Background/Objectives: MYH9 gene variants cause MYH9-related disease (MYH9-RD), which is also known as Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, and Sebastian syndrome. MYH9-RD is characterized by sensorineural hearing loss, macrothrombocytopenia, thrombocytopenia, hematuria/proteinuria, glomerulonephritis, cataracts purpura, and mucosal bleeding. In addition, the MYH9 gene is also known to be causative of autosomal dominant non-syndromic hearing loss (DFNA17). MYH9-RD is a relatively rare disorder, and the detailed clinical features and mutational spectra remain unclear. Methods: In this study, we performed next-generation sequencing analysis for 15,684 hearing loss patients and identified MYH9-associated hearing loss patients. Detailed clinical information was collected for these patients and summarized. Results: In this study, we identified 24 patients from 18 families with MYH9-associated hearing loss. We clarified the details of hearing deterioration observed in patients based on collected serial audiogram data. Some cases showed rapid hearing deterioration that worsened by about 50 dB within 5 years. Hearing loss is more likely to progress in patients with myosin head domain variants than in patients with myosin tail domain variants, but hearing loss in each set of patients finally deteriorates to bilateral profound hearing loss. Conclusions: In this study, we were able to clarify the detailed characteristics of MYH9-RD- and DFNA17-related hearing loss in a relatively large number of patients, particularly in some cases that showed rapid and asymmetrical hearing deterioration progressing to bilateral profound hearing loss. Our data will be useful for providing more appropriate treatment and follow-up for MYH9-associated hearing loss. The May-Hegglin anomaly (MHA) is a rare autosomal dominant disease due to MYH9 gene mutation characterized by neutrophils with abnormal cytoplasmic inclusions, large platelets, and variable thrombocytopenia. It is part of myosin heavy chain (MHC) single gene defect group that also includes Fechtner syndrome, Sebastian syndrome, and Epstein syndrome. All of these entities represent hereditary forms of macrothrombocytopenia associated with leukocyte inclusions (Dohle-like bodies), and variable clinical features of sensorineural hearing loss, presenile (early) cataracts, and renal failure.

MYH9 disease is a rare genetic disorder in which there is a mutation in the gene for the non-muscle myosin heavy chain IIA. It initially causes macrothrombocytopenia followed by other clinical manifestations. When the patient reaches adulthood, he can develop chronic kidney failure. Thus, the risk of suffering a hemorrhage, difficulty in repairing and, infections increases in individuals with this disease. In addition, the use of drugs in these patients should be carefully evaluated. An adult patient sought dental care with a complaint associated with a tooth with advanced dental caries. He had severe thrombocytopenia (7000 platelets/mm3 ), hearing loss, and chronic kidney failure. The diagnosis of MYH9 disease was confirmed through genotyping. After clinical examination, extraction was planned. Local and systemic procedures were used to prevent hemorrhage, especially postoperatively. Although the patient had an infection at the surgical wound site and no episode of postoperative bleeding, the repair process occurred normally. The purpose of this article is to report the surgical management of a patient with MYH9 disease.

