KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.

An abnormality of the intestinal rotation and fixation that normally occurs during the development of the gut. This can lead to volvulus, or twisting of the intestine that causes obstruction and necrosis.

Opsismodysplasia (OPSMD) is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by Below et al., 2013 and Fradet and Fitzgerald, 2017).

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

X-linked intellectual developmental disorder-9 (XLID9) is characterized by moderately to severely impaired intellectual development. Some patients have also been reported with delayed motor development, seizures, and/or behavioral problems (Hamel et al., 1999; Froyen et al., 2007).

Intellectual developmental disorder-29 (XLID29) is a nonspecific form of XLID. It is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (DEE1; 308350) to Partington syndrome (309510) (Kato et al., 2004; Wallerstein et al., 2008).

Pontocerebellar hypoplasia (PCH) refers to a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. Clinical features vary, but usually include severe developmental delay, dysmorphic features, seizures, and early death (summary by Durmaz et al., 2009). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

Roifman syndrome is a multisystem disorder characterized by growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy, distinctive facial dysmorphism, and immunodeficiency (summary by de Vries et al., 2006).

Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies. The facial features include thick eyebrows with lateral flare, vertically narrow and downslanted palpebral fissures, widely spaced eyes, long eyelashes, wide nasal bridge, broad nasal tip, thin vermilion of the upper lip, and thick scalp hair. About 60% of affected individuals have hypertrichosis cubiti ("hairy elbows"), which was once thought to be pathognomic for the syndrome, with a majority having hypertrichosis of other body parts. Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies.

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common.

A very rare syndrome including short stature, facial dysmorphism, hand abnormalities and shawl scrotum. It has been observed in 16 subjects from five distantly related sibships of a large Kuwaiti Bedouin tribe. The affected patients had no intellectual deficit. Transmitted as an autosomal recessive trait.

Mandibulofacial dysostosis-macroblepharon-macrostomia syndrome is a rare developmental defect during embryogenesis disorder characterized by macroblepharon, ectropion, and facial dysmorphism which includes severe hypertelorism, downslanting palpebral fissures, posteriorly rotated ears, broad nasal bridge, long and smooth philtrum, and macrostomia with thin upper lip vermilion border. Other features may include large fontanelles, prominent metopic ridge, thick eyebrows, mild synophrys, increased density of upper eyelashes, anterverted nares, abnormal dentition and capillary hemangioma.

A rare partial autosomal trisomy/tetrasomy characterized by global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low set, dysplastic ears, short or shallow philtrum, high arched or narrow palate, micrognathia). Other associated clinical features include sleep disturbances, seizures, aplasia/hypoplasia of the corpus callosum, skeletal abnormalities (large hands and feet, long fingers and toes, talipes).

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

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3) is an autosomal recessive disorder characterized by severe intellectual disability, hypotonia with poor motor development, poor speech, and increased serum alkaline phosphatase (summary by Hansen et al., 2013). However, the severity of the disorder can also vary to include more mild intellectual impairment (Krawitz et al., 2013). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of HPMRS, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common.

Hyperphosphatasia with impaired intellectual development syndrome-2 (HPMRS2) is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with impaired intellectual development syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Martinez-Glez et al. (2012) described osteogenesis imperfecta type XIII, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity.

A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, feeding difficulties, behavioral anomalies, vision anomalies and mild facial dysmorphism. Other associated features may include microcephaly, short stature, urogenital or palatal anomalies (e.g. cleft palate), minor cardiac defects, recurrent infections or hearing loss.

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.

PDE4D haploinsufficiency syndrome is a rare syndromic intellectual disability characterized by developmental delay, intellectual disability, low body mass index, long arms, fingers and toes, prominent nose and small chin.

MPPH (megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus) syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria (BPP). At birth the occipital frontal circumference (OFC) ranges from normal to 6 standard deviations (SD) above the mean for age, sex, and gestational age; in older individuals the range is from 3 to 10 SD above the mean. A variable degree of ventriculomegaly is seen in almost all children with MPPH syndrome; nearly 50% of individuals have frank hydrocephalus. Neurologic problems associated with BPP include oromotor dysfunction (100%), epilepsy (50%), and mild-to-severe intellectual disability (100%). Postaxial hexadactyly occurs in 50% of individuals with MPPH syndrome.

