Lymphoma arising in the setting of inborn errors of immunity: A six-case series of XMEN-associated pediatric lymphoma

<title>Abstract</title> <p> <bold>Background</bold> Inborn errors of immunity (IEIs), formerly termed primary immunodeficiencies (PIDs), frequently predispose affected individuals to early-onset, recurrent malignant neoplasms as a core clinical hallmark. X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) represents an ultra-rare X-linked recessive IEI driven by loss-of-function variants in the <italic>MAGT1</italic> gene. Per the classification framework issued by the Expert Committee of the International Union of Immunological Societies, XMEN is categorized under immune dysregulation disorders, and it exhibits remarkable heterogeneity across clinical presentations and immunological phenotypes. Inborn errors of immunity (IEIs) represent a large group of monogenic immune disorders characterized by impaired host defense and immune dysregulation, which confer a markedly increased risk of early-onset infection and hematological malignancy. X-linked immunodeficiency with magnesium defect, Epstei-Barr virus (EBV) infection, and neoplasia (XMEN) is an ultra-rare X-linked recessive IEI caused by loss-of-function variants in <italic>MAGT1</italic> . As classified by the International Union of Immunological Societies, XMEN belongs to the immune dysregulation disorder group and exhibits extensive interindividual clinical and immunological heterogeneity. Although the link between <italic>MAGT1</italic> deficiency and EBV-driven lymphoproliferative disorders is well established, the full phenotypic and mutational spectrum of pediatric XMEN-associated lymphoma remains incompletely defined. <bold>Case presentation</bold> This retrospective study enrolled six male pediatric patients diagnosed with XMEN-related lymphoma. All patients harbored novel, previously unreported <italic>MAGT1</italic> pathogenic variants. Notably, the underlying IEI was not identified until recurrent lymphoma episodes or persistent refractory EBV viremia in most cases. One patient presented with persistent unexplained hypoxemia, representing a previously unrecognized clinical phenotype of XMEN disease. In several patients, lymphoma occurred as the inaugural manifestation without classic immunodeficiency symptoms, further delaying genetic diagnosis. All patients received individualized chemotherapy according to pathological subtypes. Two patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). One patient died 18 months post-transplant due to severe chronic pulmonary graft-versus-host disease (cGVHD), whereas the other patient remains stable more than two months after HSCT. The remaining four patients maintain sustained complete remission after chemotherapy. <bold>Conclusions</bold> This case series expands the mutational and phenotypic spectrum of pediatric XMEN-associated lymphoma. We demonstrate distinct phenotypic stratification according to <italic>MAGT1</italic> variant types: frameshift insertion/deletion variants leading to complete protein truncation correlate with more severe, recurrent, and protracted disease courses compared with single-nucleotide or intronic variants. We report, for the first time, persistent immune-mediated hypoxemia as a novel XMEN manifestation. Our findings emphasize the necessity of comprehensive genetic and immunological evaluations for IEIs in individuals presenting with recurrent infections and hematological malignancies. </p>