Modifier-Sensitive Phenotypic Divergence in XMEN Disease (MAGT1 Deficiency): Neurodegenerative and Hematologic Trajectories

X-linked immunodeficiency with magnesium defect, Epstein–Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1 , leading to impaired N-linked glycosylation. Although chronic EBV viremia represents a core feature, the determinants of marked clinical heterogeneity remain poorly understood. We present an integrated clinical and immunological analysis of two siblings carrying the same hemizygous MAGT1 frameshift variant who followed strikingly divergent disease trajectories. Despite shared absence of NKG2D expression, one sibling developed progressive neurodegeneration with central nervous system atrophy, whereas the other presented with EBV-positive Hodgkin lymphoma complicated by lymphoma-associated thrombotic microangiopathy and recurrent autoimmune cytopenias, including the first description of lymphoma-associated thrombotic microangiopathy in XMEN disease. Comparative immunophenotyping revealed shared B-cell maturation defects but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a pragmatic three-category classification encompassing early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the central and peripheral nervous systems. Together, these findings highlight striking intrafamilial heterogeneity in XMEN disease and support a model in which modifier-sensitive factors influence organ-specific disease expression beyond the primary genetic defect, with important implications for prognosis and surveillance.