Deutsch et al. (2003) studied a Swiss family and an American family with the May-Hegglin anomaly (MHA; 155100)/Fechtner syndrome (FTNS; 153640) and found an asp1424-to-asn (D1424N) mutation in the MYH9 gene. Affected members in both families presented with severe thrombocytopenia, as well as characteristic giant platelets and Dohle-like inclusion bodies on blood smear examination. In the Swiss family, 2 affected sisters developed bilateral cataracts at a young age, whereas the third sister and her son had high-tone sensorineural deafness. Two individuals with thrombocytopenia showed no extrahematologic symptoms. None showed signs of nephritis. In the American family, 4 individuals suffered from sensorineural deafness, but no cataracts or nephritis were observed. Haplotype analysis indicated that in this family the mutation was a de novo event in 1 individual. The same mutation had been previously described in a pedigree of Japanese origin and in 2 pedigrees of American origin, most likely as a result of independent mutation events (Heath et al., 2001; Kunishima et al., 2001). Deutsch et al. (2003) demonstrated that the phenotypes result from a highly unstable MYH9 protein. No abnormalities in protein localization or mRNA stability were observed. They hypothesized that haploinsufficiency of MYH9 results in a failure to properly reorganize the cytoskeleton in megakaryocytes as required for efficient platelet production.
In the proband of the family with macrothrombocytopenia and progressive sensorineural deafness (600208) reported by Brodie et al. (1992), Mhatre et al. (2003) identified a heterozygous 4270G-A transition in exon 30 of the MYH9 gene, resulting in the D1424N substitution in the highly conserved coiled-coil region of the protein.
Seri et al. (2003) identified a heterozygous D1424N mutation in a patient described as having May-Hegglin anomaly and Sebastian syndrome (SBS; 605249). The authors suggested that the 2 disorders are not separate entities, but rather represent the same disease with a continuous clinical spectrum.
