X-linked lymphoproliferative disease

X-linked lymphoproliferative disease (XLP), also known as Duncan disease or Purtilo syndrome, is a rare primary immunodeficiency disorder that predominantly affects males. It is characterized by an extreme vulnerability to Epstein-Barr virus (EBV) infection, which can trigger life-threatening immune dysregulation. There are two recognized subtypes: XLP1 (caused by mutations in the SH2D1A gene encoding SAP protein) and XLP2 (caused by mutations in the XIAP/BIRC4 gene). The disease primarily affects the immune system, particularly T cells and natural killer (NK) cells, leading to impaired immune surveillance and uncontrolled lymphocyte proliferation. The three classical manifestations of XLP include fulminant infectious mononucleosis (often fatal hemophagocytic lymphohistiocytosis triggered by EBV infection), B-cell lymphomas (frequently extranodal, particularly affecting the intestine and central nervous system), and dysgammaglobulinemia (including hypogammaglobulinemia and combined variable immunodeficiency). Patients with XLP2 may additionally present with recurrent hemophagocytic lymphohistiocytosis (HLH), splenomegaly, and inflammatory bowel disease-like colitis, sometimes even in the absence of EBV infection. Other features can include aplastic anemia, vasculitis, and lymphoid granulomatosis. Without treatment, the prognosis is poor, with a significant proportion of affected males dying in childhood or early adulthood. Supportive treatments include intravenous immunoglobulin replacement therapy for hypogammaglobulinemia and rituximab or chemotherapy for lymphoproliferative complications. Management of HLH episodes follows established HLH protocols including etoposide-based regimens. The only curative treatment currently available is allogeneic hematopoietic stem cell transplantation (HSCT), which is recommended as early as possible, particularly before EBV exposure. Gene therapy approaches are under investigation.

Common questions about X-linked lymphoproliferative disease