A novel germline RUNX1 mutation with co-occurrence of somatic alterations in a case of myeloid neoplasm with familial thrombocytopenia: first report from India

Myeloid neoplasm with germline predisposition is a distinct entity in the WHO 2017 classification of tumors of hematopoietic and lymphoid tissues [1]. Among the three sub-categories in this group, one is myeloid neoplasms with germline predisposition and preexisting platelet disorders and is attributed to germline pathogenic mutations in RUNX1, ANKRD26, and ETV6 genes. Among these three genes, RUNX1 mutations have been most well studied. Familial platelet disorder with associated myeloid malignancy (FPDMM) is an autosomal dominant disorder and is caused by a heterozygous mutation in RUNX1 (MIM # 601399). Around 70 families of having FPDMM with inherited RUNX1 mutation have been reported in the literature [2], however, there are no reports from the Indian subcontinent. RUNX1 codes for Runt-related transcription factor 1 (RUNX1) which is essential for normal myeloid hematopoiesis [3]. Germline RUNX1 mutation confers a 30–40% lifetime risk of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) [4,5]. Translocations in RUNX1 gene has been found to be the most frequent recurrent genetic abnormality seen in cases of AML and in such sporadic cases, these mutations is a secondary event while in myeloid neoplasm with germline predisposition, RUNX1 mutation is the initiating event [6]. Variable penetrance of the inherited gene and acquisition of additional genetic abnormalities are postulated to explain the heterogeneity in clinical phenotypes [4]. RUNX1 protein has a Runt homology domain (RHD) towards N-terminal and a transactivating domain (TAD) towards C-terminal [7]. RHD interacts with core binding factor beta (CBFb) and this happens to be a critical and the commonest site for mutation [2,8]. TAD plays a role in transactivation of RHD-CBFb complex for its functioning [4]. We present a 29-year-old female of Indian ethnicity who presented with fever, fatigue, and moderate pallor for 6 weeks. However, there was no hepatosplenomegaly. Complete blood counts showed pancytopenia (hemoglobin – 64gm/L, total leukocyte count (TLC) – 1.3 10/L and platelets – 98 10/L) with no circulating blasts. Bone marrow (BM) examination revealed hypercellular marrow with 82% myeloperoxidase negative blasts. There were no features of dyshemopoiesis. On immunophenotyping these blasts showed CD13, CD33, CD117, CD34, HLADR, CD38, CD19, and TdT expression and were negative for CD10, CD20, CD3, CD4, CD8, CD5, cytoplasmic CD79a, cytoplasmic CD22, and MPO. A diagnosis of minimally differentiated AML with aberrant CD19 expression was made. BM cytogenetics was 46,XX and molecular testing for RUNX1-RUNX1T1, PML-RARA, CBFB-MYH11 were negative by reverse transcription polymerase chain reaction (PCR). Allele-specific PCR for NPM1, FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD), and CEBPA mutations were negative. Patient received 7þ 3 induction chemotherapy (cytarabine 200mg/m and daunorubicin 60mg/m). Post-induction BM examination showed 68% blasts. She was planned for salvage chemotherapy followed by allogeneic hematopoietic stem cell transplant (HSCT). She attained complete remission (CR) with residual thrombocytopenia with FLAG-M (fludarabine, cytarabine, GCSF, and mitoxantrone) regime. Her parents were screened as potential donors for haploidentical transplant. Sister was pregnant at that time and HLA typing was not done. Mother was detected to have thrombocytopenia with a platelet count of 54 10/L and the father was normal. Detailed family history revealed thrombocytopenia and easy bruising in the patient, mother, and maternal cousins. Due to persistent thrombocytopenia among family members, a detailed past and family history was taken.