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  • br Case report We report a case

    2019-05-16


    Case report We report a case of an 18 year-old Caucasian male who was found to have thrombocytopenia at birth, with a platelet count of 58,000/mm3. Bone marrow biopsy was first performed in 1993, at 13 months of age, and showed 70–80% cellular marrow with occasional megakaryocytes and no evidence of dysplastic changes or increased monocytes. There was no history of thrombocytopenia or bleeding tendency in his family. Throughout childhood, his platelet counts averaged between 90,000 and 120,000/mm3. He had a lifelong history of easy bruising, however had no major bleeding episodes. He underwent several operations including spinal fusion surgery for scoliosis, later requiring revision, and a tonsillectomy with adenoidectomy. He received pre- and post-operative platelet transfusions as well as intravenous aminocaproic Statistical Analyses for his spinal operations without significant bleeding. He also had history of several infections, including lower extremity cellulitis, periorbital cellulitis, and a perirectal abscess. The patient was otherwise developmentally and phenotypically normal and was of normal intelligence. In 2007, the patient was noted to have a mild normocytic anemia with hemoglobin and hematocrit of 10g/dL and 30%. Four years later, at 18 years of age, the patient developed a mild leukopenia (3200/mm3), as well as worsening of his baseline thrombocytopenia to around 60,000/mm3. Bone marrow biopsy revealed 65–70% cellular marrow with 10% myeloblasts aberrantly expressing CD7, dysplastic erythroid progenitors and megakaryocytes, increased monocytes (25%), increased eosinophils, and no fibrosis. Cytogenetic analysis revealed normal male karyotype. FISH was negative for AML1-ETO (RUNX1-RUNX1T1) gene fusion and CBFB gene rearrangements. Molecular studies for CEBPA, c-MPL, FLT3, and NPM1 gene mutations were negative. The bone marrow pathology was interpreted as a high grade MDS (RAEB-1, Intermediate-2 IPSS risk). Although there were some features of CMML in the bone marrow, the patient did not have an elevated number of peripheral blood monocytes to meet criteria for this diagnosis. The patient׳s pancytopenia worsened over the ensuing weeks and follow-up bone marrow biopsy revealed a marrow that was 75% cellular with 15% dysplastic myeloblasts aberrantly expressing CD7, 23% dysplastic monocytes, and 5% eosinophils. Cytogenetics showed normal male karyotype. FISH was negative for abnormalities in chromosomes 5, 7, 8 and 20. Additionally, FISH probes for PDGFRA, PDGFRB, CBFB, and FGFR1 detected no gene rearrangements. Genetic analysis found no mutations in FLT3 or NPM1. Lumbar puncture showed no evidence of central nervous system (CNS) involvement. Because of his history of thrombocytopenia since birth evolving to MDS, DNA sequencing of RUNX1 was performed on both blood and buccal swab specimens. Two mutations were discovered: the first mutation, c.837G>A, was a nucleotide base substitution from guanine to adenine within exon 8 (Fig. 1), which is predicted to result in a nonsense mutation of amino acid tryptophan (W) to a premature stop codon (X) (p.W279X) in the DNA-binding inhibitory domain of the Runx1 protein. This mutation was found in 100% of cells analyzed. The second mutation identified, c.422_423insAAGGCC, was an in-frame six nucleotide base pair insertion in exon 5 of the RUNX1 gene, which is predicted to result in an insertion of an arginine (R) and proline (P) (p.S141_A142insRP) in the DNA-binding runt homology domain (RHD) of the Runx1 protein. This second mutation displayed a mosaic pattern. Peripheral blood from both the mother and father showed wild type RUNX1 only and no evidence of mutations. The patient was diagnosed with a RUNX1 double mutant, pre-leukemic MDS with myelomonocytic differentiation and administered induction chemotherapy with cytarabine and idarubicin. Prior to receiving induction chemotherapy, the patient elected for sperm banking to prepare for possible assisted reproductive technology in the future. The patient achieved an immediate complete remission (CR) following induction chemotherapy and then received once cycle of consolidation treatment with high dose cytarabine. Because of his underlying RUNX1 mutations and high risk for relapse disease [10], he immediately underwent an allogeneic hematopoietic cell transplant (allo-HCT) from a matched unrelated donor. Six months after transplant, oral mucosa cells harvested by buccal swab were analyzed for RUNX1 sequencing and revealed persistence of the exon 8 RUNX1 mutation with disappearance of the exon 5 insertion mutation. These results support the notion of a constitutional RUNX1 mutation in exon 8 and an accessory somatic RUNX1 mutation in exon 5.