Multiple Synostoses Syndrome 2

A number sign (#) is used with this entry because of evidence that multiple synostoses syndrome-2 (SYNS2) is caused by heterozygous mutation in the GDF5 gene (601146) on chromosome 20q11.

For a general phenotypic description and a discussion of genetic heterogeneity of multiple synostoses syndrome, see SYNS1 (186500).

Clinical Features

Akarsu et al. (1999) described a large Iranian family with tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism inherited in an autosomal dominant pattern. These findings were considered consistent with the syndrome described by Pearlman (see 186400) but showed considerable overlap with other multiple synostosis syndromes. They referred to the phenotype as multiple synostosis type 2 (SYNS2).

Dawson et al. (2006) described a large 4-generation Ashkenazi Jewish family with multiple synostoses syndrome. Phenotypic findings in the family included a broad hemicylindrical nose, progressive symphalangism, and carpal, tarsal, and vertebral fusion. There was phenotypic variability among family members in the extent of joint fusions and in the presence or absence of equinovarus.

Mapping

Akarsu et al. (1999) mapped the multiple synostoses syndrome in an Iranian family to markers on chromosome 20q11.2, with the highest lod score observed at D20S200 (Z = 13.58, theta = 0.0).

In a 4-generation Ashkenazi Jewish family with multiple synostoses syndrome in which linkage to 17q21-q22 was excluded, Dawson et al. (2006) found linkage of the phenotype to marker D20S195, 2.2 Mb centromeric to the GDF5 gene (601146).

Molecular Genetics

By mutation screening of a proband with multiple synostoses syndrome, Akarsu et al. (1999) identified a heterozygous missense mutation in the GDF5 gene (S475N; 601146.0013).

In a family with multiple synostoses syndrome, Dawson et al. (2006) demonstrated that affected individuals were heterozygous for a missense mutation that predicted an R438L substitution in the GDF5 protein (601146.0011). Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C (113100), the protein encoded by the multiple synostoses syndrome allele was secreted as a mature GDF5 dimer.