Brachydactyly, Type B2

A number sign (#) is used with this entry because of evidence that brachydactyly type B2 (BDB2) is caused by heterozygous mutation in the noggin gene (NOG; 602991) on chromosome 17q22.

Description

Brachydactyly type B2 (BDB2) is a subtype of brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with distal symphalangism, fusion of carpal/tarsal bones, and partial cutaneous syndactyly (summary by Lehmann et al., 2007).

Clinical Features

Brachydactyly type B (see BDB1, 113000) is characterized by terminal deficiency of fingers and toes and is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2; 602337) in most patients. Lehmann et al. (2007) described a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis. All patients exhibited a distinct clinical phenotype featuring absent/hypoplastic terminal and/or middle phalanges with an amputation-like phenotype similar to that observed in BDB. In most patients, fingers 4 and 5 showed a severe transverse distal reduction, and fingers 2 and 3 were less severely affected. In those fingers in which the distal phalanges were present, abnormal proximal interphalangeal joints were observed, which resulted in the inability to bend the fingers and in missing flexion creases. The most severely affected patients showed a BDB phenotype, with entire aplasia of the distal and middle phalanges of digits 2 through 5. A few patients had a milder phenotype featuring hypoplastic distal phalanges 2 through 5. In those individuals in whom fingers 2 through 5 consisted of 2 or 3 phalanges, a fusion of the proximal interphalangeal joints (SYM1; see 185800) was typically present. Fusion of the distal interphalangeal joints similar to fingers observed in patients with ROR2 mutations associated with a mild phenotype, was also observed.

Lehmann et al. (2007) suggested that the disorder in the kindred reported by Herrmann (1974) and some of the patients reported by Maroteaux et al. (1972) as a form of multiple synostoses syndrome (see 186500) may have been the same as BDB2.

Molecular Genetics

Lehmann et al. (2007) screened the NOG gene for mutation in patients with BDB2 and identified 6 different heterozygous missense mutations (e.g., 602991.0017). In contrast to previously described loss-of-function mutations in NOG, which cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations did not indicate a major loss of function. Rather, they presumably alter the ability of NOG to bind to bone morphogenetic proteins (BMPs) and growth/differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. Lehmann et al. (2007) concluded that the combined features observed in this phenotypic subtype of BDB argued for a functional connection between BMP and ROR2 signaling and supported previous findings of a modulating effect of ROR2 on the BMP receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface.