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X-linked Lymphoproliferative Syndrome

(Duncan Syndrome)

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Last full review/revision Dec 2019| Content last modified Dec 2019
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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 a primary immunodeficiency disorder that involves cellular immunity deficiencies. It 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, an uncommon disorder that causes immunodeficiency in infants and young children. XLP2 is caused by mutations in a gene that encodes the X-linked inhibitor of apoptosis protein (XIAP).

Symptoms and Signs

X-linked lymphoproliferative 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 of X-linked lymphoproliferative syndrome should be considered in young males who have severe Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis, 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

  • An inverted CD4:CD8 ratio

These findings are typical before and after Epstein-Barr virus infection. A bone marrow biopsy can help confirm hemophagocytic lymphohistiocytosis.

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

Treatment of X-linked lymphoproliferative syndrome is 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 Epstein-Barr virus infection or other disorders become irreversible.

Rituximab can help prevent severe EBV infection before transplantation.

Click here for Patient Education
NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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