PURA-related neurodevelopmental disorders include PURA syndrome, caused by a heterozygous pathogenic sequence variant in PURA, and 5q31.3 deletion syndrome, caused by a genomic 5q31.3 deletion encompassing all or part of PURA. PURA-related neurodevelopmental disorders are characterized by moderate-to-severe neurodevelopmental delay with absence of speech in most and lack of independent ambulation in many. Early-onset problems can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common.

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.

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

Developmental and epileptic encephalopathy-48 (DEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech; poor, if any, motor development; and onset of seizures usually in the first year of life, although later onset has been reported. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (summary by Assoum et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Thauvin-Robinet-Faivre syndrome is an autosomal recessive disorder characterized by generalized overgrowth, mainly of height, and mildly delayed psychomotor development with mild or severe learning difficulties. More variable features may include congenital heart defects, kidney abnormalities, and skeletal defects. Patients may have an increased risk for Wilms tumor (summary by Akawi et al., 2016).

Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the TBL1XR1 gene.

Distal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by poor overall growth, slender habitus, microcephaly, delayed development, intellectual disability with poor or absent speech, and feeding difficulties. Additional features include dysmorphic facies, signs of ectodermal dysplasia, hand and foot anomalies, and genitourinary anomalies, particularly in males (summary by Chowdhury et al., 2014).

IDDFSDA is an autosomal recessive severe multisystem disorder characterized by poor overall growth, developmental delay, early-onset seizures, intellectual disability, and dysmorphic features. There is phenotypic variability. The most severely affected patients have a neurodevelopmental disorder with microcephaly, absent speech, and inability to walk, and they require feeding tubes. Some patients have congenital heart defects or nonspecific abnormalities on brain imaging. Less severely affected individuals have mild to moderate intellectual disability with normal speech and motor development (summary by Santiago-Sim et al., 2017).

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities.

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

Hyperphosphatasia with impaired intellectual development syndrome-1 (HPMRS1) is an autosomal recessive disorder characterized by impaired intellectual development, various neurologic abnormalities such as seizures and hypotonia, and hyperphosphatasia. Other features include facial dysmorphism and variable degrees of brachytelephalangy (summary by Krawitz et al., 2010). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Hyperphosphatasia with Impaired Intellectual Development Syndrome See also HPMRS2 (614749), caused by mutation in the PIGO gene (614730) on chromosome 9p13; HPMRS3 (614207), caused by mutation in the PGAP2 gene (615187) on chromosome 11p15; HPMRS4 (615716), caused by mutation in the PGAP3 gene (611801) on chromosome 17q12; HPMRS5 (616025), caused by mutation in the PIGW gene (610275) on chromosome 17q12; and HPMRS6 (616809), caused by mutation in the PIGY gene (610662) on chromosome 4q22. Knaus et al. (2018) provided a review of the main clinical features of the different types of HPMRS, noting that some patients have a distinct pattern of facial anomalies that can be detected by computer-assisted comparison, particularly those with mutations in the PIGV and PGAP3 genes. Individuals with HPMRS have variable increased 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 HPMRS and MCAHS (see, e.g., 614080), 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 under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).

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).

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).

ROR2-related Robinow syndrome is characterized by distinctive craniofacial features, skeletal abnormalities, and other anomalies. Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism, prominent eyes, midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia. Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly. Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy. The disorder is recognizable at birth or in early childhood.

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

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).

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).

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).

Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021).

Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).

Developmental delay with variable neurologic and brain abnormalities (DENBA) is characterized most often by motor and speech delay apparent from early childhood. Most patients have delayed walking and variably impaired intellectual development. Additional neurologic features may include seizures, spasticity, and ocular abnormalities. Brain imaging often shows thin corpus callosum and may show white matter atrophy, myelination abnormalities, or enlarged ventricles. The severity of the disorder and clinical manifestations are highly variable (summary by Malhotra et al., 2021).

Neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF) is an autosomal dominant disorder characterized by global developmental delay, impaired intellectual development, seizures, distinctive facial features, scoliosis, delayed closure of the anterior fontanel, and nonspecific brain abnormalities (Wakeling et al., 2021).

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).

Autosomal recessive primary microcephaly-30 (MCPH30) is characterized by small head circumference, poor overall growth, and global developmental delay with variably impaired intellectual development. Affected individuals have been reported to have variable additional congenital anomalies, including atrial septal defect, dysmorphic facial features, tracheal stenosis, and anomalies of the skin and teeth (Carvalhal et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

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 microcephaly and speech delay, with or without brain abnormalities (NEDMSBA) is an autosomal recessive disorder characterized by global developmental delay, hypotonia, delayed or absent walking, impaired intellectual development, and poor or absent speech, apparent from early infancy. Affected individuals have postnatal progressive microcephaly and may show poor overall growth and dysmorphic facial features. Additional more variable features include cortical visual impairment, seizures, hypotonia, spasticity, and sensorineural deafness. Brain imaging is abnormal in most patients, showing myelination defects, cortical atrophy, or thin corpus callosum. There is phenotypic variability, even within families (Bogershausen et al., 2022; Lin et al., 2022).

Autosomal dominant intellectual developmental disorder-71 with behavioral abnormalities (MRD71) is a neurodevelopmental disorder characterized by global developmental delay with hypotonia, speech delay, and variably impaired cognitive development. Almost all affected individuals show marked behavioral manifestations, including autism spectrum disorder (ASD), ADHD, hypersensitivity, and aggression. Many have dysmorphic features, although there is not a common gestalt (Harris et al., 2021).

Developmental and epileptic encephalopathy-31B (DEE31B) is an autosomal recessive neurologic disorder with early-onset epilepsy, generalized muscular hypotonia, visual impairment, and severe neurodevelopmental delay (Yigit et al., 2022).

Autosomal dominant intellectual developmental disorder-73 (MRD73) is a highly variable neurodevelopmental disorder characterized by impaired intellectual development that ranges from mild to severe, speech delay, behavioral abnormalities, and nonspecific dysmorphic facial features (Janssen et al., 2022).

Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (NEDHSS) is characterized by global developmental delay, impaired intellectual development with poor or absent speech, and fine and gross motor delay. Most affected individuals are severely affected and may be unable to walk, have feeding difficulties requiring tube-feeding, and develop early-onset seizures. Additional features may include cortical blindness and nonspecific structural brain abnormalities. Rare individuals present only with hypotonia and mild developmental delay (Paul et al., 2023).

Congenital cranial dysinnervation disorder with absent corneal reflex and developmental delay (CCDDRD) is an autosomal recessive disorder characterized by abnormal development of the proximal cranial sensory ganglia and nerves, mainly CN V (trigeminal nerve) and CN VIII (vestibulocochlear nerve). Affected individuals present at birth or in early infancy with corneal opacities due to absent blinking. Most patients also have sensorineural deafness associated with hypoplastic or malformed cochlea and hypoplasia or agenesis of CN VIII. Developmental delay with poor speech and autistic behavior are also present. Additional features may include expressionless face, feeding or chewing difficulties due to oromotor dysfunction, and dysmorphic facial features (Dupont et al., 2021; Sheth et al., 2023).

Jeffries-Lakhani neurodevelopmental syndrome (JELANS) is an autosomal recessive disorder characterized by hypotonia, early-onset seizures, and global developmental delay apparent from infancy. Affected individuals have motor delay, speech delay, and impaired intellectual development, and about half of patients are nonambulatory and/or nonverbal. Some patients have cardiac arrhythmia, but congenital cardiac septal defects are only rarely observed. Additional features may include feeding difficulties, recurrent infections, ocular defects, and nonspecific dysmorphic features. Premature death due to cardiac arrhythmia or epilepsy may occur (Jeffries et al., 2024).

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