エプスタイン症候群

BACKGROUND: Accurate diagnosis of MYH9-related disease (MYH9-RD) is frequently impeded by a reactive process. Clinical suspicion typically arises only following immune thrombocytopenia (ITP) treatment failure, family history identification, or emergence of extra-hematological manifestations. However, de novo variants or delayed syndromic onset may obscure these indicators, leading to misdiagnosis as ITP and unnecessary immunosuppression. OBJECTIVES: This study prospectively evaluated a multiparameter platelet size trigger as an accessible screening entry point for early MYH9-RD recognition, independent of a family history, treatment refractoriness, or syndromic features. METHODS: Consecutive patients with persistent, unexplained thrombocytopenia were screened using predefined thresholds for mean platelet volume (≥ 14.55 fL), platelet-large cell ratio (≥ 58%), or manual identification of giant platelets when automated values were unobtainable. Individuals meeting any criterion underwent targeted high-throughput sequencing for inherited thrombocytopenia genes (including MYH9), with subsequent confirmation by immunofluorescence. RESULTS: Among 42 screened patients, 7 (16.7%) were diagnosed with MYH9-RD, including 2 with novel MYH9 variants in the coiled-coil domain, supported by blood smear findings (including giant platelets and neutrophil inclusions), bioinformatics assessment, and structural-modeling data. All 7 patients were diagnosed within 1 month following the screening, avoiding unnecessary ITP-directed therapy. The composite trigger (mean platelet volume, platelet-large cell ratio, and smear-based morphology) provided higher diagnostic yield than any single parameter alone. CONCLUSION: This streamlined 3-step strategy provides a practical, potentially resource-conscious pathway for early MYH9-RD diagnosis, 1 better aligned with current clinical practice in China than the existing diagnostic paradigms.

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.

BACKGROUND: MYH9-related disease (MYH9-RD) is an autosomal dominant disorder characterized by thrombocytopenia, giant platelets, and variable systemic manifestations including nephropathy. While most pathogenic MYH9 variants are missense substitutions causing dominant-negative effects, the pathogenic potential of non-missense variants, particularly those affecting splicing, remains unclear. METHODS: MYH9 (NM_002473.6) variants registered as "DM" (disease-causing variant) or "DM?" (possible disease-causing variant) in HGMD® were curated. After excluding missense and non-analyzable variants, ten intronic or single-base deletions were selected. Splicing effects were assessed by minigene assays in HEK293T cells and compared with SpliceAI predictions. Clinical information was reviewed. RESULTS: Aberrant splicing was confirmed in three variants: c.3838-2A>G, c.5765+2T>A, and c.5765+2T>G. The c.3838-2A>G variant caused in-frame skipping of exon 29, non-truncating variant, whereas the latter two induced inclusion of a cryptic 50-bp exon with premature termination codons in the final exon that can escape nonsense-mediated decay. These spliceogenic variants were associated with MYH9-RD phenotypes producing abnormal proteins that likely exert dominant-negative effects. The remaining seven variants showed no splicing abnormalities and were reported in non-MYH9-RD contexts, suggesting limited evidence for pathogenicity. SpliceAI predictions were concordant with experimental results. CONCLUSIONS: This study provides systematic evidence that some aberrant splicing MYH9 variants can lead to MYH9-RD with dominant-negative pathogenesis. Conversely, several variants previously annotated as "DM?" showed no functional or clinical relevance, arguing against a pathogenic role and supporting their consideration as likely benign or uncertain significance. Integrating in silico prediction with experimental validation improves variant interpretation and has implications for the clinical management of MYH9-RD.

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.