Arthrogryposis, Distal, Type 2b2

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 2B2 (DA2B2) is caused by heterozygous mutation in the TNNT3 gene (600692) on chromosome 11p15.

Description

Distal arthrogryposis type 2B2 (DA2B2) is characterized by congenital contractures of the distal limb joints and facial dysmorphism. Marked inter- and intrafamilial variability has been reported (summary by Daly et al., 2014).

For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see 108120.

Clinical Features

Sung et al. (2003) reported a mother and daughter with distal arthrogryposis type 2B with an R63H mutation in the TNNT3 gene (600692.0001). Clinical features were not described.

Gurnett et al. (2009) reported a child (Pt 5186001) with 4-extremity arthrogryposis and no evidence of facial abnormalities who carried the same R63H mutation in the TNNT3 gene. The boy had bilateral clenched fists and adducted thumbs and bilateral severe clubfoot deformities with fixed forefoot adduction, hindfoot varus, and hindfoot equinus contractures. Gurnett et al. (2009) classified the disorder in this boy as distal arthrogryposis type 1, but noted 'it is admittedly difficult to diagnose mild forms of facial weakness, particularly in infancy, and thus it may be difficult to clearly distinguish patients with DA1 [see 108120] (affecting only the hands and feet) from other types of distal arthrogryposis.'

Zhao et al. (2011) reported a Chinese family in which 5 members over 3 generations had DA2B2. The proband (III1) was a 10-year-old boy with bilateral symmetric congenital contractures of the distal limbs. His hands showed severe camptodactyly, overlapping fingers with abnormal digital flexion creases, ulnar deviation of fingers, absent creases, and adducted thumbs. His foot deformity was vertical talus. He had minor facial anomalies, including a triangular face, downslanting palpebral fissures, and a small mouth. He also had 3 preauricular tags in front of the left tragus. All affected individuals had bilateral symmetric clubfoot with vertical talus, and 3 affected adults (I1, II1, and II3) had facial features similar to those in the proband. Patient II3 presented with short middle fingers on both hands, which were the same length as the index and ring fingers. Patient III2 was a 5-month-old girl with severe varus of the right foot, slight equinovalgus of the left foot, ulnar deviation of both hands, and no distinct facial features. None of those affected had mouth-opening difficulty.

Daly et al. (2014) reported a 4-generation Indian family in which 18 members had distal arthrogryposis with marked variable expression. The hands showed variable partial cutaneous syndactyly, brachydactyly, camptodactyly, proximally placed thumbs, decreased palmar creases, ulnar deviation of the wrists, and tapering fingers. The feet were either normal or showed mild brachydactyly and increased sandal gaps. Dislocations of the hip, talipes equinovarus, vertical talus, and forefoot adduction (metatarsus varus) were occasionally observed. Three individuals had only subtle brachydactyly and decreased palmar creases, and 1 individual had severe hip involvement. All affected individuals had a triangular face and normal intellect. None of the patients had cleft palate, scoliosis, ophthalmic manifestations, sensorineural hearing loss, trismus, multiple pterygium, or crumpled ears. Daly et al. (2014) classified the phenotype in this family as 'DA1 or a milder variant of DA2B.'

Mapping

By linkage analysis in a Chinese family segregating distal arthrogryposis type 2B, Zhao et al. (2011) obtained a lod score of 1.20 at theta = 0.0 with marker 11p15CCT in a region close to the TNNI2 (191043) and TNNT3 genes.

Molecular Genetics

Sung et al. (2003) sequenced the TNNT3 gene in 47 families with either classic Freeman-Sheldon syndrome (DA2A; 193700) or DA2B, and identified an arg63-to-his mutation (R63H; 600692.0001) in a woman with DA2B and her 2 affected daughters.

In a child diagnosed with distal arthrogryposis type 1, Gurnett et al. (2009) identified heterozygosity for the R63H mutation in the TNNT3 gene. Neither of the unaffected parents carried the mutation.

In all affected members of a Chinese family segregating DA2B2, Zhao et al. (2011) identified heterozygosity for a missense mutation (R63C; 600692.0002) in the TNNT3 gene. The mutation was not found in an unaffected member of the family or in 100 controls. No causative mutations were identified in the TNNI2 gene.

By whole-exome sequencing in affected members of an Indian family segregating DA2B2, Daly et al. (2014) identified heterozygosity for the R63H mutation in the TNNT3 gene, demonstrating that R63 in the TNNT3 gene is a hotspot for mutation causing distal arthrogryposis.

Pathogenesis

In in vitro studies, Robinson et al. (2007) demonstrated that the TNNI2 R174Q (191043.0001) and R156X (191043.0002) mutations and the TNNT3 mutation R63H (600692.0001) resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. In patients, Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA2B.