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Branchiootorenal spectrum disorder (BORSD) is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Some individuals progress to end-stage renal disease (ESRD) later in life. Extreme variability can be observed in the presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality from right side to left side in an affected individual and also among individuals in the same family. [from GeneReviews]

Congenital myopathy-1A (CMYP1A) 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 (CMYP1B; 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 CMYP1B (255320), caused by mutation in the RYR1 gene (180901) on chromosome 19q13; CMYP2A (161800), CMYP2B (620265), and CMYP2C (620278), caused by mutation in the ACTA1 gene (102610) on chromosome 1q42; CMYP3 (602771), caused by mutation in the SELENON gene (606210) on chromosome 1p36; CMYP4A (255310) and CMYP4B (609284), caused by mutation in the TPM3 gene (191030) on chromosome 1q21; CMYP5 (611705), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMYP6 (605637), caused by mutation in the MYH2 gene (160740) on chromosome 17p13; CMYP7A (608358) and CMYP7B (255160), caused by mutation in the MYH7 gene (160760) on chromosome 14q11; CMYP8 (618654), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMYP9A (618822) and CMYP9B (618823), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYP10A (614399) and CMYP10B (620249), caused by mutation in the MEGF10 gene (612453) on chromosome 5q23; CMYP11 (619967), caused by mutation in the HACD1 gene (610467) on chromosome 10p12; CMYP12 (612540), caused by mutation in the CNTN1 gene (600016) on chromosome 12q12; CMYP13 (255995), caused by mutation in the STAC3 gene (615521) on chromosome 12q13; CMYP14 (618414), caused by mutation in the MYL1 gene (160780) on chromosome 2q34; CMYP15 (620161), caused by mutation in the TNNC2 gene (191039) on chromosome 20q13; CMYP16 (618524), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; CMYP17 (618975), caused by mutation in the MYOD1 gene (159970) on chromosome 11p15; CMYP18 (620246), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; CMYP19 (618578), caused by mutation in the PAX7 gene (167410) on chromosome 1p36; CMYP20 (620310), caused by mutation in the RYR3 gene (180903) on chromosome 15q13; CMYP21 (620326), caused by mutation in the DNAJB4 gene (611327) on chromosome 1p31; CMYP22A (620351) and CMYP22B (620369), both caused by mutation in the SCN4A gene (603967) on chromosome 17q23; CMYP23 (609285), caused by mutation in the TPM2 gene (190990) on chromosome 9p13; and CMYP24 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. [from OMIM]

PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive generalized connective tissue disorder characterized by hypotonia, early-onset kyphoscoliosis, and generalized joint hypermobility in association with skin fragility and ocular abnormality. Intelligence is normal. Life span may be normal, but affected individuals are at risk for rupture of medium-sized arteries. Adults with severe kyphoscoliosis are at risk for complications from restrictive lung disease, recurrent pneumonia, and cardiac failure. [from GeneReviews]

Focal dermal hypoplasia is a multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face. Skin manifestations present at birth include atrophic and hypoplastic areas of skin; cutis aplasia; fat nodules in the dermis manifesting as soft, yellow-pink cutaneous nodules; and pigmentary changes. Verrucoid papillomas of the skin and mucous membranes may appear later. The nails can be ridged, dysplastic, or hypoplastic; hair can be sparse or absent. Limb malformations include oligo-/syndactyly and split hand/foot. Developmental abnormalities of the eye can include anophthalmia/microphthalmia, iris and chorioretinal coloboma, and lacrimal duct abnormalities. Craniofacial findings can include facial asymmetry, notched alae nasi, cleft lip and palate, and pointed chin. Occasional findings include dental anomalies, abdominal wall defects, diaphragmatic hernia, and renal anomalies. Psychomotor development is usually normal; some individuals have cognitive impairment. [from GeneReviews]

McKusick-Kaufman syndrome (MKS) is characterized by the combination of postaxial polydactyly (PAP), congenital heart disease (CHD), and hydrometrocolpos (HMC) in females and genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee). HMC in infants usually presents as a large cystic abdominal mass arising out of the pelvis, caused by dilatation of the vagina and uterus as a result of the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by failure of the distal third of the vagina to develop (vaginal agenesis), a transverse vaginal membrane, or an imperforate hymen. PAP is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot. A variety of congenital heart defects have been reported including atrioventricular canal, atrial septal defect, ventricular septal defect, or a complex congenital heart malformation. [from GeneReviews]

ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression. [from GeneReviews]

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]

The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males. CHILD syndrome is characterized by unilateral distribution of ichthyosiform (yellow scaly) skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Nail changes are also common. The heart, lung, and kidneys can also be involved. CK syndrome (named for the initials of the original proband) is characterized by mild to severe cognitive impairment and behavior problems (aggression, attention deficit hyperactivity disorder, and irritability). All affected males reported have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported. [from GeneReviews]

