X-linked lymphoproliferative disease is a hereditary immunodeficiency characterized, in the majority of cases, by an inadequate immune response to infection with the Epstein-Barr virus (EBV). Prevalence is estimated at 1/1,000,000. Infection with the Epstein-Barr virus can result in one or several of the following manifestations: fulminant infectious mononucleosis, macrophage-activation syndrome or hemophagocytic lymphohistiocytosis (HLH; see this term), and/or progressive hypogammaglobulinemia and/or lymphomas. Hemophagocytic lymphohistiocytosis is a potentially fatal complication, caused by activation and excessive proliferation of T cells and macrophages, which manifests as fever, hepatosplenomegaly and lymphadenopathy. Coagulopathy and central nervous system dysfunction can follow as well as multiple organ failure syndrome. In rare cases, aplastic anemia and lymphocytic vasculitis are observed. In some cases the same phenotype is observed in the absence of infection with Epstein-Barr virus. Transmission is X-linked recessive. In 60% of cases the gene responsible codes for the protein SAP (signaling lymphocyte activation molecule (SLAM)-associated protein), which regulates T lymphocyte activation. In three families without mutations of the SH2D1A gene, mutations of the gene which codes for the protein XIAP (X-linked inhibitor of apoptosis), also called BIRC4, have been identified. The failure to express XIAP is associated with increased apoptosis of lymphocytes triggered by diverse stimuli. Patients with SAP and XIAP deficiency have few Natural Killer T lymphocytes (NKT cells), which suggests that NKT cells play a key role in the immune response to EBV. Definitive diagnosis is based on genetic analysis. Differential diagnoses include other hereditary forms of HLH (familial lymphohistiocytosis) and HLH acquired through infection with EBV. Antenatal diagnosis with mutation analysis can be done when the mutation has been identified in the family. The only cure for X-linked lymphoproliferative disease (SAP or XIAP deficiency) is by an allograft of hematopoietic stem cells. Treatment of HLH requires the use of corticosteroids, chemotherapy by VP16 (cf protocol HLH-2004) or by antithymocyte globulin. The anti-CD20 antibody (Rituximab) can be used to reduce the EBV viral load and indirectly reduce T lymphocyte activation. Prognosis depends on the occurrence of complications, such as lymphomas and hemophagocytic lymphohistiocytosis.
Last update: November 2006