Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem inflammatory process due to cytokine activation from overly-stimulated lymphocytes and macrophages [1
]. The etiology of HLH is either primary, due to a genetic mutation, or secondary from over-activation of the immune system [3
]. In the familial form of HLH, mutations in three genes – perforin (PRF1
), mammalian homolog of uncoordinated (MUNC13-4
), and syntaxin (STX11
) – have been linked to HLH [2
]. Impairment of these gene products causes disruption of granule mediated toxicity, which can lead to ineffective cytolytic activity. Secondary HLH can be due to an infection, autoimmune process or malignancy which causes excessive stimulation of the immune system [5
]. Usually, in the case of malignancy, HLH is a complication of the primary disease, not a preceding diagnosis [6
Current diagnostic guidelines [7
] for HLH include: (1) molecular diagnosis consistent with HLH, or (2) five out of following eight diagnostic criteria: fever; splenomegaly; cytopenias affecting ≥ 2 lineages; hypertriglyceridemia or hypofibrinogenemia; hemophagocytosis in bone marrow, spleen, or lymph nodes with no evidence for malignancy; low or absent NK cell activity; ferritin ≥ 500 µg/L; and soluble CD25 (IL-2 receptor) ≥ 2,400 U/ml.
We report two unique cases in which secondary HLH was the initial diagnosis, with progression to acute leukemia. In the first case, the child was diagnosed with HLH, found to be heterozygous for MUNC13-4 mutation, and later progressed to acute monoblastic leukemia with a MLL-AF9 gene fusion. A second child was diagnosed with HLH and later progressed to acute lymphoblastic leukemia; further investigation revealed decreased natural killer (NK) cell function and perforin expression. To our knowledge, these are the only cases of HLH with progression to leukemia with an underlying MUNC13-4 mutation or decreased perforin expression.