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 ... 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.
By mutation screening of a proband with multiple synostoses syndrome, Akarsu et al. (1999) identified a heterozygous missense mutation in the GDF5 gene (601146.0013).
In a family with multiple synostoses syndrome, Dawson et al. (2006) demonstrated ... By mutation screening of a proband with multiple synostoses syndrome, Akarsu et al. (1999) identified a heterozygous missense mutation in the GDF5 gene (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.