X-linked lymphoproliferative syndrome (XLP1) is a primary immunodeficiency that causes an uncontrolled immune response to a primary EBV infection. Infection leads to proliferation of B‑lymphocytes and cytotoxic T-lymphocytes with fulminant infectious mononucleosis, B-cell lymphomas, immune deficiency or, more rarely, aplastic anemia, necrotizing vasculitis and lymphoid granulomatosis. Before EBV infection, which occurs at the age of 5 years on average, most patients are clinically healthy and other viral infections result in normal immune responses. In fulminant infectious mononucleosis, over 60% of patients die of acute liver failure. EBV-associated hemophagocytic syndrome with bone marrow aplasia also has a high mortality rate. As the disease progresses, a combined immunodeficiency with hypogammaglobulinemia, similar to common variable immune deficiency (CVID), often occurs. About 30% of patients develop malignancies, especially non-Hodgkin lymphomas of the Burkitt type. XLP1 has the highest risk of malignancy of all immune defects. Peripheral blood shows lymphocytosis with atypical lymphocytes and abnormal lymphocyte functions, the CD4:CD8 ratio is shifted in favor of the CD8 cells. EBV titers may be low or undetectable. The therapy of choice today is bone marrow or stem cell transplantation, without which about 70% of patients die before the age of 10.
The disease is caused by mutations in the SH2D1A gene (SH2 domain-containing gene 1A), whose gene product, as an adaptor protein, plays a role in signal transduction mediated by SLAM (CD150) and 2B4 (NK cell activating receptor, CD244), among other things. Reduced protein expression leads to severely limited T and NK cell-mediated cytotoxicity and to the absence of inhibitory NkT cells and B memory cells. Carriers are normally clinically healthy.
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