X-linked Lymphoproliferative Syndrome

Updated: Nov 26, 2015
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

X-linked lymphoproliferative (XLP) syndrome is a rare immunodeficiency disease that is characterized by a predilection for hemophagocytic lymphohistiocytosis, fatal or near-fatal Epstein-Barr virus (EBV) –induced infectious mononucleosis in childhood, subsequent hypogammaglobulinemia, and a markedly increased risk of lymphoma or other lymphoproliferative diseases. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]

For excellent patient education resources, visit eMedicineHealth's Infections Center. Also, see eMedicineHealth's patient education article Mononucleosis.

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Pathophysiology

X-linked lymphoproliferative syndrome (XLP) is characterized by a high susceptibility to severe infection with EBV. Hemophagocytic lymphohistiocytosis is the most common presenting feature. Other patients develop fulminant infectious mononucleosis following infection with EBV. Most succumb to hepatic necrosis and/or bone marrow failure. Those that survive manifest chronic hypogammaglobulinemia and are at risk for lymphoma and aplastic anemia.

In 1998, the gene for classic X-linked lymphoproliferative syndrome (XLP) was isolated on the long arm of the X chromosome at Xq25. This locus encodes a 128-amino acid src homology2 (SH2) domain-containing protein and was named SH2D1A. Codiscovery by other groups led to the other designations, DSHP and SAP (signaling lymphocytic activation molecule [SLAM]–associated protein). The latter is based on the encoded protein's association with SLAM.

Deficiency of SAP results in sustained T-cell proliferation in response to EBV infection due to reduced ability to kill EBV-infected B cells. In the absence of SAP, interaction of CD48 on EBV-infected cells with 2B4 (a receptor belonging to the immunoglobulin superfamily that is found on natural killer [NK] cells as well as a small subset of T cells) on NK cells inhibits their ability to kill the EBV-infected cell. In addition, in the absence of SAP, SLAM molecules interact with SHP-2, resulting in an inhibitory effect on T-cell function. Therefore the defect in X-linked lymphoproliferative syndrome (XLP) converts normally activating signals into inhibitory signals. [13, 14, 15, 16]

An X-linked lymphoproliferative syndrome (XLP) caused by mutations in the inhibitor-of-apoptosis gene XIAP has also been reported. [2, 17]

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Epidemiology

Frequency

United States

X-linked lymphoproliferative syndrome (XLP) is rare. Fewer than 400 cases of X-linked lymphoproliferative syndrome (XLP) in fewer than 100 families have been reported.

International

X-linked lymphoproliferative syndrome (XLP) is estimated to affect 1-3/1,000,000 males worldwide.

Mortality/Morbidity

Historically, 70% of patients with X-linked lymphoproliferative syndrome (XLP) died by age 10 years, and 60% developed fulminant infectious mononucleosis. Few patients survived into adulthood.

More recently, stem cell transplantation has significantly prolonged the survival of these patients. In a report by Booth et al of 43 patients who underwent transplantation compared with 48 patients who did not, survival was 81.4% for transplanted patients compared with 62.5% for untransplanted patients. [11] Follow-up ranged from 4 to 148 months. Patients with a history of hemophagocytic lymphohistiocytosis had an inferior survival, 50% if transplanted and only 18.8% if not transplanted. The outcomes was best for older patients (especially older than 15 years), with a matched sibling donor and no prior history of hemophagocytic lymphohistiocytosis.

Race

There is no known ethnic association with X-linked lymphoproliferative syndrome (XLP).

Sex

Because X-linked lymphoproliferative syndrome (XLP) is an X-linked disorder, all patients are male.

Age

The median age of onset of clinical symptoms of X-linked lymphoproliferative syndrome (XLP) is approximately 3-5 years.

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