Arthrogryposis, Distal, Type 2b3

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 2B3 (DA2B3) is caused by heterozygous mutation in the MYH3 gene (160720) on chromosome 17p13.

Description

Distal arthrogryposis type 2B3 (DA2B3) is characterized by facial dysmorphism and congenital joint contractures with predominantly distal involvement. Some patients exhibit muscle weakness (Tajsharghi et al., 2008). Considerable inter- and intrafamilial variability has been reported (Xu et al., 2018).

Clinical Features

Tajsharghi et al. (2008) reported 2 unrelated families with distal arthrogryposis and mutations in the MYH3 gene. The first family consisted of a mother and daughter (patients 1 and 2) whose clinical features included short stature, scoliosis, mild facial dysmorphism, decreased muscle strength, and contractures in proximal and distal joints, including the shoulders. In the second family, the proband was a man (patient 3) who exhibited a milder form of DA2B, with contractures primarily of the hands and mild involvement of the jaw, elbows, and feet, with normal muscle strength. The man was reported to have 3 children with signs of distal arthrogryposis. Muscle biopsies from patients 1 and 2 showed slight pathologic changes, with increased variability of fiber size due to frequent small type 1 fibers, which showed a slight predominance. Deltoid biopsy from patient 3 revealed scattered small type 1 fibers but no obvious pathologic changes. The embryonic MYH3 isoform was not detected in any of the biopsy samples, consistent with normal developmental downregulation. Tajsharghi et al. (2008) suggested that distal arthrogryposis associated with MYH3 mutations may cause a severe myopathy during fetal development, resulting in congenital joint contractures, with residual muscle defects that manifest as a myopathy after embryonic myosin is downregulated postnatally.

Kimber et al. (2012) reported 3 Swedish families with distal arthrogryposis, noting that they exhibited variable penetrance and expressivity. (Kimber (2019) confirmed that 2 of these families (families 1 and 2) had previously been reported by Tajsharghi et al. (2008)). After detailed clinical examination of the father and 3 affected children from family 2, who were all heterozygous for the same A234T mutation in the MYH3 gene (160720.0008), Kimber et al. (2012) designated the father and 1 twin sister to represent DA2B, whereas the other twin sister and a younger brother were designated as having a DA1 (see 108120) phenotype. In family 3, 2 brothers with contractures of the hands and feet but no facial dysmorphism, who carried a missense mutation in MYH3, were given a diagnosis of DA1. The authors also noted that asymptomatic carriers were present in the 2 families, demonstrating variable penetrance: in family 2, the unaffected paternal grandfather carried the same mutation as his affected son and 3 affected grandchildren; and in family 3, the father was an asymptomatic carrier of the same mutation found in his 2 sons, although he had a history of contractures of the feet in childhood.

Xu et al. (2018) examined 7 affected individuals from a large 4-generation Chinese family with distal arthrogryposis and marked intrafamilial phenotypic variation. Most affected members exhibited dysmorphic facial features, including triangular face, ptosis, prominent nasolabial folds, and attached earlobes; 2 had a broad-bridged nose, and 2 showed a slightly small mouth as well. The proband and a paternal uncle presented the most severe arthrogryposis of the hands, and the proband had clubfeet. In contrast, 3 other affected family members showed primarily facial dysmorphism, with almost no hand involvement.

Molecular Genetics

In a cohort of 38 probands diagnosed with DA2B (Sheldon-Hall syndrome; SHS) who were negative for mutation in the TNNI2 (191043) or TNNT3 (191044) genes, Toydemir et al. (2006) screened the MYH3 gene and identified heterozygous mutations (see, e.g., 160720.0003, 160720.0005, and 160720.0006) in 5 (42%) of 12 familial and 7 (27%) of 26 sporadic cases. Three patients with Freeman-Sheldon syndrome (DA2A; 193700) and 2 patients diagnosed with DA2B shared the T178I mutation in the MYH3 gene (160720.0003). The authors noted that mutations in the MYH3, TNNI2, and TNNT3 genes account for about half of all studied cases of DA2B.

Tajsharghi et al. (2008) analyzed the coding sequence of MYH3 in 2 unrelated families with distal arthrogryposis and identified 2 different heterozygous mutations (160720.0007 and 160720.0008) that segregated with disease in the respective families.

By whole-exome capture and massively parallel sequencing in affected members of a 4-generation Chinese family with distal arthrogryposis type 2B, Xu et al. (2018) identified heterozygosity for a missense mutation in the MYH3 gene (Y387C; 160720.0012) that segregated fully with disease and was not found in 250 Chinese controls or in the ExAC database. The authors stated that this was the first Asian family with distal arthrogryposis due to a mutation in the MYH3 gene.

Associations Pending Confirmation

Alvarado et al. (2011) studied a family in which 6 members had clubfoot, requiring multiple surgeries for correction, and/or mild hand contractures. The family was negative for mutation in the MYBPC1 gene, but exome sequencing revealed a heterozygous missense mutation (F437I) in the MYH3 gene (chr17:10488494A-T, NCBI36) that was found in 2 sibs with clubfoot and hand contractures, in 2 sibs with only clubfoot, and in 1 sib with adolescent-onset mild hand contractures involving the distal interphalangeal joints. The phenotype appeared to be incompletely penetrant. The parents were apparently unaffected, and their mutation status was not reported. Two unaffected sibs and an unaffected daughter of 1 of the sibs did not carry the mutation, whereas another daughter of the same sib had clubfoot and carried the F437I variant. No functional studies were reported. The authors suggested that a diagnosis of distal arthrogryposis type 1 should be considered in cases of isolated clubfoot, especially when hand contractures are present in any family member or when clubfoot is severe and resistant to treatment.