Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

X-Linked Lymphoproliferative Syndrome (XLP1) [D82.3]

OMIM numbers: 308240, 300490 (SH2D1A)

Dr. rer. nat. Barbara Bangol, Dr. med. Imma Rost

Scientific Background

The X-chromosomal lymphoproliferative syndrome (XLP1) is a primary immunodeficiency, which mainly causes an uncontrolled immune response to an EBV primary infection. The infection leads to proliferation of B lymphocytes and cytotoxic T lymphocytes with fulminant infectious mononucleosis, B cell lymphomas, an immune defect or more rarely, aplastic anemia, necrotizing vasculitis and lymphoid granulomatosis. Prior to an EBV infection, which on average occurs at the age of five, most patients are healthy and other virus infections trigger a normal immune response. More than 60% of all patients die from a fulminant infectious mononucleosis due to acute liver failure. EBV-associated hemophagocytic syndrome with bone marrow aplasia exhibits high letality as well. The ongoing course is frequently marked by a combined immune defect with hypogammaglobulinemia, similar to a CVID (common variable immunodeficiency). Approximately 30% of all patients develop malignomas, especially Burkitt's lymphomas of the group of non-Hodgkin lymphomas. Among all immune defects, XLP1 exhibits the highest risk of developing malignomas. Lymphocytosis with atypical lymphocytes and abnormal lymphocyte functions are found in the peripheral blood; the CD4:CD8 ratio has shifted in favor of CD8 cells. EBV titers may be low or not detectable. Today, therapy of choice is bone marrow or stem cell transplantation. Without transplantation, approximately 70% of all patients die before 10 years of age.

Mutations in the SH2D1A gene (SH2 domain-containing gene 1A) are causing the disease. Its gene product plays a role as an adaptor protein in the signal transduction mediated by the SLAM (CD150) and 2B4 (NK cell-activating receptor, CD244). A decreased expression of the protein results in severely impaired T and NK cell-mediated cytotoxicity and to the absence of inhibitory NKT cells as well as B memory cells. Female carriers usually remain clinically healthy.