Bone Marrow, Laboratory, and Clinical Features in Pediatric Patients with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

Background: Germline RUNX1 mutation is associated with an autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), most commonly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but lymphoblastic leukemias are also reported. FPDMM is characterized by thrombocytopenia from an early age associated with abnormal platelet function. Herein we report the bone marrow features, in addition to laboratory and clinical findings, of a large pediatric cohort (N=29) with RUNX1-FPDMM. These data have value in guiding early investigation of neonatal/pediatric thrombocytopenia, and baseline bone marrow interpretation to avoid overdiagnosis of MDS or misdiagnosis of immune-mediated thrombocytopenias.

Design: The clinical, laboratory, bone marrow pathology, and molecular findings of 29 pediatric patients (<18 years) with germline RUNX1 mutation followed by the natural history study at the National Institutes of Health (NIH) (ClinicalTrials.gov Identifier: NCT03854318), were analyzed.

Results: Among the patients, 13 were female and 16 male, in 21 pedigrees, with a median age at bone marrow biopsy of 6 years (range: 17 months to 17 years). Germline RUNX1 mutations were familial in 26 patients and de novo in 3 patients. Easy bruising and propensity for bleeding were common (87%). The median platelet count was 123 x 10⁹/L (range: 38 – 244). Abnormal platelet aggregation assay was present in all 9 patients tested. Abnormal transmission electron microscopy of platelets was found in 14/21 (67%) patients tested; the majority had decreased platelet dense granules, with or without decreased alpha granules. Three patients had normal platelet counts.

Hematologic neoplasm was identified in 4 patients: one with AML with JAK3 and KRAS mutations; one with B-lymphoblastic leukemia with EBF1::PDGFRB; one with T-lymphoblastic leukemia with a complex karyotype; and one with MDS with excess blasts and no detectable acquired genetic alterations. 3/4 of patients with malignancy had hypercellular marrows. Of the remaining patients, 19/25 (76%) had hypocellular bone marrows for age. The majority had normal numbers of megakaryocytes. Dysmegakaryopoiesis with features overlapping with “dysplasia” (small hypolobated, small with convoluted nuclei and minimal cytoplasm, separation of nuclear lobes) in greater than 10% of megakaryocytes was present in 92% of cases. At least one patient was previously misdiagnosed with immune thrombocytopenic purpura (ITP). 18 patients had eosinophilia in bone marrow sections, six of whom had peripheral blood eosinophilia. Flow cytometric analysis of the marrow commonly showed T-cells with inverted CD4:CD8 ratios (17/22) and increased eosinophils (16/22). The one patient with MDS had increased (10%) immunophenotypically abnormal myeloblasts expressing CD7 and CD123. 23/25 patients had targeted NGS: one patient had a pathogenic mutation in BCOR and the remaining had no pathogenic mutations in genes associated with hematologic malignancy; 15 patients had VUSs reported. At least four patients had large RUNX1 deletions that were not detected by conventional NGS. 23 patients tested had a normal karyotype except one female patient with monosomy X in 11/20 metaphases.

Allergy (drug, food and seasonal) was present in 11 patients, and eczema was common. A spectrum of gastrointestinal (GI) symptoms was seen in 11 patients, including constipation, eosinophilic esophagitis, gastroesophageal reflux, and celiac disease. 2 patients were diagnosed with autism, 1 with coarse facies and KDM6B mutation, 1 with brachydactyly syndrome related to PRMT7 mutation, and 1 with non-syndromic hearing loss related to GJB2 mutation.

Conclusion: Germline mutation in RUNX1 should be considered in pediatric patients with thrombocytopenia and/or abnormal platelet function and a hypocellular marrow with or without dysmegakaryopoiesis. Dysmegakaryopoiesis in the setting of RUNX1-FPDMM should not be overinterpreted as pediatric MDS without other supporting criteria such as MDS-defining cytogenetic/molecular abnormalities, multilineage dysplasia, or increased blasts. Patients with large deletions in RUNX1 may be missed on routine NGS testing hence proper germline testing in an experienced laboratory is recommended if suspicion is high. Close monitoring is crucial for early identification of emerging myeloid or lymphoid malignancy.