Purpose: The autosomal dominant macrothrombocytopenia syndromes are a group of rare disorders, characterized by triads of giant platelets, thrombocytopenia, and Dohle body-like leukocyte inclusions. MYH9, a gene encoding the nonmuscle myosin heavy cha...
Purpose: The autosomal dominant macrothrombocytopenia syndromes are a group of rare disorders, characterized by triads of giant platelets, thrombocytopenia, and Dohle body-like leukocyte inclusions. MYH9, a gene encoding the nonmuscle myosin heavy chain-ⅡA, was known to be a causative gene. This study was aimed to identify Korean patients with giant platelet syndromes and define clinical findings and molecular characteristics on them.
Materials and Methods: After taking meticulous family history, peripheral blood smear was examined for platelet size and number, and the presence of leukocyte inclusions. Mutation of MYH9 was studied from mononuclear cells from peripheral blood by direct sequencing of previously known 8 exons (exon 1, 10, 16, 25, 26, 30, 38, 40) after PCR amplification of genomic DNA.
Results: Twenty patients with these syndromes from 5 unrelated families were identified (4 of 5 studied from Family Ⅰ; 2 of 4 from Family Ⅱ; 6 of 9 from Family Ⅲ; 6 of 14 from Family IV; 2 of 4 from Family V). The inheritance patterns were autosomal dominant in all families. Giant platelets, greater than red cells on blood smear, were found to be 3.1% (range, 1-11%), and large platelets, greater than half of red cells, being 18.1% (range, 1-40%). The median platelet count was 61,000/μL (range, 4,000 - 280,000/μL). Do¨hle-like inclusion bodies were found in Family Ⅰ, Ⅱ, and Ⅲ. Father in Family V had suffered from chronic renal failure and hearing impairment, while father in Family IV had hearing impairment and proteinuria. Among five families, two families were found to have previously reported mutations. Family I had Arg1933Ter in exon 40, located in tail portion of myosin, while Family IV had Lys373Asn in exon 10, located in the proximal portion of myosin head. The mutations were placed in highly conserved amino acids in mammals and xenopus, and even in human paralog. The mutations are found only in the affected patients, but not in the normal siblings or unrelated families.
Conclusion: In this study, the author identified several families with autosomal dominant giant platelet syndromes by through history taking and meticulous search of peripheral blood smears. Two families were identified to have known MYH9 mutations, Arg1933Ter and Lys373Asn. Search for unknown mutations in the remaining families as well as study of protein structural and functional alteration seems to be necessary for the further delineation of these rare genetic disorders.