Abstract
Background: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening condition commonly observed in young children. Distinguishing primary HLH from secondary HLH, such as malignancy-associated HLH, can be challenging, potentially leading to misdiagnosis and inappropriate treatment. Case presentation: A 16-month-old female presented with fever, decreased appetite, and rhinorrhea. A review of the peripheral blood smear revealed anemia and leukopenia, with absolute neutropenia characterized by a high lymphocyte count (approximately 80% were T cells by flow cytometry). Flow cytometry was negative for immunophenotypically abnormal cells. Initially, the cytopenia was attributed to a viral infection. However, the cytopenia did not improve, and a bone marrow evaluation revealed evidence of HLH but no immunophenotypically abnormal population. An extensive work-up for HLH, including next-generation sequencing (NGS) and cytogenetic testing identified the KMT2A::MLLT3 fusion transcript, indicating malignancy-associated HLH in the setting of evolving leukemia. Because there was no increase in blasts or immunophenotypically abnormal cells, the diagnosis of leukemia could not be made at that time. The patient was closely monitored and, seven weeks later, was diagnosed with acute myeloid leukemia/acute monocytic leukemia. In addition to the KMT2A::MLLT3 fusion, pathogenic variants in the PTPN11 and FLT3 genes were detected by NGS. Conclusions: The presentation of evolving acute monocytic leukemia can be nonspecific, mimicking conditions such as HLH, without an initial increase in immature cells or monocytes. Maintaining a broad differential diagnosis and including comprehensive molecular genetic testing may facilitate early diagnosis and appropriate treatment.