eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoproliferative Syndrome, X-linked

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

Updated: Sep 15, 2008

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.
  

More on Lymphoproliferative Syndrome, X-linked

Overview: Lymphoproliferative Syndrome, X-linked
Differential Diagnoses & Workup: Lymphoproliferative Syndrome, X-linked
Treatment & Medication: Lymphoproliferative Syndrome, X-linked
Follow-up: Lymphoproliferative Syndrome, X-linked
References
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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].

  17. Purtilo DT, Cassel C, Yang JP. Fatal infectious mononucleosis in familial lymphohistiocytosis (letter). N Engl J Med. Oct 3 1974;291(14):736. [Medline].

  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].

  22. Tran H, Nourse J, Hall S, et al. Immunodeficiency-associated lymphomas. Blood Rev. Sep 2008;22(5):261-81. [Medline].

  23. Williams LL, Rooney CM, Conley ME, et al. Correction of Duncan's syndrome by allogeneic bone marrow transplantation. Lancet. Sep 4 1993;342(8871):587-8. [Medline].

  24. Ziegner UH, Ochs HD, Schanen C, et al. Unrelated umbilical cord stem cell transplantation for X-linked immunodeficiencies. J Pediatr. Apr 2001;138(4):570-3. [Medline].

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Further Reading

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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

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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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