X-linked lymphoproliferative syndrome, also known as XLP or Duncan’s syndrome, is a rare inherited immunodeficiency. It is characterized by severe immune dysregulation, which generally manifests as an exaggerated immune response to infection. XLP belongs to the group of familial hemophagocytic lymphohistiocytosis syndromes. Patients typically present in childhood or early adolescence, often following infection with Epstein-Barr virus (which causes what is commonly known as “mono,” or infectious mononucleosis); up to 90% of XLP patients are seropositive for Epstein-Barr virus.1 Following the response to the pathogen, the exaggerated proliferation of T-cells, B-cells, and macrophages may clinically manifest as hemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinemia, and/or lymphoma.
XLP is divided into two specific types that are characterized by their clinical presentation and associated genetic abnormalities. XLP1 is defined by the SH2D1A mutation, which affects the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). XLP1 patients are more likely to present with fulminant infectious mononucleosis (FIM) and/or HLH following EBV, dysgammaglobulinemia, and/or lymphoma. Mutations in BIRC4, also known as x-linked apoptosis inhibitor protein (XIAP), define XLP2. Patients with XLP2 tend to present with colitis and/or splenomegaly; they may also present following EBV infection with or without subsequent HLH. The common presentation of HLH following EBV suggests there may be a functional or molecular link between the SAP and XIAP proteins.2
1 Sumegi J, Huang D, Lanyi A, et al. Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood, 2000;96(9):3118-25.
2 Schmid JP, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood, 2011;117(5):1522-9.
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