Arthrogryposis, Distal, Type 2b1

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 2B1 (DA2B1) is caused by heterozygous mutation in the TNNI2 gene (191043) on chromosome 11p15.

Description

Distal arthrogryposis is a clinically and genetically heterogeneous disorder characterized by clenched fist, overlapping fingers, camptodactyly, ulnar deviation, and positional foot deformities from birth. It is a disorder of primary limb malformation without primary neurologic or muscle disease. DA1 is not associated with other abnormalities, whereas other forms of DA have additional phenotypic features (Bamshad et al., 1996). The congenital contractures in DA2B (Sheldon-Hall syndrome, SHS) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by Bamshad et al., 2009).

For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).

Clinical Features

Krakowiak et al. (1997) reported a family in which 21 individuals in 5 generations were affected with a disorder, designated DA2B, with features intermediate between DA1 and DA2A (193700). Clinical features included a triangular face, downslanting palpebral fissures, attached earlobes, prominent nasolabial folds, small mouth, small mandible, arched palate, cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. The shape of the mouth and chin was different from that of DA2A (also known as Freeman-Sheldon syndrome; FSS); no members of the family had feeding difficulties at birth or underwent surgical revision of the mouth, which are nearly universal features of children with FSS.

Krakowiak et al. (1998) reported 3 additional families with DA2B characterized by camptodactyly, ulnar deviation, vertical talus, talipes equinovarus, small mouth, prominent nasolabial folds, small chin, and triangular face. The authors reviewed the findings in 3 families reported by Moore and Weaver (1989), Kawira and Bender (1985), and the second case of FSS reported by Freeman and Sheldon (1938), and concluded that they also had DA2B. In 3 and possibly 4 generations of a family, Moore and Weaver (1989) observed distal arthrogryposis associated with facial asymmetry, hypertelorism, downslanting palpebral fissures, high nasal bridge, malar hypoplasia, micrognathia, highly arched palate, notched chin, and posteriorly angulated ears.

Reiss and Sheffield (1986) described a family in which 3 sisters and a son and daughter of one of the sisters had various features of type II arthrogryposis: cleft lip and palate, micrognathia, ptosis, webbed neck, kyphoscoliosis, and short stature. All of those with distal arthrogryposis had trismus.

Kimber et al. (2006) reported a 3-generation Swedish family in which 5 members had congenital distal arthrogryposis. All had congenital contractures in the hands and feet, and most had congenital hip dislocation. Four of the patients were adults and had other features, including proximal joint contractures, short neck muscles, thin calves, and camptodactyly. The adults also had mildly increased serum creatine kinase without clinical muscle weakness. Muscle biopsies showed myopathic changes mainly affecting type 2 fibers. Some of the phenotypic traits in this family were similar to those classically found in DA2B, such as narrow palpebral fissures and limited mouth opening, but height was normal and facial involvement was mild. Genetic analysis identified a heterozygous mutation in the TNNI2 gene (191043.0004), confirming the diagnosis of DA2B.

Mapping

In a large family with DA2B, Krakowiak et al. (1997) mapped the disease locus to chromosome 11p15.5. A positive lod score of 5.31 at theta = 0.0 was observed with marker D11S922, and recombinants localized the gene to a region of approximately 3.5 to 6.5 cM between the tyrosine hydroxylase gene (TH; 191290) and the telomere. Analysis of additional unrelated families improved the lod score to 6.45 at theta = 0.0 and suggested linkage homogeneity for DA2B.

Molecular Genetics

Sung et al. (2003) determined that DA2B is caused by mutations in the TNNI2 gene (191043.0001-191043.0002).

In 9 affected members of a large Chinese family with DA2B, Jiang et al. (2006) identified a heterozygous mutation in the TNNI2 gene (191043.0003). The family had a total of 32 affected individuals spanning 7 generations. There was marked phenotypic variability, ranging from mild camptodactyly only to severe hand and foot involvement with facial anomalies.

In affected members of a family with DA2B, Shrimpton and Hoo (2006) identified 3-bp deletion in the TNNI2 gene (191043.0005).

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.

Nomenclature

DA2B is distinct from the disorder formerly referred to as DAIIB by Hall et al. (1982). DAIIB was renamed DA5 (108145) in the revised classification scheme of Bamshad et al. (1996).

History

Klemp and Hall (1995) described a Maori family in which dominant distal arthrogryposis showed marked variability of expression. The index case was a Maori bushman who presented with severe congenital spinal stenosis and manifestations of distal arthrogryposis. One son and 2 sisters, as well as 2 sons of one sister and 2 daughters of the second, were definitely affected. Two affected members had severe hand and foot involvement as well as craniofacial changes compatible with a diagnosis of Freeman-Sheldon syndrome (193700).