eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoproliferative Syndrome, X-linked

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
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

Updated: Sep 15, 2009

Introduction

Background

X-linked lymphoproliferative (XLP) syndrome is a rare immunodeficiency disease that is characterized by a predilection for 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}

For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Mononucleosis.

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. 

Physical

• Infectious mononucleosis
  • Fever
  • Pallor
  • Pharyngitis
  • Hepatosplenomegaly
  • Lymphadenopathy
  • Jaundice
  • Ecchymosis
• Lymphoma: Findings related to the site of involvement

Causes

In the majority of cases, X-linked lymphoproliferative syndrome (XLP) is caused by an inherited defect in the SH2D1A gene. In some patients, X-linked lymphoproliferative syndrome (XLP) is related to an inherited defect in XIAP.
  

Differential Diagnoses

Other Problems to Be Considered

Hemophagocytic syndrome

Workup

Laboratory Studies

Peripheral blood smears will show atypical lymphocytosis.

Chemistry profiles will show transaminitis and other findings of acute hepatitis.

Coagulations studies will be abnormal in patients with liver failure.

Patients with acute 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 X-linked lymphoproliferative syndrome (XLP) is with mutation analysis for the SH2D1A gene mutation.

Imaging Studies

No specific imaging studies are helpful in X-linked lymphoproliferative syndrome (XLP).

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 NK 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

Currently, the only cure for X-linked lymphoproliferative disease (XLP) is allogeneic stem cell transplantation.¹⁴

As reported by the David Purtilo International XLP registry: Seven patients were treated with human leukocyte antigen (HLA)-identical allogeneic stem cell transplantation (sibling bone marrow: 5 patients; unrelated bone marrow: 1 patient; sibling umbilical cord: 1 patient). Four patients were alive with normal immune function more than 3 years after transplantation. Six patients developed acute grade I-II graft versus host disease. Three patients died within 100 days, 1 due to sepsis, 1 due to disseminated adenovirus infection, and 1 with multi-organ system failure.

• Anti-CD20 rituximab: Milone et al administered the anti-CD20 antibody rituximab to 2 patients who presented with acute EBV infection.⁴ Following treatment, both patients exhibited a complete resolution of symptoms and no longer demonstrated detectable EBV DNA within circulating lymphocytes. Moreover, neither patient has developed fulminant infectious mononucleosis (FIM) or lymphoma in more than 2 years of follow-up. These data suggest that the preemptive use of B-cell–directed therapy may reduce the morbidity and mortality of primary EBV infection in X-linked lymphoproliferative disease (XLP)–affected individuals.
• Cytotoxic chemotherapy
  • Suggestions exist that treatment with cytotoxic chemotherapy during the acute IgM syndrome might be helpful in controlling proliferation of EBV-transformed B cells, as well as potentially activated cytotoxic lymphocytes that may be causing the severe tissue reactions observed in X-linked lymphoproliferative disease (XLP).
  • In a small number of cases, etoposide has been shown to lead to control of lymphocyte proliferation, at least temporarily. Limited anecdotal data confirm that this or other cytotoxic agents may be a successful treatment modality; however, further study is needed.¹⁵
• Patients with B-cell lymphomas should be treated with the standard therapy for that disease. Special attention should be paid toward the potential infectious complications of these therapies.

Consultations

Consultation by a genetic counselor could assist the family, if available.

Medication

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

Antineoplastic Agents

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.

Dosing

Adult

Not established

Pediatric

Not established; 200 mg/m²/d IV for 3 d is suggested

Interactions

May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; IT administration may cause death

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur; decrease dose in the presence of hyperbilirubinemia and renal dysfunction; avoid extravasation; should only be administered by trained physician; adverse effects include myelosuppression, nausea, and vomiting (can be controlled with serotonin-antagonist antiemetics such as ondansetron, granisetron, or dolasetron)

Monoclonal Antibody

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.

Dosing

Adult

Not established; 375 mg/m²/ IV is suggested

Pediatric

Not established

Interactions

Coadministration with cisplatin is known to cause severe renal toxicity, including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)

Contraindications

Documented hypersensitivity; IgE-mediated reaction to murine proteins; caution in patients with human immunodeficiency virus and hepatitis B

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease the incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion: do not administer IV push or bolus

Blood Products

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.

Dosing

Adult

Not established; most patients are children

Pediatric

500 mg/kg/d IV throughout acute course of mononucleosis is suggested; once the acute phase has begun to resolve, maintenance therapy can be administered at a decreased frequency; one report of a single case added interferon alfa (2 X 10⁶ IU/m²/d) to this regimen, with ultimately a good outcome.

Interactions

Increases the toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine

Contraindications

Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Check serum IgA before IVIG (use an IgA-depleted product; eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase the risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases the risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Follow-up

Complications

• See Pathophysiology.

