[May-Hegglin anomaly--from genome research to clinical laboratory]

The autosomal dominant macrothrombocytopenia with leukocyte inclusions, May-Hegglin anomaly (MHA), Sebastian syndrome (SBS) and Fechtner syndrome (FTNS), are rare disorders characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like cytoplasmic inclusions in granulocytes. Epstein syndrome (EPS) is another autosomal dominant macrothrombocytopenia associated with Alport syndrome but without leukocyte inclusions. We previously mapped the locus for MHA on chromosome 22q12.3-q13.2 by genome-wide linkage analysis and found that MYH9, the gene for the nonmuscle myosin heavy chain-A (NMMHCA), is responsible for the disorder, by positional cloning. Mutations of MYH9 have also been found in SBS, FTNS, and EPS; the term "MYH9 disorders" has been proposed, but clear phenotype-genotype relationships were not found. We developed an immunofluorescence technique for conventional air-dried peripheral blood smears and studied the neutrophil NMMHCA localization in MYH9 disorders. Abnormal subcellular localization of NMMHCA was observed in every neutrophil from individuals with MYH9 mutations and the localization pattern was classified into three groups according to the number, size, and shape of the NMMHCA-positive granules. Patients without neutrophil inclusions on conventional May-Grünwald-Giemsa-stained blood smears but with abnormal NMMHCA localization on immunofluorescence analysis had MYH9 mutations. In contrast, patients with EPS and isolated macrothrombocytopenia with normal NMMHCA localization had no MYH9 mutations. Immunofluorescence analysis of neutrophil NMMHCA is useful as a novel screening test for the differential diagnosis of macrothrombocytopenia and clear hematopathological classification of MYH9 disorders.