MedGen

ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, and syndactyly), elbow and knee flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), and craniofacial abnormalities (which can include bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, and underdeveloped ala nasi), ear malformation, and corneal opacities. Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected pregnancies and newborns; mildly affected individuals may survive to adulthood. [from GeneReviews]

Congenital myopathy-1A (CMYO1A) with susceptibility to malignant hyperthermia is an autosomal dominant disorder of skeletal muscle characterized by muscle weakness primarily affecting the proximal muscles of the lower limbs beginning in infancy or early childhood, although later onset of symptoms has been reported. There is significant phenotypic variability, even within families, and the wide clinical diversity most likely depends on the severity of the RYR1 mutation. The disorder is static or slowly progressive; affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Some patients present with orthopedic deformities. Serum creatine kinase is usually not elevated. Respiratory involvement is rare and there is no central nervous system or cardiac involvement. Patients with dominant mutations in the RYR1 gene are at risk for malignant hyperthermia and both disorders may segregate in the same family. Historically, patients with congenital myopathy due to RYR1 mutations were diagnosed based on the finding of pathologic central cores (central core disease; CCD) on muscle biopsy, which represent areas that lack oxidative enzymes and mitochondrial activity in type 1 muscle fibers. However, additional pathologic findings may also be observed, including cores and rods, central nuclei, fiber type disproportion, multiminicores, and uniform type 1 fibers. These histopathologic features are not always specific to RYR1 myopathy and often change over time (Quinlivan et al., 2003; Jungbluth et al., 2007; Klein et al., 2012; Ogasawara and Nishino, 2021). Some patients with RYR1 mutations have pathologic findings on muscle biopsy, but are clinically asymptomatic (Shuaib et al., 1987; Quane et al., 1993). Rare patients with a more severe phenotype have been found to carry a heterozygous mutation in the RYR1 gene inherited from an unaffected parent. However, in these cases, there is a possibility of recessive inheritance (CMYO1B; 255320) with either a missed second RYR1 mutation in trans or a genomic rearrangement on the other allele that is undetectable on routine genomic sequencing, since the RYR1 gene is very large and genetic analysis may be difficult (Klein et al., 2012). Genetic Heterogeneity of Congenital Myopathy See also CMYO1B (255320), caused by mutation in the RYR1 gene (180901) on chromosome 19q13; CMYO2A (161800), CMYO2B (620265), and CMYO2C (620278), caused by mutation in the ACTA1 gene (102610) on chromosome 1q42; CMYO3 (602771), caused by mutation in the SELENON gene (606210) on chromosome 1p36; CMYO4A (255310) and CMYO4B (609284), caused by mutation in the TPM3 gene (191030) on chromosome 1q21; CMYO5 (611705), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMYO6 (605637), caused by mutation in the MYH2 gene (160740) on chromosome 17p13; CMYO7A (608358) and CMYO7B (255160), caused by mutation in the MYH7 gene (160760) on chromosome 14q11; CMYO8 (618654), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMYO9A (618822) and CMYO9B (618823), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYO10A (614399) and CMYO10B (620249), caused by mutation in the MEGF10 gene (612453) on chromosome 5q23; CMYO11 (619967), caused by mutation in the HACD1 gene (610467) on chromosome 10p12; CMYO12 (612540), caused by mutation in the CNTN1 gene (600016) on chromosome 12q12; CMYO13 (255995), caused by mutation in the STAC3 gene (615521) on chromosome 12q13; CMYO14 (618414), caused by mutation in the MYL1 gene (160780) on chromosome 2q34; CMYO15 (620161), caused by mutation in the TNNC2 gene (191039) on chromosome 20q13; CMYO16 (618524), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; CMYO17 (618975), caused by mutation in the MYOD1 gene (159970) on chromosome 11p15; CMYO18 (620246), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; CMYO19 (618578), caused by mutation in the PAX7 gene (167410) on chromosome 1p36; CMYO20 (620310), caused by mutation in the RYR3 gene (180903) on chromosome 15q13; CMYO21 (620326), caused by mutation in the DNAJB4 gene (611327) on chromosome 1p31; CMYO22A (620351) and CMYO22B (620369), both caused by mutation in the SCN4A gene (603967) on chromosome 17q23; CMYO23 (609285), caused by mutation in the TPM2 gene (190990) on chromosome 9p13; and CMYO24 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. [from OMIM]

