Juvenile Myelomonocytic Leukemia Presenting with Unusual Immunonologic Manifestations: Report of a Case with Multiple Somatic Genetic Aberrations Including KRAS and Novel ETV6 Mutations

Abstract

We report an unusual case of juvenile myelomonocytic leukemia (JMML) in a 4-year-old male who had persistent monocytosis and intermittent anemia and thrombocytopenia beginning at 1 year of age. Given a history of recurrent skin infections, the patient initially received an evaluation for a primary immune disorder, but workup was inconclusive. Bone marrow examination was performed to further evaluate persistent and progressive cytopenias. The findings fulfilled the criteria for JMML with peripheral blood monocytosis ≥ 1×10⁹/L, blast/promonocyte percentage of <20% in peripheral blood and bone marrow, clinical evidence of organ infiltration with hepatosplenomegaly, and absent BCR::ABL1 fusion and KMT2A gene rearrangements. Additionally, next generation sequencing (NGS) studies performed on the bone marrow aspirate revealed multiple acquired somatic mutations, including a KRAS G12D mutation, meeting criteria for the diagnosis of JMML in the context of this case. A novel ETV6 R369W mutation in the setting of JMML was also detected, which may explain the striking megakaryocytic dysplasia in the bone marrow beyond what is typically seen in JMML. This case showed interesting features overlapping with Ras-associated autoimmune leukoproliferative disorder (RALD), including monocytosis and recurrent infections. Furthermore, this case demonstrated a need for more definitive criteria for distinguishing JMML from RALD.