Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families.

Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).

Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by Patel et al., 2014).

Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by distal joint laxity and a combination of distal and proximal joint contractures. The age at onset is highly variable, ranging from infancy to adulthood. Disease progression is slow and ambulation is usually retained into adulthood (summary by Butterfield et al., 2013). Genetic Heterogeneity of Bethlem Myopathy See Bethlem myopathy-1B (BTHLM1B; 620725), caused by mutation in the COL6A2 gene (120240) on chromosome 21q22; Bethlem myopathy-1C (620726), caused by mutation the COL6A3 gene (120250) on chromosome 2q37; and Bethlem myopathy-2 (BTHLM2; 616471), caused by mutation in the COL12A1 gene (120320) on chromosome 6q13-q14.

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.

MDDGB5 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (Brockington et al., 2001). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2006). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).

Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1A (CPSFS1) is characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported (Carapito et al., 2016; Zieba et al., 2017; Cameron-Christie et al., 2018). An autosomal recessive form of CPSFS (CPSFS1B; 618469) is caused by compound heterozygous mutation in the MYH3 gene.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

Kahrizi syndrome is an autosomal recessive neurodevelopmental disorder characterized by mental retardation, cataracts, coloboma, kyphosis, and coarse facial features (summary by Kahrizi et al., 2009). See also congenital disorder of glycosylation type Iq (CDG1Q; 612379), an allelic disorder with overlapping features.

LMNA-related congenital muscular dystrophy (L-CMD) is a condition that primarily affects muscles used for movement (skeletal muscles). It is part of a group of genetic conditions called congenital muscular dystrophies, which cause weak muscle tone (hypotonia) and muscle wasting (atrophy) beginning very early in life.\n\nIn people with L-CMD, muscle weakness becomes apparent in infancy or early childhood and can worsen quickly. The most severely affected infants develop few motor skills, and they are never able to hold up their heads, roll over, or sit. Less severely affected children may learn to sit, stand, and walk before muscle weakness becomes apparent. First the neck muscles weaken, causing the head to fall forward (dropped-head syndrome). As other skeletal muscles become weaker, these children may ultimately lose the ability to sit, stand, and walk unassisted.\n\nOther features of L-CMD often include spinal rigidity and abnormal curvature of the spine (scoliosis and lordosis); joint deformities (contractures) that restrict movement, particularly in the hips and legs; and an inward-turning foot. People with L-CMD also have an increased risk of heart rhythm abnormalities (arrhythmias).\n\nOver time, muscle weakness causes most infants and children with L-CMD to have trouble eating and breathing. The breathing problems result from restrictive respiratory insufficiency, which occurs when muscles in the chest are weakened and the ribcage becomes increasingly rigid. This problem can be life-threatening, and many affected children require support with a machine to help them breathe (mechanical ventilation).

A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).

Congenital myopathy-10B (CMYO10B) is an autosomal recessive skeletal muscle disorder characterized by infantile- or childhood-onset myopathy, areflexia, dysphagia, and respiratory distress that usually requires nocturnal ventilation. Other common features include facial and neck muscle weakness, feeding difficulties, contractures, scoliosis, high-arched palate, hyporeflexia, and difficulties walking. The disorder is slowly progressive and most patients follow a chronic course. Muscle biopsy shows variable findings, including type 1 fiber predominance, minicore lesions, and myofibrillar disorganization (Boyden et al., 2012; Harris et al., 2018). Patients with missense mutations affecting conserved cysteine residues in the EGF-like domain show the mild variant phenotype (CMYO10B) with later onset of respiratory failure and minicores on muscle biopsy, whereas patients with more damaging mutations, including nonsense or frameshift null mutations, show the severe variant phenotype (CMYO10A) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay (Begemann et al., 2015; Yamoto et al., 2017). For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860).

Periventricular nodular heterotopia-7 (PVNH7) is a neurologic disorder characterized by abnormal neuronal migration during brain development resulting in delayed psychomotor development and intellectual disability; some patients develop seizures. Other features include cleft palate and 2-3 toe syndactyly (summary by Broix et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049.

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia characterized by supraorbital hyperostosis, undermodeling of the small bones, and small and large joint contractures, as well as extraskeletal developmental abnormalities, primarily of the cardiorespiratory system and genitourinary tract. Patients with FMD2 appear to have a propensity for keloid formation (summary by Wade et al., 2016). For a discussion of genetic heterogeneity of frontometaphyseal dysplasia, see FMD1 (305620).

Krakow-type spondyloepimetaphyseal dysplasia is characterized by severe skeletal dysplasia, severe immunodeficiency, and developmental delay (Csukasi et al., 2018).

Mitochondrial complex IV deficiency nuclear type 23 (MC4DN23) is an autosomal recessive disorder characterized by infantile-onset encephalopathy (Rius et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.

Congenital myopathy-20 (CMYO20) is an autosomal recessive neuromuscular disorder that shows wide phenotypic variability. Some patients present in early childhood with proximal muscle weakness affecting the lower and upper limbs resulting in difficulties running and climbing, whereas others present soon after birth with congenital limb or distal contractures. Additional features may include dysmorphic facial features and global developmental delay. Skeletal muscle biopsy may show nemaline rods (Nilipour et al., 2018; Pehlivan et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B) is a skeletal muscle disorder in which patients usually present with proximal muscle weakness of the lower and upper limbs in a limb-girdle distribution, resulting in gait abnormalities; however, most remain ambulatory even into late adulthood. Some affected individuals show delayed motor development. There is axial weakness and atrophy of the paraspinal muscles, along with kyphosis, scoliosis, and rigid spine, as well as variable limitations of the large joints. Most patients develop restrictive respiratory insufficiency with decreased forced vital capacity; some need noninvasive ventilation. Serum creatine kinase may be elevated. Muscle biopsy can show variable features, including nemaline rods, multiminicore lesions, endomysial fibrosis, and myofibrillar changes (Pellerin et al., 2020; Lee et al., 2022). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by proximal muscle weakness and a combination of distal and proximal flexion joint contractures. The age at onset is highly variable, ranging from infancy to adulthood, and there is intrafamilial variability. Muscle biopsy may show myopathic and dystrophic features; serum creatine kinase is elevated. The progression is slow and ambulation is usually retained into adulthood (summary by Butterfield et al., 2013; Scacheri et al., 2002). For a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1A (158810).

Ullrich congenital muscular dystrophy-1 (UCMD1) is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (summary by Kirschner, 2013). For general phenotypic information and a discussion of genetic heterogeneity of Ullrich congenital muscular dystrophy, see UCMD1A (254090).