RUNX1-FPDMM in families with mild thrombocytopenia and platelet function anomalies, a case series

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Introduction RUNX1-Familial Platelet Disorder with associated Myeloid Malignancy (RUNX1-FPDMM) is caused by heterozygous germline variants of RUNX1 [ 1 ]. With the broader application of next generation sequencing (NGS)-based gene panel analysis in individuals presenting with benign hematologic abnormalities such as thrombocytopenia, pathogenic RUNX1 variants were more frequently identified, independent of a hematologic malignancy [ 2 ] [ 3 ]. The main objective of this case series is to describe the functional platelet defects in individuals with pathogenic germline RUNX1 variants. Method We retrospectively analyzed 10 individuals from 6 families with genetically confirmed RUNX1-FPDMM. Platelet counts and function, assessed by light transmission aggregometry and flow cytometry, were evaluated. For genetic analysis NGS-based panel sequencing for inherited platelet disorders, Sanger sequencing, karyotyping, fluorescence in situ hybridization (FISH), and microarray analysis were performed. Results Platelet counts ranged between 40 and 208 G/L. LTA performed for 6 individuals revealed impaired aggregation in response to collagen, ADP, and epinephrine in all tested individuals. FC analysis identified a pronounced granule secretion defects in 3 of 8 tested individuals. Disease-causing RUNX1 variants included whole gene or intragenic deletions, one missense, two novel nonsense variants, and a mosaic RUNX1 loss most probably due to the loss of a derivative chromosome 21. One patient has developed acute myeloid leukemia (AML), and another was diagnosed with RUNX1-FPDMM due to thrombocytopenia onset following T-lymphoblastic lymphoma. Conclusion RUNX1-FPDMM is a challenging disease due to its associated increased risk for hematologic malignancies, mainly myelodysplastic syndrome (MDS) or AML. Increased risk of bleeding due to qualitative platelet function defects, particularly granule secretion abnormalities, must be considered when managing patients, especially prior to invasive procedures. Genetic diagnosis in individuals with thrombocytopenia or functional platelet defects of unknown origin is crucial to offer structured surveillance and patient education. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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