Lymphoproliferative Disease, X-Linked

Clinical characteristics: X-linked lymphoproliferative disease (XLP) has two recognizable subtypes, XLP1 and XLP2. XLP1 is characterized predominantly by one of three commonly recognized phenotypes:

1. Inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis

2. Dysgammaglobulinemia

3. Lymphoproliferative disease (malignant lymphoma)

XLP2 is most often characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease. HLH resulting from EBV infection is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The malignant lymphomas are typically B-cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine.

Diagnosis/testing: The diagnosis of XLP is established in a male by identification of a hemizygous pathogenic variant in SH2D1A (associated with XLP1) or XIAP (associated with XLP2) on molecular genetic testing.

Management: Treatment of manifestations: Treatment of XLP-related HLH is similar to that of other life-threatening genetic hemophagocytic disorders and includes immunosuppressive agents such as steroids and etoposide or anti-thymocyte globulin. Rituximab therapy may also be considered when HLH is associated with EBV infection. Hypogammaglobulinemia is treated with IVIG replacement therapy. Lymphoma is treated with standard chemotherapy appropriate to the tumor. Inflammatory bowel disease is treated with immunosuppression. For all clinical phenotypes of XLP, the only curative treatment is allogeneic hematopoietic cell transplantation (HCT), which should be considered in most individuals as early as possible.

Prevention of primary manifestations: Boys with known or suspected XLP and hypogammaglobulinemia should receive regular intravenous (IV) IgG replacement therapy every three to four weeks until definitive treatment can be provided.

Surveillance: Blood should be monitored by EBV-PCR for evidence of EBV infection if symptoms of infection and/or HLH develop; blood counts, hepatic profiles, coagulation studies, and inflammatory markers should be monitored as needed based on clinical status for early evidence of HLH; IgG levels should be monitored as needed based on clinical phenotype.

Agents/circumstances to avoid: Individuals with XLP who come into contact with EBV are at risk until curative treatment with allogeneic HCT has been performed. Individuals are also at risk of developing HLH or inflammatory problems with other infections.

Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs and other relatives for the family-specific pathogenic variant facilitates early diagnosis and treatment.

Genetic counseling: XLP is inherited in an X-linked manner. The risk to the sibs of a male proband depends on the genetic status of the mother: if the mother is a carrier, the chance of transmitting the SH2D1A and XIAP pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be heterozygotes and will typically not be affected (in rare cases, heterozygous females may be symptomatic due to skewed X-chromosome inactivation). Carrier testing of at-risk female relatives is most informative if the pathogenic variant has been identified in the proband. Prenatal testing is possible for a pregnancy at increased risk if the familial pathogenic variant is known.