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.

Floating-Harbor syndrome (FHS) is characterized by typical craniofacial features; low birth weight, normal head circumference, and short stature; bone age delay that normalizes between ages six and 12 years; skeletal anomalies (brachydactyly, clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities); severe receptive and expressive language impairment; hypernasality and high-pitched voice; and intellectual disability that is typically mild to moderate. Difficulties with temperament and behavior that are present in many children tend to improve in adulthood. Other features can include hyperopia and/or strabismus, conductive hearing loss, seizures, gastroesophageal reflux, renal anomalies (e.g., hydronephrosis / renal pelviectasis, cysts, and/or agenesis), and genital anomalies (e.g., hypospadias and/or undescended testes).

A severe form of developmental verbal apraxia with characteristics of a deficit in spontaneous speech, writing, grammatical judgment and repetition, defective articulation, moderate to severe degree of dyspraxia, a reduced use of consonant clusters and comprehension delay. Hearing and intelligence are normal. Inheritance is autosomal dominant with full penetrance.

Specific language impairment (SLI) is diagnosed in children who exhibit significant language deficits despite adequate educational opportunity and normal nonverbal intelligence. SLI2 represents a locus influencing language-related traits on chromosome 19q (SLI Consortium, 2002, SLI Consortium, 2004). For a phenotypic description and a discussion of genetic heterogeneity of specific language impairment, see SLI1 (602081).

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.

MRT18 is an autosomal recessive disorder characterized by impaired intellectual development with or without epilepsy. Other features may include spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography (summary by Trehan et al., 2015).

The 10q22.3-q23.2 region is characterized by a complex set of low-copy repeats (LCRs), which can give rise to various genomic changes mediated by nonallelic homologous recombination (NAHR). Recurrent deletions of chromosome 10q22.3-q23.2, including the BMPR1A gene (601299) have been associated with dysmorphic facies, developmental delay, and multiple congenital anomalies. Some patients with deletions that extend distally to include the PTEN gene (601728) have a more severe phenotype with infantile/juvenile polyposis, macrocephaly, dysmorphic facial features, and developmental delay (summary by van Bon et al., 2011).

Optic atrophy-11 (OPA11) is an autosomal recessive disorder characterized by delayed psychomotor development, intellectual disability, ataxia, optic atrophy, and leukoencephalopathy on brain imaging. Laboratory studies are consistent with mitochondrial dysfunction (summary by Hartmann et al., 2016). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.

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).

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) is an autosomal recessive multisystemic disorder characterized by global neurodevelopmental delay, severely impaired intellectual development, poor overall growth, and spasticity of the lower limbs resulting in gait difficulties. Most affected individuals also develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Additional more variable features include dysmorphic facies and axonal sensory peripheral neuropathy. Brain imaging tends to show thin corpus callosum and polymicrogyria (summary by Garcia-Cazorla et al., 2020).

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by Williams et al., 2019 and Zeiad et al., 2021). For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (616263).

Childhood-onset parkinsonism-dystonia-3 (PKDYS3) is an autosomal recessive neurodegenerative disorder with onset in infancy or early childhood. Affected individuals present with progressive movement abnormalities, including parkinsonism with tremor, dystonia, myoclonus ataxia, and hyperkinetic movements such as ballismus. The parkinsonism features may be responsive to treatment with levodopa, although many patients develop levodopa-induced dyskinesia. Some patients may have mild cognitive impairment or psychiatric disturbances (summary by Burke et al., 2018 and Skorvanek et al., 2022). For a discussion of genetic heterogeneity of PKDYS, see 613135.

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).

Familial hyperinsulinemic hypoglycemia-8 (HHF8) is an autosomal recessive disorder characterized by protein-related hypoglycemia and persistent mild hyperammonemia (summary by Shahroor et al., 2022). For a phenotypic description and a discussion of genetic heterogeneity of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).

Classic congenital myopathy-22A (CMYP22A) is an autosomal recessive muscle disorder characterized by onset of muscle weakness in utero or soon after birth. Early features may include fetal hypokinesia, breech presentation, and polyhydramnios. Affected individuals are born with severe hypotonia and require respiratory and feeding assistance. Those who survive the neonatal period show a 'classic' phenotype of congenital myopathy with delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. Some have persistent respiratory insufficiency; dysmorphic facial features may be present (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Severe fetal congenital myopathy-22B (CMYP22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Autosomal dominant nemaline myopathy-5C (NEM5C) is a relatively mild skeletal muscle disorder with wide clinical variability, even within families. Affected individuals develop symptoms of muscle weakness in the first or second decades; those with earlier onset tend to have a more severe disease course. Features include difficulty walking on the heels, waddling gait, proximal muscle weakness affecting the upper and lower limbs, and Gowers sign. Additional features may include myopathic facies, high-arched palate, scoliosis or kyphosis, and ankle weakness. Patients remain ambulatory into late adulthood. Skeletal muscle biopsy shows hypotrophy of type 1 fibers, hypertrophy of type 2 fibers, fiber size variation, and myofibrillar disorganization. Nemaline rods in type 1 fibers are often observed, but are not always present (Konersman et al., 2017; Holling et al., 2022). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).