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.

Curry-Jones syndrome (CRJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas (summary by Twigg et al., 2016).

Wieacker-Wolff syndrome (WRWF) is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia), which results in arthrogryposis multiplex congenita (AMC) apparent at birth. Affected boys are born with severe contractures, show delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and foot deformities. Additional features include global developmental delay with poor or absent speech and impaired intellectual development, feeding difficulties and poor growth, hypotonia, hypogenitalism, and spasticity. Carrier females may be unaffected or have mild features of the disorder (summary by Hirata et al., 2013 and Frints et al., 2019).

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.

Retinitis pigmentosa with or without skeletal anomalies (RPSKA) is characterized by retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurologic defects. Night blindness occurs around 10 years of age, followed by restriction of visual fields. Brachydactyly affects primarily the distal phalanges. Craniofacial abnormalities include frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears (summary by Xu et al., 2017).

Immunodeficiency-59 and hypoglycemia (IMD59) is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocytopenia and B-cell and dendritic cell deficiency are present (Haapaniemi et al., 2017).

Pierpont syndrome (PRPTS) is a multiple congenital anomaly syndrome associated with learning disability. Key features include distinctive facial characteristics, especially when smiling, plantar fat pads, and other limb anomalies (summary by Burkitt Wright et al., 2011).

THOC6 intellectual disability syndrome is associated with moderate-to-severe developmental delay or intellectual disability; nonspecific dysmorphic facial features (tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella); microcephaly (typically 2-3 SD below the mean); teeth anomalies (dental caries, malocclusion, and supernumerary teeth); cardiac anomalies (most typically atrial and/or ventricular septal defects); prenatal ventriculomegaly and hydrocephalus; cryptorchidism in males; and renal malformations (most commonly unilateral renal agenesis). More rarely, affected individuals may have hypergonadotropic hypogonadism (in females), seizures, poor growth, feeding difficulties, hearing loss, refractive errors and/or other eye abnormalities, vertebral anomalies, micro/retrognathia, and imperforate / anteriorly placed anus.

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).

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

Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013). For a discussion of genetic heterogeneity of Van Maldergem syndrome, see 601390.

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.

Luscan-Lumish syndrome (LLS) is characterized by macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures (Luscan et al., 2014; Lumish et al., 2015)

Any cleft lip/palate in which the cause of the disease is a mutation in the DLX4 gene.

Singleton-Merten syndrome (SGMRT) is an uncommon autosomal dominant disorder characterized by abnormalities of blood vessels, teeth, and bone. Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty and can lead to early death. Dental findings include delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization, leading to tooth loss. Osseous features consist of osteoporosis, either generalized or limited to distal extremities, distal limb osteolysis, widened medullary cavities, and easy tearing of tendons from bone. Less common features are mild facial dysmorphism (high anterior hair line, broad forehead, smooth philtrum, thin upper vermilion border), generalized muscle weakness, psoriasis, early-onset glaucoma, and recurrent infections. The disorder manifests with variable inter- and intrafamilial phenotypes (summary by Rutsch et al., 2015). Genetic Heterogeneity of Singleton-Merten Syndrome An atypical form of Singleton-Merten syndrome (SGMRT2; 616298) is caused by mutation in the DDX58 gene (609631) on chromosome 9p21.

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).

Congenital heart defects and ectodermal dysplasia (CHDED) is a rare disorder characterized by these cardinal features, with additional variable features of microcephaly, craniofacial or skeletal dysmorphism, feeding difficulties, or hypotonia (Sifrim et al., 2016).

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

The name HIST1H1E syndrome has been proposed as a mnemonic for the characteristic features of this emerging, recognizable phenotype: hypotonia; intellectual disability with behavioral issues; skeletal; testes (undescended) and thyroid; heart anomalies (most commonly atrial septal defect); and ectodermal issues (including sparse hair, thin nails, and abnormal dentition). In the 47 affected individuals reported to date, predominant findings were intellectual disability (ranging from mild to profound) and behavioral problems (combinations of anxiety/phobias, obsessive behaviors, attention-deficit/hyperactivity disorder, and autistic spectrum disorder/traits among others). Skeletal involvement can include scoliosis and decreased bone mineral density. Other findings in some include seizures, craniosynostosis, and hearing loss. Life expectancy does not appear to be reduced in HIST1H1E syndrome.

The blepharocheilodontic syndrome is a rare autosomal dominant disorder characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. An additional rare manifestation is imperforate anus (summary by Weaver et al., 2010).

Alacrima, achalasia, and impaired intellectual development syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing deficits. The disorder shows similarity to the triple A syndrome (231550), but patients with AAMR do not have adrenal insufficiency (summary by Koehler et al., 2013). See also 300858 for a phenotypically similar disorder that shows X-linked inheritance.

Mullegama-Klein-Martinez syndrome (MKMS) is an X-linked recessive disorder with features of microcephaly, microtia, hearing loss, developmental delay, dysmorphic features, congenital heart defect, and digit abnormalities. Females are generally affected more severely than males (Mullegama et al., 2019).

