MYH9-Related Disorders.

Clinical characteristics. MYH9-related disorders (MYH9RD) are characterized by large platelets (i.e., >40% of platelets >3.9 μm in diameter) and thrombocytopenia (platelet count <150 x 109/L), both of which are present from birth. MYH9RD is variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, elevation of liver enzymes, and renal disease manifesting initially as glomerular nephropathy. Before identification of the gene in which mutation is causative, MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. However, the realization that they all are due to heterozygous pathogenic variants in MYH9 and that the clinical findings often worsen throughout life as a result of late onset of non-hematologic manifestations has led the four conditions to be regarded as one disorder, now known as MYH9RD. Diagnosis/testing. The diagnosis is established by the finding of typical MYH9 protein aggregates in neutrophils detected through immunofluorescence analysis of a peripheral blood smear and/or by the identification of a heterozygous pathogenic variant in MYH9. Absence of MYH9 protein aggregates in neutrophils excludes the diagnosis of MYH9RD. Management. Treatment of manifestations: For active hemorrhage, application of local measures, desmopressin (DDAVP), and antifibrinolytic agents are used; platelet transfusion is necessary for: hemorrhages not controlled by the above treatments, life-threatening bleeding, or hemorrhages at critical sites. Hearing loss, renal complications, and cataract are managed in a standard fashion; individuals with severe/profound deafness benefit from cochlear implantation. Prevention of primary manifestations: Platelet transfusion, desmopressin, antifibrinolytic drugs, or eltrombopag can be used to reduce the risk of bleeding prior to surgery or invasive procedures; oral contraceptives may be effective in preventing or treating menorrhagia; regular dental care to prevent gingival bleeding. Surveillance: In those with bleeding episodes, blood count at least every six months to identify anemia. In all affected individuals, annual urinalysis (including 24-hour protein or protein [albumin]/creatinine ratio on a spot urine sample) and measurement of serum concentration of creatinine prior to onset of renal disease; serum liver enzyme measurements and audiometric and ophthalmologic evaluations every three years. Agents/circumstances to avoid: Drugs that inhibit platelet function or blood coagulation; ototoxic, nephrotoxic, and hepatotoxic drugs should be used only after careful assessment of risk versus benefit; hazardous noise and activities with high risk of injury should be avoided. Evaluation of relatives at risk: Screen at-risk newborns with molecular genetic testing if the family-specific pathogenic variant is identified; otherwise assess platelet count and size. Pregnancy management: Deliveries should be managed as they are in women with other forms of thrombocytopenia; a platelet count of ≥50 x 109/L is generally recommended for safe delivery. Genetic counseling. MYH9RD is inherited in an autosomal dominant manner. Approximately 35% of affected individuals represent simplex cases, half of whom have a documented de novo pathogenic variant. Each offspring of an individual with MYH9RD has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.