Prognosis

• Except for reported cases of optimal outcome after monoclonal anti-CD20, and remission due to stem cell transplantation, few children with X-linked lymphoproliferative syndrome (XLP) survive to adulthood. Therefore, most patients with available matched donors apparently should be referred for transplantation. However, more data are needed to substantiate the efficacy of this form of therapy for X-linked lymphoproliferative disease (XLP).

Miscellaneous

Medicolegal Pitfalls

• X-linked lymphoproliferative syndrome (XLP) should be suspected in the case of an exceptionally severe lymphadenopathic reaction in a patient with mononucleosis. Otherwise, the rarity of X-linked lymphoproliferative syndrome (XLP) suggests little likelihood of legal risk.

References

1. Chaganti S, Ma CS, Bell AI, et al. Epstein-Barr virus persistence in the absence of conventional memory B cells: IgM+IgD+CD27+ B cells harbor the virus in X-linked lymphoproliferative disease patients. Blood. Aug 1 2008;112(3):672-9. [Medline].

2. Rigaud S, Fondanèche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. Nov 2 2006;444(7115):110-4. [Medline].

3. Lankester AC, Visser LF, Hartwig NG, et al. Allogeneic stem cell transplantation in X-linked lymphoproliferative disease: two cases in one family and review of the literature. Bone Marrow Transplant. Jul 2005;36(2):99-105. [Medline].

4. Milone MC, Tsai DE, Hodinka RL, et al. Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy. Blood. Feb 1 2005;105(3):994-6. [Medline]. [Full Text].

5. Sullivan JL. The abnormal gene in X-linked lymphoproliferative syndrome. Curr Opin Immunol. Aug 1999;11(4):431-4. [Medline].

6. Brandau O, Schuster V, Weiss M, et al. Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). Hum Mol Genet. Dec 1999;8(13):2407-13. [Medline]. [Full Text].

7. Coffey AJ, Brooksbank RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. Oct 1998;20(2):129-35. [Medline].

8. Nichols KE, Harkin DP, Levitz S, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci U S A. Nov 10 1998;95(23):13765-70. [Medline]. [Full Text].

9. Purtilo DT, Grierson HL, Davis JR, Okano M. The X-linked lymphoproliferative disease: from autopsy toward cloning the gene 1975-1990. Pediatr Pathol. Sep-Oct 1991;11(5):685-710. [Medline].

10. Harrington DS, Weisenburger DD, Purtilo DT. Malignant lymphoma in the X-linked lymphoproliferative syndrome. Cancer. Apr 15 1987;59(8):1419-29. [Medline].

11. Ma CS, Nichols KE, Tangye SG. Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu Rev Immunol. 2007;25:337-79. [Medline].

12. Tangye SG, Lazetic S, Woollatt E, et al. Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J Immunol. Jun 15 1999;162(12):6981-5. [Medline]. [Full Text].

13. Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. Oct 1 1998;395(6701):462-9. [Medline].

14. Gross TG, Filipovich AH, Conley ME, et al. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone Marrow Transplant. May 1996;17(5):741-4. [Medline].

15. Gürgey A, Sayli T, Kara A, Kale G, Berkel I. Treatment of X-linked lymphoproliferative disease (Duncan disease) with high-dose methylprednisolone and etoposide (VP-16). Turk J Pediatr. Apr-Jun 1996;38(2):217-22. [Medline].

16. Amrolia P, Gaspar HB, Hassan A, et al. Nonmyeloablative stem cell transplantation for congenital immunodeficiencies. Blood. Aug 15 2000;96(4):1239-46. [Medline]. [Full Text].

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18. Purtilo DT, Cassel CK, Yang JP, Harper R. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet. Apr 26 1975;1(7913):935-40. [Medline].

19. Purtilo DT, DeFlorio D Jr, Hutt LM, et al. Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome. N Engl J Med. Nov 17 1977;297(20):1077-80. [Medline].

20. Purtilo DT, Yang JP, Allegra S, et al. Hematopathology and pathogenesis of the X-linked recessive lymphoproliferative syndrome. Am J Med. Feb 1977;62(2):225-33. [Medline].

21. Sumegi J, Huang D, Lanyi A, et al. Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. Nov 1 2000;96(9):3118-25. [Medline]. [Full Text].

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Keywords

X-linked lymphoproliferative syndrome, X-linked lymphoproliferative disorder, lymphoproliferative disorders, lymphoproliferative diseases, XLP syndrome, Duncan syndrome, Duncan's syndrome, X-linked recessive progressive combined variable immunodeficiency syndrome, familial fatal EBV infection, Purtilo syndrome, Epstein-Barr virus, EBV, infectious mononucleosis, hypogammaglobulinemia, lymphoma

Contributor Information and Disclosures

Author

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Coauthor(s)

Doris Ponce, MD, Fellow, Department of Hematology/Oncology, New York Medical College
Doris Ponce, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

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
M Wayne Saville, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Koyamangalath Krishnan, MD, FRCP, FACP, Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

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