De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100. Genetic Heterogeneity of de Barsy Syndrome Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25. [from OMIM]

Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). It is classified as a form of Ehlers-Danlos syndrome (Malfait et al., 2017). Genetic Heterogeneity of Brittle Cornea Syndrome Brittle cornea syndrome-2 (BCS2; 614170) is caused by mutation in the PRDM5 gene (614161) on chromosome 4q27. [from OMIM]

ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression. [from GeneReviews]

Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. The term "arthrogryposis" comes from the Greek words for joint (arthro-) and crooked or hooked (gryposis). The characteristic features of this condition include permanently bent fingers and toes (camptodactyly), overlapping fingers, and a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation). Clubfoot, which is an inward- and upward-turning foot, is also commonly seen with distal arthrogryposis type 1. The specific hand and foot abnormalities vary among affected individuals. However, this condition typically does not cause any signs and symptoms affecting other parts of the body. [from MedlinePlus Genetics]

KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype. [from GeneReviews]

The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009). For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100). [from OMIM]

Heterotaxy Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. Multiple Types of Congenital Heart Defects Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011). Reviews Obler et al. (2008) reviewed published cases of double-outlet right ventricle and discussed etiology and associations. Genetic Heterogeneity of Visceral Heterotaxy See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22; HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q21; HTX7 (616749), caused by mutation in the MMP21 gene (608416) on chromosome 10q26; HTX8 (617205), caused by mutation in the PKD1L1 gene (609721) on chromosome 7p12; HTX9 (618948), caused by mutation in the MNS1 gene (610766) on chromosome 15q21; HTX10 (619607), caused by mutation in the CFAP52 gene (609804) on chromosome 17p13; HTX11 (619608), caused by mutation in the CFAP45 gene (605152) on chromosome 1q23; and HTX12 (619702), caused by mutation in the CIROP gene (619703) on chromosome 14q11. Genetic Heterogeneity of Multiple Types of Congenital Heart Defects An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26. CHTD2 (614980) is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q31. CHTD4 (615779) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26. CHTD5 (617912) is caused by mutation in the GATA5 gene (611496) on chromosome 20q13. CHTD6 (613854) is caused by mutation in the GDF1 gene (602880) on chromosome 19p13. CHTD7 (618780) is caused by mutation in the FLT4 gene (136352) on chromosome 5q35. CHTD8 (619657) is caused by mutation in the SMAD2 gene (601366) on chromosome 18q21. CHTD9 (620294) is caused by mutation in the PLXND1 gene (604282) on chromosome 3q22. [from OMIM]

Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by Ng et al., 2010). [from OMIM]

Rothmund-Thomson syndrome (RTS) is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; skeletal and dental abnormalities; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age two years) as erythema, swelling, and blistering on the face, subsequently spreading to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, telangiectasias, and punctate atrophy (collectively known as poikiloderma) that persist throughout life. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities can include radial ray defects, ulnar defects, absent or hypoplastic patella, and osteopenia. [from GeneReviews]

Yunis-Varon syndrome (YVS) is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013). [from OMIM]

Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses. [from GeneReviews]

Congenital fiber-type disproportion is a condition that primarily affects skeletal muscles, which are muscles used for movement. People with this condition typically experience muscle weakness (myopathy), particularly in the muscles of the shoulders, upper arms, hips, and thighs. Weakness can also affect the muscles of the face and muscles that control eye movement (ophthalmoplegia), sometimes causing droopy eyelids (ptosis). Individuals with congenital fiber-type disproportion generally have a long face, a high arch in the roof of the mouth (high-arched palate), and crowded teeth.

Individuals with congenital fiber-type disproportion may have joint deformities (contractures) and an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). Approximately 30 percent of people with this disorder experience mild to severe breathing problems related to weakness of muscles needed for breathing. Some people who experience these breathing problems require use of a machine to help regulate their breathing at night (noninvasive mechanical ventilation), and occasionally during the day as well. About 30 percent of affected individuals have difficulty swallowing due to muscle weakness in the throat. Rarely, people with this condition have a weakened and enlarged heart muscle (dilated cardiomyopathy).

The severity of congenital fiber-type disproportion varies widely. It is estimated that up to 25 percent of affected individuals experience severe muscle weakness at birth and die in infancy or childhood. Others have only mild muscle weakness that becomes apparent in adulthood. Most often, the signs and symptoms of this condition appear by age 1. The first signs of this condition are usually decreased muscle tone (hypotonia) and muscle weakness. In most cases, muscle weakness does not worsen over time, and in some instances it may improve. Although motor skills such as standing and walking may be delayed, many affected children eventually learn to walk. These individuals often have less stamina than their peers, but they remain active. Rarely, people with this condition have a progressive decline in muscle strength over time. These individuals may lose the ability to walk and require wheelchair assistance. [from MedlinePlus Genetics]