X-linked Lymphoproliferative Syndrome 

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

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.

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]

Etiology

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

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]

 

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]

 

Presentation

History

XLP1

The main clinical features of X-linked lymphoproliferative syndrome type 1 (XLP1) are hemophagocytic lymphohistiocytosis (HLH) , dysgammaglobulinemia, severe fulminant infectious mononucleosis and lymphoma. Less frequent manifestations of XLP1 are aplastic anemia, vasculitis, and lymphoid granulomatosis.[13]

Up to 50% of patients demonstrate a range of immune abnormalities, ranging from impaired vaccine responses to generalized hypo-gammaglobulinemia. These may be incidental findings during a diagnostic workup or lead to recurrent infections, particularly respiratory infections.[6]

One third of patients 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

Up to 35% of patients have no evidence of previous Epstein-Barr virus (EBV) infection; many of these patients are diagnosed based on family history.  In EBV-negative patients, XLP1 is associated with higher rates of dysgammaglobulinemia and lymphoma. However, EBV-negative boys with XLP1 can still develop HLH, although less frequently than those with EBV infection, and the trigger is unknown.[5]  

XLP2

Males with XLP2 are more likely to develop HLH without EBV infection, usually have an enlarged spleen (splenomegaly). They may also have inflammation of the large intestine (colitis).[4, 13]

 

 

Physical Examination

Fulminant infectious mononucleosis/HLH associated with EBV

Affected individuals typically have lymphadenopathy and hepatosplenomegaly with extensive parenchymal damage including fulminant hepatitis, hepatic necrosis, and profound bone marrow failure. Involvement of other organs may include the spleen ("white pulp" necrosis), heart (mononuclear myocarditis), and kidney (mild interstitial nephritis).[13]

Lymphoma

The lymphomas seen in XLP1 are typically high-grade B-cell lymphomas, non-Hodgkin type, often extranodal, particularly involving the intestine. Approximately 75% of lymphomas occur in the ileocecal region. Other sites include the central nervous system, liver, and kidney.[13]

 

DDx

 

Workup

Laboratory Studies

Laboratory findings in X-linked lymphoproliferative (XLP) syndrome include the following:

  • Peripheral blood smears will show atypical lymphocytosis.
  • Serum chemistry profiles will show transaminitis and other findings of acute hepatitis.
  • Coagulation studies will be abnormal in patients with liver failure.

Patients with acute Epstein-Barr virus (EBV) infection will demonstrate positive serologic tests for EBV IgM antibodies and quantitative EBV-specific polymerase chain reaction (EBV-PCR). However, as many as one third of patients in the acute infection phase do not produce antibodies, probably due to impaired lymphocyte function and response to EBV antigens.

A definitive diagnosis of XLP is with mutation analysis for the SH2D1A or XIAP gene mutation. Flow cytometry can be used to measure lymphocyte SAP or XIAP protein expression and can be used to detect lymphocyte phenotypes and functional defects related to XLP.[15, 16]

Histologic Findings

Liver biopsy results typically show an intense periportal B-cell lymphoid infiltrate containing EBV-nuclear antigen (EBNA-1) often surrounded by numerous CD8-positive T lymphocytes and natural killer cells. In later stages, periportal necrosis is observed in most patients. Other organs that can be involved include the liver, heart, brain, and thymus. Findings in the bone marrow are generally reactive.

 

Treatment

Medical Care

Patients with dysgammaglobulinemia or recurrent infections due to X-linked lymphoproliferative (XLP) syndrome may benefit from immunoglobulin replacement therapy. This can be delivered intravenously every few weeks or subcutaneously every week, which is usually performed at home. Other manifestations of dysregulation, such as aplastic anemia or vasculitis, may respond to treatment with corticosteroids or other immunosuppressive agents.[6]

Colitis associated with XLP type 2 (XLP2) is treated symptomatically and with immunosuppression similar to that used for irritable bowel disease.[13]

