Cohen syndrome is characterized by failure to thrive in infancy and childhood; truncal obesity in the teen years; early-onset hypotonia and developmental delays; microcephaly developing during the first year of life; moderate to profound psychomotor retardation; progressive retinochoroidal dystrophy and high myopia; neutropenia in many with recurrent infections and aphthous ulcers in some; a cheerful disposition; joint hypermobility; and characteristic facial features.

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities); and, commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.

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.

Claes-Jensen type of X-linked syndromic intellectual developmental disorder (MRXSCJ) is characterized by impaired intellectual development with substantial clinical heterogeneity in affected males. However, males are usually reported to have short stature, microcephaly, hyperreflexia, and aggressive behavior. In rare cases, female carriers exhibit mildly impaired intellectual development or learning difficulties (summary by Guerra et al., 2020).

Spastic paraplegias (SPGs) are a genetically heterogeneous group of neurologic disorders characterized by progressive weakness and spasticity of the legs. Complicated SPGs are accompanied by additional neurologic symptoms such as cerebellar ataxia, sensory loss, mental retardation, nystagmus, and optic atrophy (summary by Steinmuller et al., 1997). A locus for spastic paraplegia-16 has been mapped to Xq11.2-q23 (Steinmuller et al., 1997). For a discussion of genetic heterogeneity of X-linked spastic paraplegia, see 303350.

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.

A rare genetic neurological disorder with characteristics of pregnancy complicated by polyhydramnios, severe intractable epilepsy presenting in infancy, severe hypotonia, decreased muscle mass, global developmental delay, craniofacial dysmorphism (long face, large forehead, peaked eyebrows, broad nasal bridge, hypertelorism, large mouth with thick lips), and macrocephaly due to megalencephaly and hydrocephalus in most patients. Additional features that have been reported include cardiac anomalies like atrial septal defects, diabetes insipidus and nephrocalcinosis among others.

SATB2-associated syndrome (SAS) is a multisystem disorder in which all affected individuals have developmental delay / intellectual disability that can range from mild to profound but is most commonly moderate to profound. Speech delay and/or absent speech is observed in all affected individuals. Other neurobehavioral manifestations can include jovial or friendly personality, autistic tendencies, agitation or aggressive outbursts, self-injury, impulsivity, hyperactivity, anxiety, difficulty falling asleep or maintaining sleep, and sensory issues. Most affected individuals have hypotonia. EEG abnormalities are frequent but may be without clinically recognizable seizures. While only about 20% of affected individuals have clinical seizures, a subset of affected individuals have electrical status epilepticus in sleep. Craniofacial findings can include nonspecific dysmorphic features, palatal anomalies (cleft palate, high-arched palate, velopharyngeal insufficiency, bifid uvula), and dental anomalies (abnormal shape or size or the upper central incisors, dental crowding, hypodontia, and delayed teeth eruption, among others). Skeletal anomalies can include scoliosis, tibial bowing, and joint contractures. At least one third of individuals have a history of previous fractures and about one quarter of affected individuals have documented low bone mineral density. Other finding can include pre- and postnatal growth restriction, feeding issues, and eye anomalies (strabismus, refractive error). In those with a larger deletion involving SATB2 and adjacent genes, cardiovascular, genitourinary, and ectodermal findings may also be present.

16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.

The 17q12 recurrent duplication is characterized by intellectual abilities ranging from normal to severe disability and other variable clinical manifestations. Speech delay is common, and most affected individuals have some degree of hypotonia and gross motor delay. Behavioral and psychiatric conditions reported in some affected individuals include autism spectrum disorder, schizophrenia, and behavioral abnormalities (aggression and self-injury). Seizures are present in 75%. Additional common findings include microcephaly, ocular abnormalities, and endocrine abnormalities. Short stature and renal and cardiac abnormalities are also reported in some individuals. Penetrance is incomplete and clinical findings are variable.

DYNC1H1-related disorders are primarily characterized by an axonal neuropathy with a wide phenotypic spectrum ranging from a neuromuscular-only phenotype (DYNC1H1-related neuromuscular disorder, or DYNC1H1-NMD) to phenotypes involving both the central nervous system and peripheral nervous system referred to collectively as DYNC1H1-related neurodevelopmental disorder (DYNC1H1-NDD). DYNC1H1-NMD manifestations are limited to the peripheral nervous system and characterized predominantly by motor neuropathy initially most pronounced in the lower limbs; muscle weakness and atrophy variably associated with foot deformities, contractures, and other skeletal involvement; and/or delayed motor milestones. DYNC1H1-NDD manifestations include motor axonal neuropathy and often global developmental delay / intellectual disability, epilepsy, neurobehavioral/psychiatric manifestations, and movement disorders with or without malformations of cortical development and/or microcephaly. In an individual with more significant central nervous system involvement, the motor axonal neuropathy may not be evident clinically and, thus, is only detected on further evaluation such as electrophysiologic testing.

The musculocontractural type of Ehlers-Danlos syndrome (EDSMC2) is characterized by progressive multisystem fragility-related manifestations, including joint dislocations and deformities; skin hyperextensibility, bruisability, and fragility, with recurrent large subcutaneous hematomas; cardiac valvular, respiratory, gastrointestinal, and ophthalmologic complications; and myopathy, featuring muscle hypoplasia, muscle weakness, and an abnormal muscle fiber pattern in histology in adulthood, resulting in gross motor developmental delay (summary by Muller et al., 2013). For a discussion of genetic heterogeneity of the musculocontractural type of Ehlers-Danlos syndrome, see EDSMC1 (601776).

Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination (summary by Akizu et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

UNC80 deficiency is characterized by developmental delay, neonatal hypotonia, severe intellectual disability, dysmorphic facial features, strabismus, dyskinetic limb movements, and neurobehavioral manifestations. The majority of individuals do not learn to walk. All individuals lack expressive speech; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional common features include clubfeet, joint contractures, scoliosis, postnatal growth deficiency, increased risk of infections, sleeping difficulties, and constipation. Individuals have slow acquisition of developmental skills and do not have features suggestive of neurodegeneration.

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.

PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp).

Xq25 duplication syndrome is an X-linked neurodevelopmental disorder characterized by delayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected (summary by Leroy et al., 2016).

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

Birk-Landau-Perez syndrome (BILAPES) is an autosomal recessive syndromic developmental disorder characterized by global developmental delay apparent from infancy or early childhood. Some patients have developmental regression with loss of speech and motor skills, whereas other patients never achieve these milestones. More variable features may include hypotonia, poor overall growth, ataxia, dystonia, abnormal eye movements, and renal insufficiency (Perez et al., 2017; Kleyner et al., 2022).

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

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).

Facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome (FHEIG) is a neurodevelopmental disorder characterized by these cardinal features. The distinctive facial gestalt includes bushy eyebrows, long eyelashes, short philtrum, thin and everted upper lip, and prominent upper and lower vermilion. Hypertrichosis is significant and generalized, and gingival overgrowth varies in severity. Developmental delay is variable, and seizures or EEG anomalies are present (Bauer et al., 2018).

Neurodevelopmental disorder with progressive movement abnormalities, cognitive decline, and brain abnormalities (NEDMCB) is an autosomal recessive disorder characterized by global developmental delay and developmental regression resulting in variably impaired intellectual development with poor or absent speech, difficulty walking or inability to walk, and various movement abnormalities, including spasticity, hypertonia, dystonia, tremor, and myoclonus. Affected individuals usually show poor overall growth, often with microcephaly, hypotonia, limb contractures, and cataracts. Most have progressive brain imaging abnormalities, including enlarged ventricles, white matter loss, and cerebellar atrophy. A subset of patients have combined malonic and methylmalonic aciduria (CMAMMA), although this is not a reliable biomarker (Ortigoza-Escobar et al., 2024).

Congenital myopathy-19 (CMYO19) is an autosomal recessive skeletal muscle disorder characterized by infantile-onset of progressive muscle weakness and atrophy associated with scoliosis, variably impaired walking, and dysmorphic facial features (Feichtinger et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Snijders Blok-Fisher syndrome (SNIBFIS) is a neurodevelopmental disorder characterized by global developmental delay, hypotonia, variable impaired intellectual development, and specifically impaired speech and language acquisition. Patients achieve independent ambulation and most have mildly to moderately impaired cognition with autistic features, although a few may develop seizures and have a more severe phenotype. Dysmorphic features include abnormal, cupped, or prominent ears and ocular anomalies. Mutations usually occur de novo, although 1 family with autosomal dominant inheritance has been reported (summary by Snijders Blok et al., 2019).

Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019).

TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS) is a condition within the spectrum of mendelian disorders of the epigenetic machinery (MDEMs) or chromatinopathies. Clinical features typically include intellectual disability / developmental delay ranging from mild to severe affecting both motor and language skills. Most affected individuals are verbal and ambulatory, with most walking by age 15-36 months. Hypotonia in infancy and childhood can exacerbate motor and expressive speech delay and, in some cases, cause feeding difficulties that require nasogastric or gastrostomy tube feeding. Some affected individuals display movement disorders. About one third of affected individuals have epilepsy. Other neurobehavioral features can include autism, anxiety, and attention-deficit/hyperactivity disorder. Strabismus and refractive errors are found in about half of affected individuals. Both conductive and sensorineural hearing loss have been observed. Approximately half of individuals exhibit typical growth and half exhibit growth abnormalities, with overgrowth being more common than undergrowth and macrocephaly being the most common manifestation of altered growth. While many affected individuals have dysmorphic features, these are typically nonspecific. Congenital heart defects, brain malformations, and genitourinary anomalies are less common findings.

Autosomal dominant intellectual developmental disorder-65 (MRD65) is characterized by delayed motor and speech acquisition, variably impaired intellectual development, and behavioral abnormalities. Affected individuals also have dysmorphic facial features. Brain imaging may be normal or may show abnormalities, including cerebellar hypoplasia, poor development of the corpus callosum, dysmorphic hippocampus, and polymicrogyria. Feeding difficulties, hypotonia, and seizures may also be observed (Duncan et al., 2020).

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).

PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) is characterized by mild-to-profound neurodevelopmental delay, pronounced hypotonia, and macrocephaly. Onset of independent walking varies widely, and ataxia and movement disorders, including early-onset parkinsonism, are reported. Almost all individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is also reported in some individuals. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Gastrointestinal and skeletal manifestations are reported. Endocrine, cardiac, and genitourinary issues are each reported in a few individuals. To date, more than 100 individuals with PPP2R5D-NDD have been reported.

Autosomal dominant intellectual developmental disorder-72 (MRD72) is characterized by developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight/obesity, and dysmorphic features (Cuinat et al., 2022).

ReNU syndrome (RENU), also known as neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA), is characterized by hypotonia, global developmental delay, severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, seizures (in most), dysmorphic facial features, and brain anomalies, including ventriculomegaly, thin corpus callosum, and progressive white matter loss (Greene et al., 2024; Schot et al., 2024; Chen et al., 2024).

Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.