Unmasking HLH: A BCOR mutation as the hidden driver of immune dysregulation and fulminant hepatic failure

Abstract

Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome triggered by infections, malignancies, or autoimmune conditions. Secondary HLH may also arise from acquired factors such as clonal hematopoiesis (CH) or clonal cytopenia of undetermined significance (CCUS), which promote immune dysregulation. Mutations in BCOR, a transcriptional corepressor, have been associated with disrupted immune homeostasis and may predispose individuals to HLH. Case Presentation A 64-year-old woman with autoimmune enteropathy presented with fever, diffuse maculopapular rash, abdominal pain, and bicytopenia. She met five of the eight HLH-2004 diagnostic criteria, including hyperferritinemia, elevated soluble IL-2 receptor, and elevated CXCL9—consistent with secondary HLH. Imaging revealed multiple hypodense hepatic lesions. Initial bone marrow biopsy demonstrated hypocellularity without hemophagocytosis or evidence of malignancy. The patient responded to dexamethasone and dose-reduced etoposide at first; however, a small bowel perforation requiring surgical intervention interrupted immunosuppressive therapy, resulting in HLH reactivation. Repeat marrow biopsy showed profound hypocellularity, and next-generation sequencing identified a pathogenic BCOR mutation (p.Arg1163*). Despite resumption of therapy, the patient progressed to fulminant hepatic failure and ultimately died. Discussion While BCOR mutations are well-recognized in myeloid neoplasms and BCL6-driven lymphomas, their role in HLH pathogenesis is less understood. In this case, pancytopenia with hypocellular marrow in the absence of B-cell expansion may reflect marrow exhaustion or immune-mediated suppression, further exacerbated by HLH-related cytokine storms. T-cell predominance with absent plasma cells, despite preserved immunoglobulin levels, suggests selective B-cell suppression or preexisting immune dysregulation. The presence of multifocal hepatic lesions and rapid progression to liver failure supports a macrophage activation syndrome (MAS)-like phenotype, a severe and treatment-refractory HLH variant. The role of resuming etoposide in the context of marrow suppression remains uncertain, highlighting the complexity of balancing immunosuppression with hematopoietic reserve in HLH associated with CH or autoimmunity. Conclusion This case underscores the diagnostic and therapeutic challenges of adult HLH, particularly in the context of underlying clonal hematopoiesis or autoimmune disease. Genetic evaluation—including BCOR mutation analysis—may provide critical insights into prognosis and therapeutic strategy in such complex presentations.