X-linked lymphoproliferative disease (XLP) is caused by mutations in SH2D1A and XIAP (BIRC4). XLP may also occur in rare instances with no identified underlying genetic cause. The three most commonly recognized phenotypes of SH2D1A-related XLP are hemophagocytic lymphohistiocytosis (HLH) associated with Epstein-Barr virus (EBV) infection (58% of individuals), dysgammaglobulinemia (31%), and lymphoproliferative disorders (malignant lymphoma) (30%). Manifestations of SH2D1A-related XLP, including HLH, can also occur in the absence of EBV. XIAP-related XLP also presents with HLH (often associated with EBV) or dysgammaglobulinemia, but no cases of lymphoma have been described to date. HLH resulting from EBV infection, sometimes referred to as severe infectious mononucleosis, is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Fulminant hepatitis, hepatic necrosis, and profound bone marrow failure are typical, resulting in mortality that is higher than 90%, though prompt recognition of the disorder and aggressive treatment interventions likely improve survival. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The prognosis is improved if affected males are managed with regular intravenous immunoglobulin (IVIG) therapy. The malignant lymphomas are typically high-grade B cell lymphomas, non-Hodgkin type, often extranodal, and in particular involve the intestine.
XLP is typically suspected based on clinical history and tests of immune function. Diagnosis can be confirmed with molecular genetic testing of SH2D1A and/or XIAP, which is available on a clinical basis. SH2D1A and XIAP encode SLAM-associated protein (SAP) and baculoviral IAP repeat-containing protein 4 (X-linked inhibitor of apoptosis; XIAP), respectively. Absence of SAP or XIAP strongly supports the diagnosis of XLP as well.
XLP is inherited in an X-linked manner. Carrier females have a 50% chance of transmitting the disease-causing mutation in each pregnancy: males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Carrier testing of at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known. Because of the possibility of germline mosaicism, it is appropriate to offer prenatal diagnosis to couples who have had a child with XLP if the disease-causing mutation in the proband is known.