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. [from GeneReviews]

Autosomal recessive limb-girdle muscular dystrophy-3 (LGMDR3) affects mainly the proximal muscles and results in difficulty walking. Most individuals have onset in childhood; the disorder is progressive. Other features may include scapular winging, calf pseudohypertrophy, and contractures. Cardiomyopathy has rarely been reported (summary by Babameto-Laku et al., 2011). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600). [from OMIM]

Charcot-Marie-Tooth disease type 4J is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from early childhood to adulthood. Most patients have both proximal and distal asymmetric muscle weakness of the upper and lower limbs. There is significant motor dysfunction, followed by variably progressive sensory loss, which may be mild. Nerve conduction studies and nerve biopsies indicate demyelination as well as axonal loss (summary by Nicholson et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400). [from OMIM]

Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579). [from OMIM]

MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (summary by Hara et al., 2011). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308). [from OMIM]

Syndrome with characteristics of severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products. So far, only two cases have been described. The disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus. [from SNOMEDCT_US]

Bruck syndrome-1 (BRKS1) is characterized by congenital contractures with pterygia, onset of fractures in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis (McPherson and Clemens, 1997). Genetic Heterogeneity of Bruck Syndrome Bruck syndrome-2 (BRKS2; 609220) is caused by homozygous mutation in the PLOD2 gene (601865) on chromosome 3q24. Van der Slot et al. (2003) stated that they were unaware of any phenotypic differences between the 2 forms of Bruck syndrome. [from OMIM]

Spastic paraplegia-43 (SPG43) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive spasticity affecting the lower and upper limbs (summary by Meilleur et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800. [from OMIM]

Charcot-Marie-Tooth disease type 2X (CMT2X) is an autosomal recessive, slowly progressive, axonal peripheral sensorimotor neuropathy characterized by lower limb muscle weakness and atrophy associated with distal sensory impairment and gait difficulties. Some patients also have involvement of the upper limbs. Onset usually occurs in the first 2 decades of life, although later onset can also occur (summary by Montecchiani et al., 2016) For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210). [from OMIM]

Multicentric osteolysis nodulosis and arthropathy (MONA) is a skeletal dysplasia characterized by progressive osteolysis (particularly of the carpal and tarsal bones), osteoporosis, subcutaneous nodules on the palms and soles, and progressive arthropathy (joint contractures, pain, swelling, and stiffness). Other manifestations include coarse facies, pigmented skin lesions, cardiac defects, and corneal opacities. Onset is usually between ages six months and six years (range: birth to 11 years). [from GeneReviews]

Any tubular aggregate myopathy in which the cause of the disease is a mutation in the ORAI1 gene. [from MONDO]

Autosomal recessive myopathy with rigid spine and distal joint contractures (MRRSDC) is characterized by onset of slowly progressive muscle weakness in the first or second decades of life. There is initial involvement of the proximal lower limbs, followed by distal upper and lower limb muscle weakness and atrophy. Other features include joint contractures, rigid spine, and restricted pulmonary function; some patients may have mild cardiac involvement (summary by Kayman-Kurekci et al., 2014). [from OMIM]

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures (summary by Srour et al., 2015 and Heimer et al., 2015). [from OMIM]

SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported. [from GeneReviews]

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. [from OMIM]

Warburg-Cinotti syndrome (WRCN) is characterized by progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acroosteolysis (Xu et al., 2018). [from OMIM]

PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria. [from GeneReviews]

Centronuclear myopathy-6 with fiber-type disproportion (CNM6) is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy (summary by Vasli et al., 2017). For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150). [from OMIM]