Arthrogryposis, Distal, Type 7

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 7 (DA7), also known as trismus-pseudocamptodactyly syndrome, is caused by heterozygous mutation in the MYH8 gene (160741) on chromosome 17p13.

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

Description

The trismus-pseudocamptodactyly syndrome is a distal arthrogryposis characterized by an inability to open the mouth fully (trismus) and pseudocamptodactyly in which wrist dorsiflexion, but not volar flexion, produces involuntary flexion contracture of distal and proximal interphalangeal joints. In these patients, trismus complicates dental care, feeding during infancy, and intubation for anesthesia, and the pseudocamptodactyly impairs manual dexterity, with consequent occupational and social disability (summary by Veugelers et al., 2004).

Clinical Features

Hecht and Beals (1969) described father and 4 children (2 sons, 2 daughters) with inability to open the mouth completely with resulting problems in mastication, short finger-flexor tendons such that dorsiflexion of the wrist resulted in camptodactyly, and short leg muscles resulting in foot deformity. The father's mother was probably also affected. Wilson et al. (1969) described the same syndrome in 9 persons in 4 generations. They ascribed the finger peculiarity to shortening of the flexor profundus muscle-tendon unit. De Jong (1971) described a Dutch family with many affected members.

Ter Haar and Van Hoof (1974) examined 24 affected and 19 unaffected members of a large Dutch kindred with trismus and pseudocamptodactyly inherited in an autosomal dominant pattern. A connection between 2 apparently unrelated propositi with trismus and the same rare last name had been sought, and it was established that they had common ancestors 5 generations earlier, at the end of the 18th century. Ter Haar and Van Hoof (1974) found that measuring mouth opening and wrist angles was sufficient to divide family members into affected and unaffected groups and noted that although affected individuals were not under the 10th centile for height in the Dutch population, their height was less than that of unaffected sibs of the same sex.

Mabry et al. (1974) described an extensively affected kindred. Since it was traced to a Dutch girl who migrated to the United States and to Tennessee soon after the American Revolution, the possibility that all cases reported to date are related is strong.

Yamashita and Arnet (1980) reported a 4-generation family with multiple affected members showing variable presentation of hip problems, limited oral opening, micrognathia, and pseudocamptodactyly; only the proband had all of the features of the syndrome.

Robertson et al. (1982) examined 31 of 53 affected members and 77 unaffected members of a 6-generation pedigree with trismus and pseudocamptodactyly originally reported by Yamashita and Arnet (1980). Expressivity was highly variable, but there was no evidence of reduced penetrance. Robertson et al. (1982) noted that foot deformities had been described in all reports, including shortness of the Achilles tendon, hammertoe, talipes equinovarus, and metatarsus varus, and suggested that shortness of flexor muscle-tendon units could account for the mouth, hand, and foot deformities. There was no short stature in this family, and the authors stated that they could not verify any Dutch ancestry. No linkage was found with 16 markers studied.

Hall et al. (1982) reviewed published cases.

Tsukahara et al. (1985) reported 5 affected members of a 3-generation Japanese family. The proband had both trismus and pseudocamptodactyly, whereas the other 4 affected family members had only pseudocamptodactyly, indicating variable expressivity of the syndrome. Dutch ancestry, which had predominated in earlier reports, was considered unlikely.

Chen et al. (1992) reported a 6-year-old boy and his 29-year-old mother who both had inability to open their mouths fully, pseudocamptodactyly, foot deformities, and mild short stature. The mother's brother and his son were also affected but primarily with tightness of the Achilles tendon and muscle cramps. There were at least 3 generations of affected individuals in this kindred. The mother also had abnormal swallowing demonstrated by manometry and marked interphalangeal webbing; noting that the proband reported by Tsukahara et al. (1985) had soft tissue syndactyly of the toes, Chen et al. (1992) suggested that dysphagia and cutaneous syndactyly are part of the clinical spectrum.

Minzer-Conzetti et al. (2008) described a 20-year-old man with genetically confirmed trismus-pseudocamptodactyly, who had mild facial dysmorphism with macrocephaly, facial asymmetry, ptosis and downslanting palpebral features, deep philtrum, and a long chin. He also had widespread joint involvement with congenital hip dysplasia and reduced movement of the left hip, reduced elbow supination, and vertical tali and talipes. Minzer-Conzetti et al. (2008) stated that the findings in this patient broadened the phenotype.

Inheritance

The trismus-pseudocamptodactyly syndrome is an autosomal dominant trait with variable expressivity but high penetrance (summary by Veugelers et al., 2004).

Molecular Genetics

In affected members of 2 families with trismus-pseudocamptodactyly syndrome (Mabry et al., 1974; Lefaivre and Aitchison, 2003), Veugelers et al. (2004) identified an arg674-to-gln mutation in the MYH8 gene (R674Q; 160741.0001). The R674Q mutation was also identified in affected members of a large Caucasian Belgian family with Carney complex variant (608837), which is associated with trismus-pseudocamptodactyly syndrome.

Toydemir et al. (2006) identified the R674Q mutation in the MYH8 gene in all affected members of 4 families with trismus-pseudocamptodactyly syndrome, including descendants of the Dutch family reported by Ter Haar and Van Hoof (1974) and 3 kindreds ascertained in the United States, 1 originally reported by Chen et al. (1992). Analysis of haplotype sharing revealed that while each of the U.S. pedigrees shared the same MYH8 haplotype, this haplotype was not shared by the Dutch kindred. None of the affected individuals had multiple hyperpigmented macules or cardiac myxomas, and the R674Q mutation was not found in 49 unrelated cases of Carney complex who were negative for mutation in the PRKAR1A gene (188830). Toydemir et al. (2006) concluded that Dutch and U.S. pedigrees with trismus-pseudocamptodactyly syndrome do not share a founder mutation, and that R674Q rarely, if ever, causes Carney complex.

In 2 brothers with trismus-pseudocamptodactyly, Bonapace et al. (2010) identified heterozygosity for the R674Q mutation in the MYH8 gene. The mutation was not found in their unaffected parents or sister; the authors stated that their findings were most consistent with germline mosaicism, although a recurrent de novo mutation could not be excluded. Both patients had reduced oral opening and camptodactyly of the hands with flexion of the fingers upon extension of the wrist. They also had reduced bilateral hip flexion and flexion of the toes upon foot dorsiflexion.

Nomenclature

In a revised and extended classification scheme of the distal arthrogryposes, Bamshad et al. (1996) referred to this disorder as distal arthrogryposis type 7 (DA7).