Epstein-Barr virus infection

If there is evidence of  Epstein-Barr virus (EBV)–driven disease, including hemophagocytic lymphohistiocytosis (HLH), treatment with a monoclonal anti-CD20 antibody (rituximab) can be used to deplete the B cell population harboring the virus. This approach is effective at reducing and often clearing the viremia but risks exacerbating long-term hypogammaglobulinemia.[6, 17]  

Antiviral agents are poorly effective against EBV but acyclovir has been used in some circumstances.[6]

HLH

Hemophagocytic lymphohistiocytosis is treated according to standardized protocols (HLH 94 and 2004) based on the use of dexamethasone, etoposide, and cyclosporine, with the addition of intrathecal methotrexate and steroids if there is neurological involvement. This is a highly suppressive regime and can be associated with significant toxicity. The protocol follows different stages, starting with an intense period of treatment initially, with reducing doses of steroids and frequency of etoposide over time if a response is seen. Re-intensification of therapy is occasionally required.[18]

Other immunosuppressive agents have been used to control HLH, either in combination with steroids or as rescue therapy, including ATG (anti-thymocyte globulin) in combination with etoposide and the anti-CD52 antibody alemtuzumab (Campath). In addition, newer biologics are now available, and some are being tested in HLH, including the interleukin-6 receptor agonist tocilizumab (Actemra).[23]  

Lymphoma

Patients with B-cell lymphomas should be treated with the standard therapy for that disease. Special attention should be paid to the potential infectious complications of these therapies.

Gene therapy

Gene therapy offers the advantages of reduced toxicity from conditioning as, in general, less chemotherapy is required and the use of autologous cells removes the risk of graft versus host disease which causes significant morbidity and mortality post HSCT.[19]

Rivat et al reported a preliminary study in mice in which the immune function defects of XLP syndrome were corrected by lentiviral vector-mediated gene transfer of SH2D1A into autologous hematopoietic stem cells. The transfer of gene-corrected cells led to the restoration of natural killer (NK) and CD8 T cell cytotoxicity, NKT development, as well as GC formation and function upon immunological challenge.[20] However, SAP is a tightly regulated signaling protein that is predominately expressed in T cells, and the use of a ubiquitous human promoter that can drive expression in all hematopoietic cells may not be optimal.

An alternative therapeutic strategy to more directly address the T cell–dependent clinical manifestations of XLP1 is gene correction of the patient's own T cells. Murine studies utilizing gene-modified T cell transfers into mice demonstrated the correction of T follicular helper cell function, the restoration of germinal centers, and the improvement in baseline immunoglobulin levels. In addition, the correction of CD8+ T cell function was shown using an in vivo tumor model. These data support  gene therapy as a potentially useful therapeutic option.[6]

 

Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT), which includes the transfer of bone marow, mobilized CD34+ cells from peripheral blood, or umbilical cord–derived CD34+ cells, is currently the only definitive treatment for XLP syndrome. However, success is dependent on the availability of an appropriate donor who is human leukocyte antigen matched. A number of factors must be considered prior to HSCT, including the disease status, previous treatments, and the type of pre-conditioning regimen. An EBV-positive donor is preferred in patients with EBV-driven disease.

Several studies have evaluated the clinical outcomes of patients undergoing HSCT using either myeloablative-conditioning regimens or reduced-intensity-conditioning (RIC) regimens.[5, 21, 22] These studies revealed similar overall post-transplantation survival rates with RIC and myeloablative protocols in XLP1, with both averaging about 80%.[5, 22]  The outcomes of allogeneic HSCT for XLP2 are less certain at this time. Early evidence suggests that reduced-intensity conditioning regimens should be considered due to very poor early experience with myeloablative preparative regimens.[22]

 

Long-Term Monitoring

Close monitoring of EBV viral loads is important in to allow the prevention of recurrent infections, organ damage such as bronchiectasis, and permit early treatment of EBV infection and more serious complications.[6]  No formal surveillance guidelines exist; the following are general considerations[13] :

  • Blood should be monitored by EBV-PCR for evidence of EBV infection if symptoms of infection or HLH develop.
  • Blood counts, hepatic profiles, coagulation studies, and inflammatory markers (ferritin, soluble IL2R) should be monitored as needed based on clinical status for early evidence of HLH.
  • IgG levels should also be monitored as needed based on clinical phenotype.

