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

Hannah Glonnegger^1*Doris Boeckelmann¹Rebekka Wiedenhöfer¹Wolf-Achim Hassenpflug²Tim Ripperger³Dirk Lebrecht¹Ralf Knöfler⁴Oliver Tiebel⁵Udo Koehler⁶Claudia Wehr⁷Harry Sirb⁸Monika Sparber-Sauer^10,9Katrin Reinsberger¹Ayami Yoshimi¹Brigitte Strahm¹Barbara Zieger¹

• ¹Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children’s Hospital, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany, Freiburg, Germany
• ²Pediatric Hematology and Oncology, University Hospital Eppendorf, Hamburg, Germany., Hamburg, Germany
• ³Department of Human Genetics, Hannover Medical School, Hannover, Germany, Hannover, Germany
• ⁴Department of Pediatric Hemostaseology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Children's Hospital, Dresden, Sachsen, Germany., Dresden, Germany
• ⁵Department of Pediatric Hemostaseology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Children's Hospital, Dresden, Sachsen, Germany, Dresden, Germany
• ⁶Medical Genetic Center (MGZ), Munich, Bavaria, Germany
• ⁷Department of Medicine I/ Hematology, Oncology and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Freiburg, Germany
• ⁸MVZ Meerane, Meerane, Germany
• ⁹Department of Pediatric Hematology and Oncology, University Children´s Hospital Tuebingen, Tuebingen, Germany, Tübingen, Germany
• ¹⁰Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin (Olgahospital), Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Klinikum der Landeshauptstadt Stuttgart, Stuttgart, Germany

Background: RUNX1-Familial Platelet Disorder with associated Myeloid Malignancy (RUNX1-FPDMM) is caused by heterozygous germline variants of RUNX1. 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. Objective: To describe the clinical and genetic characteristics of individuals with pathogenic germline RUNX1 variants, with a particular focus on platelet function and diagnostic challenges. Methods: 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 not previously reported 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. Genetic diagnosis in individuals with thrombocytopenia or functional platelet defects of unknown origin is crucial to offer structured surveillance and patient education. 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.