Assessment of MYH9-Related Syndromes among a Series of Patients with Constitutional Macrothrombocytopenia (MT).
Authors: Schlegel Nicole , Saposnik Beatrice , Binard Sylvie , Elbaz Sandrine , Fenneteau Odile , Bardet Valerie , Gerard Benedicte , Nurden Paquita ,   French Ref Center for Inherited Plat Disorders
Published: April 2020

Abstract
MYH9-related disorders are autosomal dominant giant platelet syndromes with a wide phenotypic variability known under the following names: May Hegglin Anomaly (MHA), Fechtner Syndrome (FTNS), Epstein Syndrome (EPS), Sebastian Syndrome (SBS) and Alport-like Syndrome with MT. The aim of the study was to identify MYH9-related syndromes in a series of 43 propositi with constitutional MT. In this group, 26 have a characteristic MYH9-syndrome phenotype. The 17 other patients have a constitutional MT of uncertain etiology, 8 of them presenting a partial MYH9 syndrome phenotype. The leukocyte repartition of the Non-Muscle Myosin Heavy Chain IIa (NMMHC-IIA) encoded by the MYH9 gene was explored by May-Grunwald-Giemsa staining of blood smears or by immunofluorescence, while platelets were also examined by electron microscopy (EM). The MYH9 gene was studied by genomic DNA amplification and direct sequencing of the 8 exons in which mutations have been published (Dong, 2005). The results are the following: of the 17 patients with constitutional MT of unknown etiology, no MYH9 mutations were found; in contrast, 24/26 (92.3%) patients with a characteristic MYH9-syndrome phenotype were heterozygous for a MYH9 mutation. Among their 29 family members, 5 were heterozygous for the mutated allele. In 4 families, the mutations were found only in the propositus but not in the parents, suggesting that they might be either de novo mutations or the results of somatic mosaicism, as already published ( Kunishima et al, 2005). Six mutations are novel: F1446L, K1937X, A44P, D1424E in 4 MHA patients, W33C in 1 patient with MHA/SBS, and, interestingly, D1447V was associated with 2 different phenotypes, MHA and FTNS. As already published, the majority of the mutations in the C-terminus of the NMMHC-IIA are associated with a pure hematologic disorder. In contrast, the N-terminus mutations were more generally associated with a more severe phenotype with renal manifestations. However the same mutation can be associated with different phenotypes: S96L with FTNS, EPS and SBS/MHA, D1447V with MHA and FTNS. In addition the R702C mutation, which has been identifed in 2 cases with an identical FTNS phenotype, is associated with 2 different leukocyte NMMHC-IIA distributions. No MYH9 mutation could be detected in 2 patients with FTNS. These results, as a whole, are in agreement with the hypothesis that mutations in other genes than MYH9 might be involved in defining the phenotypes of such syndromes. The genotype of the 17 patients with uncertain etiology remains to be identified. The interest to diagnose MYH9 mutations is:
to avoid misdiagnosis and inadequate therapy for patients with thrombocytopenia (2 patients initially diagnosed as ITP patients underwent splenectomy); to detect as early as possible the risk and occurrence of renal failure, deafness and cataracts (1 patient initially diagnosed as a SBS patient developed a renal failure characteristic of FTNS).
A long-term follow-up of the patients with MYH9 mutations is of a high interest for a better knowledge of the relationship between the mutation and the phenotypic expression.