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X-linked Lymphoproliferative Syndrome

(Duncan Syndrome)

by James Fernandez, MD, PhD

X-linked lymphoproliferative syndrome results from a T-cell and natural killer cell defect and is characterized by an abnormal response to Epstein-Barr virus infection, leading to liver failure, immunodeficiency, lymphoma, fatal lymphoproliferative disease, or bone marrow aplasia.

X-linked lymphoproliferative syndrome (XLP) is caused by mutations in genes on the X chromosome. It is a recessive disorder and thus manifests only in males.

XLP type 1 is the most common type (about 60% of cases). It is caused by a mutation in the gene that encodes the signaling lymphocyte activation molecule (SLAM)–associated protein (SAP, also called the SH2 domain protein 1A [SH2D1A] or DSHP). Without SAP, lymphocytes proliferate unchecked in response to Epstein-Barr virus (EBV) infection, and natural killer (NK) cells do not function.

XLP type 2 is clinically similar to type 1 and predisposes to hemophagocytic lymphohistiocytosis (HLH), an uncommon disorder that causes immunodeficiency in infants and young children (see Hemophagocytic Lymphohistiocytosis (HLH)). XLP2 is caused by mutations in a gene that encodes the X-linked inhibitor of apoptosis protein (XIAP).

The syndrome is usually asymptomatic until EBV infection develops. Then, most patients develop fulminating or fatal infectious mononucleosis with liver failure (caused by cytotoxic T cells that react to EBV-infected B or other tissue cells). Survivors of initial infection develop B-cell lymphomas, aplastic anemia, hypogammaglobulinemia (resembling that in common variable immunodeficiency), splenomegaly, or a combination.

Diagnosis

  • Genetic testing

The diagnosis should be considered in young males who have severe EBV infection, HLH, a suggestive family history, or other common manifestations. Genetic testing is the gold standard test for confirming the diagnosis (before and after EBV infection and symptoms develop) as well as the carrier state. However, genetic testing can take weeks to complete, so other testing is done if the diagnosis must be made earlier (eg, flow cytometry to assess SH2D1A protein expression).

Suggestive findings include decreased antibody responses to antigens (particularly to EBV nuclear antigen), impaired T-cell proliferative responses to mitogens, decreased NK-cell function, and an inverted CD4:CD8 ratio. These findings are typical before and after EBV infection. Some survivors of EBV infection have hypogammaglobulinemia. A bone marrow biopsy can help confirm HLH.

In survivors, laboratory and imaging tests are done yearly to check for lymphoma and anemia.

Genetic testing is done in relatives when a case or carrier is identified in a family. Prenatal screening is recommended for people if a mutation that causes XLP has been identified in their family.

Treatment

  • Hematopoietic stem cell transplantation

About 75% of patients die by age 10, and all die by age 40 unless hematopoietic stem cell transplantation is done. About 80% of patients who receive a transplant survive. Transplantation is curative if done before EBV infection or other disorders become irreversible. Rituximab can help prevent severe EBV infection before transplantation.

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