Myosin heavy chain 9 (MYH9)-related hereditary macrothrombocytopenia is caused by mutation of the MYH9 gene encoding the heavy chain A of non-muscle myosin of class II. We present a case that emphasizes the importance of awareness of rare disorders which could potentially avoid over-investigation, especially in benign conditions. A 72-year-old Caucasian female presented for preoperative evaluation for cataract extraction. She was noted to have thrombocytopenia of 30 K/uL along with elevated creatinine. She denied any acute symptoms except for a prolonged history of easy bruising. Physical exam revealed bruising over the extremities. Upon further questioning, she was previously investigated for thrombocytopenia and had multiple diagnostic as well as therapeutic interventions including bone marrow biopsies, steroids, intravenous immunoglobulins with no improvement. Her family history is consistent with low platelet counts for at least three generations. Peripheral blood smear showed large platelets, normal red and white blood cells with Döhle bodies. Further genetic testing revealed an inherited MYH9 mutation which is autosomal dominant. MYH9-related disorders are characterized by macrothrombocytopenia, often associated with glomerulonephritis, sensorineural deafness, cataracts, and cytoplasmic inclusion bodies within leukocytes. Management is mainly conservative and directed towards the prevention of iron deficiency anemia in young females. The use of desmopressin, in combination with tranexamic acid, is recommended in a perioperative setting. Our case emphasizes the importance of history-taking skills that could potentially minimize further diagnostic or therapeutic interventions in this benign genetic disorder. MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis (i.e., >40% of platelets larger than 3.9 μm in diameter), thrombocytopenia (platelet count <150 x 109/L), and aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes. Most affected individuals develop one or more additional extrahematologic manifestations of the disease over their lifetime, including sensorineural hearing loss, renal disease (manifesting initially as glomerular nephropathy), presenile cataracts, and/or elevation of liver enzymes. The diagnosis of MYH9-related disease is established in a proband with suggestive findings and a heterozygous pathogenic variant in MYH9 identified by molecular genetic testing. Treatment of manifestations: For most active hemorrhages, consider local measures as the first-line treatment; transfusion of platelet concentrates should be used for active hemorrhages that cannot be otherwise managed, life- or organ-threatening hemorrhages, and/or bleeding at critical sites. Whenever necessary, eltrombopag or platelet transfusion should be used to prepare affected individuals for elective surgery. Antifibrinolytic agents and desmopressin are also used for covering hemostatic challenges or treating hemorrhages. Hearing loss, renal complications, and cataracts are managed in a standard fashion; individuals with severe/profound deafness benefit from cochlear implantation. Surveillance: For individuals with moderate or severe thrombocytopenia: at least annual (and in case of bleeding and/or changes in bleeding diathesis) microscopic assessment of platelet count and blood count to screen for anemia. Screening for individuals not currently under treatment for the following: annually (or every 6 months in individuals with high-risk MYH9 genotypes) for nephropathy, and every three years for hearing loss, cataracts, and abnormal liver enzymes. Agents/circumstances to avoid: Drugs that inhibit platelet function or reduce platelet count, and drugs that are ototoxic, nephrotoxic, or hepatotoxic should be used only after assessment of risk-to-benefit ratio. Hazardous noise and activities with high risk of injury should be avoided. Evaluation of relatives at risk: Clarify the status of all first-degree relatives of an affected individual in order to establish appropriate management (including treatment and surveillance) and awareness of agents and circumstances to avoid. Pregnancy management: Deliveries should be managed as they are in women with other forms of thrombocytopenia; in general, a platelet count of ≥50 x 109/L is recommended for delivery. MYH9-RD is inherited in an autosomal dominant manner. Approximately 35% of probands represent simplex cases, most of whom have a documented de novo pathogenic variant. Each child of an individual with MYH9-RD has a 50% chance of inheriting the MYH9 pathogenic variant. Once the MYH9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

The MYH9 gene encodes the heavy chain (MHCII) of non-muscle myosin II A (NMII-A). This is an actin-binding molecular motor essential for development that participates in many crucial cellular processes such as adhesion, cell migration, cytokinesis and polarization, maintenance of cell shape and signal transduction. Several types of mutations in the MYH9 gene cause an array of autosomal dominant disorders, globally known as MYH9-related diseases (MYH9-RD). These include May-Hegglin anomaly (MHA), Epstein syndrome (EPS), Fechtner syndrome (FTS) and Sebastian platelet syndrome (SPS). Although caused by different MYH9 mutations, all patients present macrothrombocytopenia, but may later display other pathologies, including loss of hearing, renal failure and presenile cataracts. The correlation between the molecular and cellular effects of the different mutations and clinical presentation are beginning to be established. In this review, we correlate the defects that MYH9 mutations cause at a molecular and cellular level (for example, deficient filament formation, altered ATPase activity or actin-binding) with the clinical presentation of the syndromes in human patients. We address why these syndromes are tissue restricted, and the existence of possible compensatory mechanisms, including residual activity of mutant NMII-A and/ or the formation of heteropolymers or co-polymers with other NMII isoforms.