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Background: Inherited macrothrombocytopenias (IMT) are rare and often misdiagnosed as immune thrombocytopenia (ITP) leading to unnecessary treatments including splenectomy. Giant platelets are suggestive of IMT rather than ITP, but are not detected by automated cell counters, which can underestimate mean platelet volume (MPV). Aim(s): MYH9 disorders are characterised by macrothrombocytopenia and leukocyte inclusions which are often missed on blood films. They may also cause nephropathy, sensorineural hearing loss or cataract, with a strong correlation between genotype and phenotype, hence the importance of correct diagnosis. Method(s): We used Next-Generation Sequencing (NGS) to investigate a large cohort (N=121) of patients with lifelong thrombocytopenia not previously diagnosed with IMT. Result(s): Variants of the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA (NMMIIA) were by far the most common with 10 rare benign variants (N=14), 3 variants of uncertain significance (VUS) (N=4) and 7 pathogenic variants (N=15) identified. NMMIIA immunofluorescent (IF) staining on blood film is the current diagnostic gold standard but not widely available. MPV values for subjects with MYH9 variants were not consistently elevated. In contrast, mean platelet diameter (MPD) derived from scanned blood films was clearly increased in IMT compared to ITP. When available, the blood films of patients with pathogenic mutations were evaluated. All demonstrated macrothrombocytopenia; however, inclusion bodies were not easily appreciated. NMMIIA-IF was performed in 4 cases; all demonstrated abnormal NMMIIA clustering, including 2 cases with a VUS. Conclusion(s): From our cohort, MYH9 disorders are the commonest cause of IMT. MPDs are markedly and consistently increased in MYH9 disorders and useful for differential diagnosis. As neutrophil inclusions are often missed on stained blood films, NMMIIA-IF is critical for diagnosis which may also include MYH9 genotyping.

Background: Inherited macrothrombocytopenias (IMT) are rare and often misdiagnosed as immune thrombocytopenia (ITP) leading to unnecessary treatments including splenectomy. Giant platelets are suggestive of IMT rather than ITP, but are not detected by automated cell counters, which can underestimate mean platelet volume (MPV). Aim(s): MYH9 disorders are characterised by macrothrombocytopenia and leukocyte inclusions which are often missed on blood films. They may also cause nephropathy, sensorineural hearing loss or cataract, with a strong correlation between genotype and phenotype, hence the importance of correct diagnosis. Method(s): We used Next-Generation Sequencing (NGS) to investigate a large cohort (N=121) of patients with lifelong thrombocytopenia not previously diagnosed with IMT. Result(s): Variants of the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA (NMMIIA) were by far the most common with 10 rare benign variants (N=14), 3 variants of uncertain significance (VUS) (N=4) and 7 pathogenic variants (N=15) identified. NMMIIA immunofluorescent (IF) staining on blood film is the current diagnostic gold standard but not widely available. MPV values for subjects with MYH9 variants were not consistently elevated. In contrast, mean platelet diameter (MPD) derived from scanned blood films was clearly increased in IMT compared to ITP. When available, the blood films of patients with pathogenic mutations were evaluated. All demonstrated macrothrombocytopenia; however, inclusion bodies were not easily appreciated. NMMIIA-IF was performed in 4 cases; all demonstrated abnormal NMMIIA clustering, including 2 cases with a VUS. Conclusion(s): From our cohort, MYH9 disorders are the commonest cause of IMT. MPDs are markedly and consistently increased in MYH9 disorders and useful for differential diagnosis. As neutrophil inclusions are often missed on stained blood films, NMMIIA-IF is critical for diagnosis which may also include MYH9 genotyping.