Epstein Barr Virus–Driven Hodgkin Lymphoma in a Patient with X-linked Lymphoproliferative Disease Type 1 and XYY Karyotype: Rare Association

Introduction X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency caused by pathogenic variants in the SH2D1A gene, characterized by a dysregulated immune response to Epstein–Barr virus (EBV), hypogammaglobulinemia, a markedly increased risk of hemophagocytic lymphohistiocytosis (HLH) and EBV-driven lymphoproliferation, while Hodgkin lymphoma (HL) represents an exceptionally rare complication. Case Presentation We report a male patient diagnosed with XLP1 at the age of six following his first episode of HLH, with confirmation of a pathogenic SH2D1A variant. Cytogenetic analysis revealed a 47, XYY karyotype. The patient remained clinically stable until the age of 28, when he experienced a new episode of EBV reactivation-associated HLH. Treatment with dexamethasone and immunomodulatory doses of intravenous immunoglobulin (IVIG) resulted in prompt clinical improvement, and a long-term IVIG replacement was initiated due to hypogammaglobulinemia. Four months later, the patient presented with severe abdominal pain, fever, pancytopenia, splenomegaly, hyperferritinemia, and markedly elevated soluble IL-2 receptor levels (9,840 IU/mL), consistent with a third episode of EBV-associated HLH (viral load 207,000 viral copies/mL). Treatment was initiated according to the HLH-2014 protocol, including dexamethasone, immunomodulatory IVIG, and rituximab. Despite transient improvement, clinical and laboratory deterioration occurred, prompting escalation with high-dose methylprednisolone pulses, leading to significant clinical improvement. Interestingly, bone marrow biopsy performed before treatment revealed infiltration consistent with HL. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated active disease in the spleen and bone marrow, establishing a stage IVA diagnosis. Chemotherapy with the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) protocol was initiated. After two cycles, interim FDG-PET/CT showed complete metabolic remission (Deauville score 1/2), and treatment continued with four cycles of AVD, according to European Society for Medical Oncology (ESMO) guidelines. Key Messages for Clinical Practice This case illustrates that XLP1 patients remain at lifelong risk for EBV-driven HLH and rare lymphomas, and emphasizes that early recognition, vigilant monitoring, and prompt targeted therapy, including rituximab and tailored chemotherapy, can achieve complete remission, even in this high-risk population.