Symphalangism, Proximal, 1a

A number sign (#) is used with this entry because of evidence that this form of proximal symphalangism (SYM1A) is caused by heterozygous mutation in the NOG gene (602991) on chromosome 17q22.

Description

Proximal symphalangism-1A (SYM1A) is an autosomal dominant disorder characterized by ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and, in some cases, conductive deafness (Strasburger et al., 1965).

Genetic Heterogeneity of Proximal Symphalangism

Another form of proximal symphalangism (SYM1B; 615298) is caused by mutation in the GDF5 gene (601146).

Clinical Features

Cushing (1916) described a large American family in which many members had ankylosis of the proximal interphalangeal joints and assigned the designation symphalangism to the disorder. Fusion of carpal and tarsal bones is also a feature (see 186400, 186750).

In the family reported by Vesell (1960), mother and daughter had also conductive deafness. The mother apparently had a new mutation.

Strasburger et al. (1965) followed up on family reported by Cushing (1916). Conductive deafness with early onset occurred sufficiently often in affected members of this large kindred to suggest that it is an effect of the same gene. Cremers et al. (1985) reemphasized the association of deafness, as pointed out by Gorlin et al. (1970), Spoendlin (1974), Baschek (1978), and others. Cremers et al. (1985) also published the first report on the histology of the stapes.

Wildervanck et al. (1967) observed 2 accessory bones in the feet of multiple affected persons in 1 family.

Attempts at surgical creation of interphalangeal joints had not been successful (Smith and Lipke, 1979).

It is not certain whether the family reported by Kassner et al. (1976) had Cushing symphalangism or a distinct disorder. The changes in the proximal phalangeal joints were typical but one member also had metacarpophalangeal synostosis. Others had radial head dislocation and radiohumeral synostosis, which have been reported. Proximal symphalangism occurs with diastrophic dysplasia (222600). Symphalangism also occurs among the multiple digital anomalies of brachydactyly type C (BDC; 113100).

Spoendlin (1974) described a family in which members over several generations in a dominant, possibly autosomal, pedigree pattern showed fusion of tarsal and carpal bones. Several of the affected female members of the family also had deafness due to congenital ankylosis of the stapes. The family was of Italian origin. The foot and hand deformities were more severe in females. No mention of short stature was made. See tarsal-carpal coalition syndrome (186570).

In a child with symphalangism reported by Stephan (2006), complete fixation of all the ossicular articulations was found at surgery for correction of her deafness, and total reconstruction of the ossicular chain was necessary.

Mapping

In the historic kindred reported by Cushing (1916) and followed up by Strasburger et al. (1965), Polymeropoulos et al. (1995) did a genomewide linkage analysis using microsatellite repeat polymorphic DNA markers to establish linkage of proximal symphalangism to markers on 17q21-q22.

Molecular Genetics

Gong et al. (1999) demonstrated 5 dominant NOG mutations in 5 unrelated families segregating proximal symphalangism and a de novo mutation in a patient with unaffected parents. They also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; 186500); thus, SYM1 and SYNS1, both of which have multiple joint fusion as their principal feature, are allelic disorders.

Gong et al. (1999) found that the mutation in the historic family with symphalangism studied by Cushing (1916), family 1 of Gong et al. (1999), was a tyr222-to-cys change in Noggin (602991.0001).

Takahashi et al. (2001) identified 3 novel mutations in Japanese patients: a cys184-to-tyr mutation (602991.0009) in a sporadic case of symphalangism, a leu129-to-ter mutation (602991.0010) in a familial case of symphalangism, and a 1-bp frameshift mutation (602991.0011) in a family with multiple synostoses syndrome.

History

Ankylosis of the proximal interphalangeal joints was thought to have the distinction of being traced through more generations than almost any other, having been identified in the first Earl of Shrewsbury who lived in the 15th century (Drinkwater, 1917). After a reexamination of the evidence, however, Elkington and Huntsman (1967) concluded that the Earl probably did not have symphalangism and that the mutation is of more recent origin in that kindred.