Pallister-Killian syndrome (PKS) is a dysmorphic condition involving most organ systems, but is also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).

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

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

Congenital myopathy-14 (CMYO14) is an autosomal recessive skeletal muscle disorder characterized by onset of severe muscle weakness apparent at birth and sometimes in utero. Affected infants have difficulty breathing independently and usually require mechanical ventilation for variable lengths of time. Other features include delayed motor development with delayed walking, hypo- or areflexia, and high-arched palate. Skeletal muscle biopsy shows variation in fiber size with specific atrophy of the fast-twitch type II fibers. Cardiac muscle is not affected (summary by Ravenscroft et al., 2018). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Combined oxidative phosphorylation deficiency-51 (COXPD51) is an autosomal recessive disorder characterized by a Leigh syndrome phenotype (see 256000). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

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

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).

Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis (NEDMSC) is an autosomal recessive disorder characterized by severely impaired global development apparent from infancy, progressive microcephaly, and neonatal cholestasis manifest as jaundice and elevated liver enzymes. The liver disease resolves, but affected individuals show feeding difficulties, failure to thrive, hypotonia, seizures, hyperkinetic movements, irritability, and poor eye contact or vision, and achieve almost no motor or cognitive developmental milestones. Brain imaging demonstrates agenesis or hypoplasia of the corpus callosum. Death in early childhood may occur (summary by Schneeberger et al., 2021).

Congenital myopathy-2C (CMYO2C) is an autosomal dominant disorder of the skeletal muscle characterized by severe congenital weakness usually resulting in death from respiratory failure in the first year or so of life. Patients present at birth with hypotonia, lack of antigravity movements, poor head control, and difficulties feeding or breathing, often requiring tube-feeding and mechanical ventilation. Decreased fetal movements may be observed in some cases. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype. Some patients with heterozygous mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation (CMYO2A; 161800). The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).