Identification of a novel MYH9 mutation in a patient with May‐Hegglin anomaly

To the Editor: May-Hegglin anomaly (MHA) is characterized by a triad of giant platelets, thrombocytopenia, and Döhle body-like cytoplasmic inclusions in granulocytes [1]. In addition to MHA, Sebastian, Fechtner, and Epstein syndromes are also included in the inherited macrothrombocytopenias, and they are caused by mutations in the MYH9 gene, which encodes the non-muscle myosin heavy chain-A (NMMHCA) [2–4]. All the disorders have been proposed to be renamed as MYH9 disorders, and MYH9 disorders have been increasingly reported [5,6]. Here we described a sporadic case of MHA with a novel MYH9 mutation. A 1-year-old male was referred to Toyama University hospital for evaluation of thrombocytopenia. He was born weighing 1,710 grams at 35 weeks’ gestation, and laboratory test revealed a platelet count of 20,000/ml. Although the patient had no bleeding tendency, he showed persistent thrombocytopenia (20,000–63,000/ml). His peripheral blood smears with May–Grünwald–Giemsa (MGG) staining, which disclosed giant platelets and leukocyte inclusion bodies (Fig. 1A). Although the patient had no family history of thrombocytopenia, the diagnosis of MHA was considered. Thus, an immunofluorescence analysis of neutrophil NMMHCA and mutational analysis of MYH9 gene were performed, as described previously [4,7]. Abnormal subcellular localization of NMMHCA was observed in every neutrophil from the patient (Fig. 1B). His family members demonstrated normal diffuse homogeneous distribution of NMMHCA throughout the cytoplasm (data not shown). Genomic DNA of the patient revealed a heterozygous singlebase substitution (C to G) at nucleotide 2116, indicated Gln (Q) to Glu (E) at residue 706 (Fig. 1C) creating a missense mutation. This substitution was not observed in normal individuals and other patients with MYH9 disorders. The diagnosis of MHA has been clinically made by the presence of macrothrombocytopenia and inclusion bodies in neutrophils [1]. It is thus important to carefully examine the peripheral blood smears using MGG staining. In addition, the faint appearance of inclusion bodies occasionally hampers proper recognition. MYH9 disorders show autosomal dominant traits, and family histories of thrombocytopenia are diagnostically helpful. However, approximately 20% of patients, as is the case with the present patient, are considered to be de novo. A few cases with MYH9 disorders are associated with macrothrombocytopenia without inclusion bodies. In the present study, we identified a novel MYH9 mutation in a sporadic MHA patient. The Q706E substitution affects codon 706, which is highly conserved among species, suggesting the presence of a strong functional or structural constraint for this residue. Adjacent to the Q706 residue, the R702C, R702H, and R705H mutations were described in other MYH9 disorders [6,8,9]. The R702 and R705 residues are located within or adjacent to the ‘‘SH1-SH2’’ helix of the globular-head domain. The SH1 and SH2 helices may play a pivotal role in the conformational changes that occur in the myosin head during force generation coupled to ATP hydrolysis. As well as R702C, R702H, and R705H mutations, Q706E mutation may cause an altered conformation of SH1 helix that affects its flexibilities and movement, thereby disrupting the function of NMMHCA. To confirm the diagnosis of MYH9 disorders, an immunofluorescence analysis of NMMHCA and mutational analysis of MYH9 gene should be performed even if the patients have no family histories of thrombocytopenia.