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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 Apr 2021| Content last modified Apr 2021
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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.

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 Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more Infectious Mononucleosis , and natural killer (NK) cells do not function.

XLP type 2 is clinically similar to type 1 and predisposes to hemophagocytic lymphohistiocytosis Hemophagocytic Lymphohistiocytosis (HLH) Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder causing immune dysfunction in infants and young children. Many patients have an underlying immune disorder, although in some... read more , 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

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

Rituximab can help prevent severe EBV infection before transplantation.

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