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UNLABELLED: MYH9-related disorders (MYH9-RD) are rare autosomal dominant disorder caused by pathogenic variants in MYH9 gene. They are characterized by macrothrombocytopenia, variably accompanied by neutrophilic inclusions, nephropathy, hearing loss, or cataracts. Due to mild symptoms and lack of awareness of the extrahematological manifestations, many cases may remain undiagnosed or misdiagnosed as immune thrombocytopenia (ITP). We report the first Indian family with three affected members with a heterozygous missense variant MYH9:c.5521G > A (p.Glu1841Lys) on targeted next generation sequencing. The index case, a 10-month-old male, was incidentally detected thrombocytopenia and giant platelets but no bleeding manifestations. Peripheral smear revealed inclusion bodies in neutrophils. His father and paternal grandfather also had macrothrombocytopenia with inclusion bodies. The father had undergone a nephrectomy for hydronephrosis, while the grandfather exhibited late-onset proteinuria and coronary artery disease. Literature review revealed this variant in 34 studies with 71 families and 133 affected individuals worldwide, who had macrothrombocytopenia and inclusion bodies but variable bleeding and extrahematological features. We describe the first Indian family with MYH9:c.5521G > A (p.Glu1841Lys) hotspot variant. The family had the characteristic macrothrombocytopenia and neutrophil inclusions. MYH9-RD should be considered in patients with macrothrombocytopenia, even without bleeding. Early molecular diagnosis is crucial for appropriate management and to avoid misclassification as ITP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12288-025-02185-7.

MYH9-related disease (MYH9-RD) is an autosomal dominant disorder caused by mutations in the MYH9 gene, characterized by macrothrombocytopenia, neutrophil inclusions, and other features. Due to its low incidence and nonspecific clinical manifestations, many patients are misdiagnosed or undiagnosed. Clinical management often includes platelet transfusion, pro-hemostatic or antifibrinolytic agents, avoidance of antiplatelet drugs, and hemorrhage prevention. Hematopoietic stem cell transplantation may be a treatment option for severe cases. For a long time, platelet transfusion has been the most commonly used treatment for preventing or managing bleeding in MYH9-RD patients, but it is associated with various adverse reactions and clinical limitations. In recent years, thrombopoietin receptor agonists (TPO-RA), as a novel therapeutic class, have been increasingly used in MYH9-RD and have demonstrated promising efficacy in increasing platelet counts and reducing bleeding symptoms. However, their mechanisms of action, clinical effectiveness, and safety profiles require further investigation. This article aims to review the application of TPO-RA in MYH9-RD, analyze their mechanisms, clinical outcomes, and future research directions, thereby providing insights and references for further studies in this field.

OBJECTIVE: To comparatively analyze platelet membrane glycoprotein expression profiles and antiplatelet-specific antibody levels in patients with MYH9-related disorders (MYH9-RD) versus immune thrombocytopenia (ITP), and to evaluate their potential clinical significance. METHODS: From July 2017 to June 2025, a total of 20 patients with MYH9-RD, 20 patients with ITP, and 20 healthy controls were enrolled. Platelet membrane glycoprotein expression of CD41 (GPIIb), CD42a (GPIX), CD42b (GPIb), CD61 (GPIIIa), and CD62P (GMP140), platelet-leukocyte aggregation ratios, and antiplatelet-specific antibody levels were analyzed using flow cytometry. Inter-group differences in platelet membrane glycoprotein expression were compared using the Kruskal-Wallis test. RESULTS: The MYH9-RD cohort demonstrated significantly higher median fluorescence intensity of platelet membrane glycoproteins (CD41, CD42a, CD42b, CD61, and CD62P) compared to ITP and healthy control groups (P < 0.05). Compared to ITP patients, the MYH9-RD group demonstrated significantly higher platelet-leukocyte (P = 0.020) and platelet-granulocyte aggregation ratios (P = 0.004), as quantified by flow cytometry. The identified MYH9-RD mutations were localized to both N-terminal and C-terminal regions of the NMMHC-IIA protein domain. However, no statistically significant differences in platelet membrane glycoprotein expression profiles were observed between the two groups (P > 0.05). Significant intergroup differences (P < 0.05) were observed in the detection rates of antiplatelet antibodies targeting GPIX, GPIb, GPIIb, GPIIIa, and P-selectin (GMP140) among MYH9-RD, ITP, and healthy control groups. The total antibody positivity rate in MYH9-RD patients was intermediate-significantly higher than in healthy controls (P = 0.0317) but lower than in ITP patients (P = 0.0017). CONCLUSION: Significant differences in platelet membrane glycoprotein expression profiles and antiplatelet-specific antibody levels distinguish MYH9-related disorders (MYH9-RD) from immune thrombocytopenia (ITP). These findings have important clinical implications, providing potential biomarkers for the differential diagnosis of MYH9-RD.

BACKGROUND: May-Hegglin anomaly, a rare autosomal dominant disorder caused by MYH9 mutations, is characterized by the classic "triad" of thrombocytopenia, giant platelets, and granulocyte cytoplasmic inclusion bodies; some patients also present non-hematological symptoms. RESULTS: We reported a family of MYH9-related disease. The proband had microscopic hematuria, proteinuria, and thrombocytopenia on physical examination; blood smear re-examination showed giant platelets and Döhle-like bodies. His medical history included childhood epistaxis; his father had unexplained thrombocytopenia/proteinuria, and his younger brother had epistaxis/purpura/thrombocytopenia. Whole-exome sequencing (validated by Sanger sequencing) confirmed the diagnosis. CONCLUSIONS: Diagnosis of MYH9-related diseases depends on combined laboratory morphology and molecular biology. Routine blood tests and smear microscopy (identifying abnormal giant platelets/Döhle-like bodies) provide initial screening clues, while gene sequencing enables accurate diagnosis and pathogenesis clarification, forming a complete screening-to-confirmation diagnostic pathway.