X-linked Lymphoproliferative Syndrome

Updated: Jan 27, 2019
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

X-linked lymphoproliferative (XLP) syndrome is a rare recessive genetic disorder that can be divided into two types based on its genetic cause and pattern of signs and symptoms. X-linked lymphoproliferative syndrome type 1 (XLP1), also known as classic XLP, is caused by mutations in SH2D1A; XLP type 2 (XLP2) is caused by the XIAP gene. [1, 2]

XLP1 is characterized by a severe Epstein-Barr virus (EBV)–induced hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, malignant lymphoma, dysgammaglobulinemia, and common variable immunodeficiency (CVID). [3]  Neither malignant lymphoma nor CVID have been reported in XLP2. Patients with XLP2 are more likely to develop HLH without EBV infection, splenomegaly, and may also have inflammation of the large intestine (colitis). [4]

Currently, the only definitive treatment available for XLP1 patients is allogeneic hematopoietic stem cell transplant (HSCT). [5]  However, depending on clinical features, less aggressive treatments may be adopted, particularly if a suitable donor for transplant is not available. As symptoms may not all be present simultaneously, and they may be of varying severity, treatment options that target specific clinical phenotypes may be appropriate. [6]

For patient education information, see the Infections Center, as well as Mononucleosis.

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Pathophysiology

X-linked lymphoproliferative (XLP) syndrome 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 XLP syndrome 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 XLP converts normally activating signals into inhibitory signals. [7, 8, 9, 10]

An XLP syndrome caused by mutations in the inhibitor-of-apoptosis gene XIAP has also been reported. [11, 12]

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Etiology

Mutations in the SH2D1A and XIAP genes cause XLP syndrome. SH2D1A gene mutations cause XLP1, and XIAP gene mutations cause XLP2. [13]

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Epidemiology

X-linked lymphoproliferative (XLP) syndrome is rare. XLP1 is estimated to occur in about 1 in 1,000,000 males worldwide. XLP2 occurs in about 1 in 5,000,000 males. [4]

XLP syndrome has been reported in families of European, African, Asian, and Middle Eastern descent and no evidence exists for a racial or ethnic predilection. Because XLP syndrome is an X-linked disorder, nearly all patients are male. However, a case of a heterozygous female who became symptomatic due to skewed X-chromosome inactivation has been reported. [13, 14]

 

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Prognosis

The overall mortality of XLP1 has decreased significantly since 1995, from 75 to 29%. This is largely due to improved chemotherapy protocols and stem cell transplantion, as well as improved monitoring and supportive care. [6]  Mortality is most often related to HLH (70%), lymphoma (12%), and complications of transplantation (12%). [13]

The mean age at death for XLP2 has been reported as 16 years with mortality due to HLH (30%), complications of HCT (30%), colitis (23%), liver failure (8%), and pneumonia (8%). However, approximately 43% of patients with XLP2 reach adulthood. Of note, some males with a pathogenic variant in XIAP are asymptomatic and their long-term prognosis is unknown. [13]

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. [5]  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 outcome was best for older patients (especially older than 15 years) with a matched sibling donor and no prior history of hemophagocytic lymphohistiocytosis.

Almost a third of patients with XLP1 develop lymphoma, with the most common form being abdominal B cell non-Hodgkin lymphoma in both EBV-positive and EBV-negative patients. Prognosis for those patients has dramatically improved over the decades due to improved  lymphoma chemotherapy protocols. [6]

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