 

 

Medication

Medication Summary

No clearly effective medications exist for X-linked lymphoproliferative disease, although cytotoxic chemotherapy agents may be useful. Further study is needed.

Antineoplastic Agents

Class Summary

Antineoplastic agents inhibit cell growth and proliferation.

Etoposide (VePesid, VP-16)

Topoisomerase II inhibitor that leads to single-strand DNA breaks and cell cycle arrest. Has activity in a number of tumors, including small cell lung cancer, germ cell tumors, and lymphoma.

One reported case used 200 mg/m2/d IV for 3 d during acute EBV infection in a boy aged 6 years. Led to dramatic, although temporary, improvement. Little data support etoposide therapy in this syndrome.

Monoclonal Antibody

Class Summary

Monoclonal antibodies are genetically engineered antibodies directed against specific antigens found in targeted cells.

Rituximab (Rituxan)

Genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes.

Blood Products

Class Summary

Blood products are use for improvement of immunodeficiency.

Immune globulin, intravenous (Gamimune, Gammar-P, Sandoglobulin, Gammagard)

Limited literature suggests that the use of intravenous immunoglobulin may help speed resolution of the acute IM syndrome and prevent some secondary infections due to humoral immunodeficiency. No controlled studies exist, and its use is still speculative.

 

Questions & Answers

Overview

What is X-linked lymphoproliferative (XLP) syndrome?

What is the pathophysiology of X-linked lymphoproliferative (XLP) syndrome?

What causes X-linked lymphoproliferative (XLP) syndrome?

What is the prevalence X-linked lymphoproliferative (XLP) syndrome?

Which patient groups have the highest prevalence of X-linked lymphoproliferative (XLP) syndrome?

What is the prognosis of X-linked lymphoproliferative (XLP) syndrome?

Presentation

Which clinical history findings are characteristic of X-linked lymphoproliferative syndrome type 1 (XLP1)?

Which clinical history findings are characteristic of X-linked lymphoproliferative syndrome type 2 (XLP2)?

Which physical findings are characteristic of X-linked lymphoproliferative (XLP) syndrome?

How is lymphoma characterized in X-linked lymphoproliferative (XLP) syndrome?

DDX

What are the differential diagnoses for X-linked Lymphoproliferative Syndrome?

Workup

What is the role of lab testing in the workup of X-linked lymphoproliferative (XLP) syndrome?

Which histologic findings are characteristics of X-linked lymphoproliferative (XLP) syndrome?

Treatment

What is the role of gene therapy in the treatment of X-linked lymphoproliferative (XLP) syndrome?

How is X-linked lymphoproliferative (XLP) syndrome treated?

How is Epstein-Barr infection treated in X-linked lymphoproliferative (XLP) syndrome?

How is hemophagocytic lymphohistiocytosis (HLH) treated in X-linked lymphoproliferative (XLP) syndrome?

How is lymphoma treated in X-linked lymphoproliferative (XLP) syndrome?

What is the role of hematopoietic stem cell transplantation (HSCT) in the treatment of X-linked lymphoproliferative (XLP) syndrome?

What is included in the long-term monitoring of X-linked lymphoproliferative (XLP) syndrome?

Medications

What is the role of medications in the treatment of X-linked lymphoproliferative (XLP) syndrome?

Which medications in the drug class Blood Products are used in the treatment of X-linked Lymphoproliferative Syndrome?

Which medications in the drug class Monoclonal Antibody are used in the treatment of X-linked Lymphoproliferative Syndrome?

Which medications in the drug class Antineoplastic Agents are used in the treatment of X-linked Lymphoproliferative Syndrome?