X-linked intellectual developmental disorder-108 (MRX108) is characterized by early hypotonia, global developmental delay, and moderately to severely impaired intellectual development. Brisk tendon reflexes, variable facial dysmorphism, and fifth finger clinodactyly may be present (Khayat et al., 2019).

Developmental and epileptic encephalopathy-83 (DEE83) is a severe autosomal recessive neurodevelopmental disorder characterized by onset of frequent seizures in the first days to months of life that are usually refractory to medical treatment and are associated with significant EEG abnormalities. Affected individuals have profoundly impaired development, with no motor or language skill acquisition, poor or absent visual tracking, and poor oromotor function necessitating tube feeding. Many patients die in the first years of life (summary by Perenthaler et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (NEDHRIT) is a severe autosomal recessive disorder characterized by neonatal respiratory distress, poor feeding, and impaired global development. Affected individuals are unable to walk or speak and have poor or absent eye contact. Some patients may develop seizures (summary by Wagner 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).

Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is an early-onset neurologic disorder characterized by global developmental delay, poor or absent speech and language development, and behavioral abnormalities reminiscent of autism spectrum disorder (ASD; 209850) or Angelman syndrome (AS; 105830). Additional features may include poor overall growth with small head circumference, axial hypotonia, spasticity, and seizures. Some patients have abnormal findings on brain imaging, including cerebral atrophy, cerebellar atrophy, and/or thin corpus callosum (summary by Mattioli et al., 2020).

Neurodevelopmental disorder with hypotonia, microcephaly, and seizures (NEDHYMS) is an autosomal recessive disorder characterized by global developmental delay with axial hypotonia, inability to sit or walk, and severely impaired intellectual development with absent language. Most patients develop early-onset intractable seizures that prevent normal development. Additional features include feeding difficulties with poor overall growth and microcephaly. Some patients may have spastic quadriplegia, poor eye contact due to cortical blindness, variable dysmorphic features, and nonspecific abnormalities on brain imaging (summary by Tan et al., 2020).

Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures (NEDHCAS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, delayed motor skills, and poor or absent speech. Most patients develop early-onset seizures and demonstrate cerebellar ataxia or dysmetria associated with progressive cerebellar atrophy on brain imaging. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Nguyen et al., 2020). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

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).

Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) is characterized by developmental delay and/or intellectual disability; corpus callosum hypoplasia or agenesis; facial dysmorphism, including upslanting palpebral fissures, broad nasal tip, and wide mouth; and skeletal abnormalities, including short stature, scoliosis, and flexion contractures, with broad fingertips and/or toes. Renal agenesis, unilateral or bilateral, has also been observed in some patients (Schneeberger et al., 2020).

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).

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).

Chopra-Amiel-Gordon syndrome (CAGS) is an autosomal dominant disorder characterized by developmental delay and/or impaired intellectual development, speech delay, facial dysmorphism, and variable other features, including recurrent bacterial infections, ophthalmologic abnormalities, and nonspecific brain abnormalities (Chopra et al., 2021).

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

Autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD) is characterized by variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; about half of patients have impaired intellectual development. Additional features include increased muscle tone and muscle cramps (Wilson et al., 2021).

Developmental delay with short stature, dysmorphic facial features, and sparse hair-2 (DEDSSH2) is an autosomal recessive syndromic disorder characterized by the constellation of these features apparent from infancy. Affected individuals may have other abnormalities, including congenital cardiac defects and distal skeletal anomalies (Hawer et al., 2020). For a discussion of genetic heterogeneity of DEDSSH2, see DEDSSH1 (616901).

Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF) is a clinically heterogeneous disorder characterized by neurologic deficits and characteristic dysmorphic facial features apparent from infancy or early childhood. Affected individuals usually show impaired intellectual development, speech delay, learning difficulties, and/or behavioral problems. Additional features may include hypotonia, hand or foot deformities, and palatal defects (Verberne et al., 2021; Verberne 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).

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

Hoxha-Aliu syndrome (HXAL) is characterized by mildly impaired intellectual development and digital anomalies of the hands and feet (Hoxha and Aliu, 2023; Guo et al., 2023). Biallelic missense mutations in the ERI1 gene have been reported to cause a more severe bone disorder, spondyloepimetaphyseal dysplasia, Guo-Campeau type (SEMDGC; 620663).

Autosomal recessive cutis laxa type ID (ARCL1D) is characterized by facial dysmorphism, joint hypermobility, muscle hypotonia, and multiple severe herniations, including inguinal, ventral, diaphragmatic, sciatic, and obturator, as well as large diverticula of the gastrointestinal tract and urinary bladder. The skin is thin and translucent with easy bruising; the degree of laxity is variable and progresses with age in some patients (Megarbane et al., 2012; Bizzari et al., 2020; Driver et al., 2020; Verlee et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).