fatal respiratory failure. Cardiac and liver involvement has been reported. Serum lactate is increased and metabolic studies show decreased activity of mitochondrial respiratory complexes I and IV in skeletal muscle.

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.

Autosomal dominant spastic paraplegia-9A is a neurologic disorder characterized by onset of slowly progressive spasticity mainly affecting the lower limbs. The age at onset usually ranges from adolescence to adulthood, and patients have gait difficulties, motor neuropathy, and dysarthria. Additional variable features include cerebellar signs, cataract, pes cavus, and urinary urgency (summary by Coutelier et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism.

Carey-Fineman-Ziter syndrome-1 (CFZS1) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS1 may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016). Di Gioia et al. (2017) determined that CFZS1 represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion. Genetic Heterogeneity of Carey-Fineman-Ziter Syndrome Carey-Fineman-Ziter syndrome-2 (CFZS2) is caused by mutation in the MYMX gene (619912) on chromosome 6p21.

Immunodeficiency-104 (IMD104) is an autosomal recessive disorder characterized by the onset of recurrent infections in early infancy. Manifestations may include oral thrush, fever, and failure to thrive. Some patients have lymphadenopathy and hepatosplenomegaly, whereas others have absence of lymph nodes and lack a thymic shadow. Laboratory studies show decreased or absent numbers of nonfunctional T cells, normal or increased levels of B cells, variable hypogammaglobulinemia, and normal NK cells. The disorder is caused by a defect in IL7 (146660) signaling due to a mutant IL7 receptor. Hematopoietic stem cell transplantation may be curative (Roifman et al., 2000 and Giliani et al., 2005). Giliani et al. (2005) provided a detailed review of IL7R deficiency, including discussion of the IL7R gene and its function in the immune system, clinical features of the disorder, and experiences with hematopoietic stem cell transplant as treatment. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.

Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features (NEDHILD) is a rare neurodevelopmental disorder associated with impaired intellectual development, speech and language impairment, microcephaly, seizures, hypotonia, ophthalmologic issues, constipation/gastroesophageal reflux, and behavioral problems, including autism and sleep disturbances (summary by Garrity et al., 2021).

Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include abnormal head shape, variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020). Genetic Heterogeneity of Bryant-Li-Bhoj Neurodevelopmental Syndrome See also BRYLIB2 (619721), caused by heterozygous mutation in the H3F3B gene (601058).

Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020). For a discussion of genetic heterogeneity of Bryant-Li-Bhoj neurodevelopmental syndrome, see BRYLIB1 (619720).

Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MNDLFH) is characterized by clinically significant pharyngeal lymphoid hypertrophy, with adenoid overgrowth, frequent upper airway infections, and sleep apnea. Macrocephaly without structural brain abnormalities is present, and patients exhibit increased weight for height as well as delayed gross motor and impaired intellectual development; autistic features and attention-deficit hyperactivity disorder have also been reported. An increased fraction of fetal hemoglobin has been observed in some patients (Ohishi et al., 2020; von der Lippe et al., 2022).

Developmental and epileptic encephalopathy-100 (DEE100) is a severe neurologic disorder characterized by global developmental delay and onset of variable types of seizures in the first months or years of life. Most patients have refractory seizures and show developmental regression after seizure onset. Affected individuals have ataxic gait or inability to walk and severe to profoundly impaired intellectual development, often with absent speech. Additional more variable features may include axial hypotonia, hyperkinetic movements, dysmorphic facial features, and brain imaging abnormalities (summary by Schneider et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Restrictive dermopathy is a rare genodermatosis characterized mainly by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial dysmorphism (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures, and an early neonatal lethal course. Liveborn children usually die within the first week of life (summary by Navarro et al., 2004). For a discussion of genetic heterogeneity of restrictive dermopathy, see RSDM1 (275210).

Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by Blakes et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS) is an autosomal recessive disorder characterized by global developmental delay apparent from infancy or early childhood. The severity of the disorder is highly variable. Affected individuals show impaired intellectual development and motor delay associated with either severe hypotonia or hypertonia and spasticity. Most affected individuals have skeletal defects and dysmorphic facial features. Some may have ocular or auditory problems, peripheral neuropathy, behavioral abnormalities, and nonspecific findings on brain imaging (Kurolap et al., 2022).

Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS) is an autosomal recessive disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have hypotonia with poor or absent motor skills, feeding difficulties with poor overall growth, microcephaly, mild dysmorphic features, and early-onset seizures. Additional variable features, such as nystagmus, cortical blindness, and spasticity, may also occur. Patients with this disorder tend to have recurrent respiratory infections, likely due to aspiration, that may lead to death in childhood (Arnadottir et al., 2022).

Developmental and epileptic encephalopathy-102 (DEE102) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay and severe to profoundly impaired intellectual development with inability to walk or speak. Most patients have onset of variable types of seizures within the first year of life, and the seizures tend to be refractory. Additional features include progressive microcephaly, visual impairment, axial hypotonia, peripheral hypertonia, and nonspecific brain imaging abnormalities (Marafi et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Pontocerebellar hypoplasia type 17 (PCH17) is a severe autosomal recessive developmental disorder characterized by neonatal hypotonia, severe feeding difficulties, and respiratory insufficiency. Brain imaging shows cerebellar and brainstem hypoplasia. Most affected individuals die in infancy. Those who survive show variable developmental delay. Other features of the disorder include distal hypertonia, poor overall growth, visual defects, autonomic problems, dysmorphic features, and seizures (Coolen et al., 2022). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

Autosomal dominant intellectual developmental disorder-67 (MRD67) is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Additional features may include behavioral abnormalities, such as autism spectrum disorder (ASD) and ADHD, as well as language and sleeping difficulties. Brain imaging is normal (Ismail et al., 2022).

Autosomal dominant intellectual developmental disorder-68 (MRD68) is characterized by developmental delay/intellectual disability, microcephaly, poor growth, feeding difficulties, and dysmorphic features. Some patients may have autism spectrum disorder or attention deficit-hyperactivity disorder (ADHD) (Cif et al., 2020).

SLC6A3-related dopamine transporter deficiency syndrome (DTDS) is a complex movement disorder with a continuum that ranges from classic early-onset DTDS (in the first 6 months) to atypical later-onset DTDS (in childhood, adolescence, or adulthood). Classic DTDS. Infants typically manifest nonspecific findings (irritability, feeding difficulties, axial hypotonia, and/or delayed motor development) followed by a hyperkinetic movement disorder (with features of chorea, dystonia, ballismus, orolingual dyskinesia). Over time, affected individuals develop parkinsonism-dystonia characterized by bradykinesia (progressing to akinesia), dystonic posturing, distal tremor, rigidity, and reduced facial expression. Limitation of voluntary movements leads to severe motor delay. Episodic status dystonicus, exacerbations of dystonia, and secondary orthopedic, gastrointestinal, and respiratory complications are common. Many affected individuals appear to show relative preservation of intellect with good cognitive development. Atypical DTDS. Normal psychomotor development in infancy and early childhood is followed by later-onset manifestations of parkinsonism-dystonia with tremor, progressive bradykinesia, variable tone, and dystonic posturing. The long-term outcome of this form is currently unknown.

Hijazi-Reis syndrome (HIJRS) is an X-linked dominant disorder characterized by global developmental delay with hypotonia, motor delay, impaired intellectual development, and speech and language delay. Affected individuals also have dysmorphic facial features, gastrointestinal issues, and ocular anomalies. Rare patients have seizures (Hijazi et al., 2022).

Neurodevelopmental disorder with epilepsy and brain atrophy (NEDEBA) is an autosomal recessive disorder characterized by early-onset progressive myoclonus epilepsy with ataxia (summary by Bott et al., 2021).

Developmental delay, hypotonia, and impaired language (DEDHIL) is a neurodevelopmental disorder characterized by variably impaired intellectual development usually with hypotonia, mild motor delay, and language difficulties. Affected individuals may also have nonspecific dysmorphic facial features, gastrointestinal problems, and abnormalities on brain imaging (Stephenson et al., 2022).

Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (NEDHLSS) is characterized by global developmental delay apparent from infancy. Affected individuals show severe hypotonia with delayed walking or inability to walk, poor or absent speech, and impaired intellectual development with behavioral abnormalities. Most patients have early-onset seizures, mild skeletal defects that are usually distal, and nonspecific dysmorphic features. More severely affected individuals have additional congenital abnormalities; however, cardiac involvement is rare (summary by Rodan et al., 2021).

Digenic dyskeratosis congenita (DKCD) is characterized clinically by a combination of mucocutaneous features including abnormal skin pigmentation, nail dystrophy, thin hair, and oral leukoplakia. Some patients may have evidence of bone marrow failure, manifest as immune defects such as recurrent infections or hypogammaglobulinemia. Telomeres are shortened in patient cells. Individuals with DKCD may show severe adverse reactions to treatment with 5-FU (Tummala et al., 2022). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).

Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (NEDSFF) is an autosomal recessive disorder characterized by distinct craniofacial features, multisystem dysfunction, profound neurodevelopmental delays, and neonatal death (Shankar et al., 2022).

Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects (NEDCDS) is characterized by global developmental delay, severely impaired intellectual development with poor or absent speech, characteristic facial features, and variable skeletal abnormalities. Additional features include feeding difficulties, inability to walk or walking with an abnormal gait, and cerebellar or other abnormalities on brain imaging (Reichert et al., 2020).

Neurodevelopmental disorder with speech impairment and with or without seizures (NEDSIS) is a phenotypically heterogeneous neurologic disorder whose severity appears to depend on the functional effect of the CACNA1I mutation. Severely affected individuals present in infancy with profound global developmental delay, hypotonia, delayed or absent walking, absent speech, feeding difficulties, cortical visual impairment, and onset of hyperexcitability and seizures in the first months or years of life. They achieve little or no developmental progress and may be tube-fed. Mutations in these individuals occurred de novo. In contrast, a milder phenotype associated with an inherited mutation has been found in a family with mild to moderate cognitive impairment and mild speech delay, usually without seizures (El Ghaleb et al., 2021).

Atelis syndrome-2 (ATELS2) is an autosomal recessive disorder characterized by poor overall growth with microcephaly and short stature, dysmorphic facial features, and congenital cardiac defects. Additional more variable features may include hematologic abnormalities, variable ocular abnormalities, motor delay, and anxiety. Patient cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy (Grange et al., 2022). See also ATELS1 (620184), caused by mutation in the SLF2 gene (610348). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).

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).

Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD) is characterized by neonatal onset of chronic cough, episodic wheezing, recurrent lower respiratory tract infections, chronic diarrhea, and failure to thrive. Despite the resemblance to cystic fibrosis (CF; 219700), these patients have normal sweat chloride and pancreatic elastase tests (Bertoli-Avella et al., 2022).

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758).

Neurodevelopmental disorder with poor growth and behavioral abnormalities (NEDGBA) is an autosomal recessive disorder characterized by global developmental delay, moderately to severely impaired intellectual development, often with absent speech, and behavioral abnormalities, including hyperactivity, short attention span, and ADHD. Affected individuals show failure to thrive with poor overall growth; some have microcephaly. Additional features may include nonspecific facial dysmorphism, hypotonia, and feeding difficulties (Vogt et al., 2022; Meng et al., 2023).

Neurodevelopmental disorder with seizures, spasticity, and partial or complete agenesis of the corpus callosum (NEDSSCC) is an autosomal recessive disorder characterized by axial hypotonia and global developmental delay apparent from the first days or months of life. Affected individuals often have feeding difficulties and develop early-onset seizures that tend to be well-controlled. Other features include peripheral spasticity with hyperreflexia, variable dysmorphic features, impaired intellectual development, behavioral abnormalities, and hypoplasia or absence of the corpus callosum on brain imaging (Faqeih et al., 2023).

Mitochondrial complex IV deficiency nuclear type 23 (MC4DN23) is an autosomal recessive disorder characterized by infantile-onset encephalopathy (Rius et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.

Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures (NEDLBAS), is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Affected individuals have significant speech delay, and most demonstrate behavioral abnormalities, including autistic features. About half of patients develop seizures, which may be controlled or refractory. More variable features include hypotonia, feeding difficulties, and subtle facial dysmorphism (Schalk et al., 2022).