XLP

Author: Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Coauthor(s): Doris Ponce, MD, Fellow, Department of Hematology/Oncology, New York Medical College; M Wayne Saville, MD, Associate Professor of Clinical Medicine, University of California at San Diego; Director, Hematology and Oncology, Global Medical Affairs, Biogen Idec Inc.
Contributor Information and Disclosures

Introduction

Background

Pathophysiology

X-linked lymphoproliferative syndrome (XLP) is characterized by a high susceptibility to severe infection with the EBV virus. Typically, patients do not manifest significant immune defects until exposure to EBV. However, after infection, up to 75% of patients develop fulminant infectious mononucleosis. Most succumb to hepatic necrosis and/or bone marrow failure. Those that survive are at risk for later development of hypogammaglobulinemia, lymphoma, hemophagocytic syndrome, 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.^11,12,13

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

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

70% of patients with X-linked lymphoproliferative syndrome (XLP) die by age 10 years, and 60% develop fulminant infectious mononucleosis. Few patients survive into adulthood.

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 X-linked lymphoproliferative syndrome (XLP) is approximately 3-5 years.

Clinical

History

The most common manifestations of X-linked lymphoproliferative syndrome (XLP) are fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia

Fatal infectious mononucleosis
- Fatal infectious mononucleosis occurs in approximately 60% of patients.
- The median age of onset is 3-5 years.
- The median survival is 1-2 months.
- Patients present with fever, malaise, fatigue, lymphadenopathy, and hepatosplenomegaly.
- Most develop fulminant hepatitis with massive hepatic necrosis, hepatic encephalopathy, and death.
Lymphoma
- 20-30% of patients with X-linked lymphoproliferative syndrome (XLP) develop malignant and nonmalignant lymphoproliferative disorders.
- The median age of onset is 5 years for EBV-exposed and 8 years for non-EBV–exposed patients.
- The lymphomas are typically high-grade B cell lymphomas. More than half are Burkitt lymphomas.
- The lymphomas are usually extranodal, including sites such as the intestines, central nervous system, liver, or kidneys.
- Patients may respond to initial therapy; however, many die from relapse or infectious complications.
- Nonmalignant disorders such as Wegener granulomatosis, lymphomatoid granulomatosis, and necrotizing vasculitis also occur.
Hypogammaglobulinemia
- One third of patients with X-linked lymphoproliferative syndrome (XLP) manifest hypogammaglobulinemia, typically by a median age of 8 years.
- Patients with isolated hypogammaglobulinemia have a less severe course than others with this disease.
- Life-threatening infections seem to be rare, especially if intravenous immunoglobulin (IVIG) is administered on a regular basis
Miscellaneous findings
- Other manifestations of X-linked lymphoproliferative syndrome (XLP) include occasional cases of aplastic anemia, lymphocytic vasculitis, red cell aplasia, and a hemophagocytic syndrome associated with the initial EBV infection. All of these occur in fewer than 10% of patients.

Lymphoproliferative Syndrome, X-linked