X-linked Lymphoproliferative Syndrome 

  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Mar 9, 2011
 

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.

Next

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]

Previous
Next

Epidemiology

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.

Previous
Proceed to Clinical Presentation
 
 
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; Celgene 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.

Specialty Editor Board

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.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

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.

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 Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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. Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. Jan 6 2011;117(1):53-62. [Medline].

  16. 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].

  17. 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].

  18. Marsh RA, Madden L, Kitchen BJ, ET AL. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. May 20 2010;epub ahead of print. [Medline].

  19. Nagy N, Klein E. Deficiency of the proapoptotic SAP function in X-linked lymphoproliferative disease aggravates Epstein-Barr virus (EBV) induced mononucleosis and promotes lymphoma development. Immunol Lett. May 4 2010;130(1-2):13-8. [Medline].

  20. Nagy N, Matskova L, Hellman U, Klein G, Klein E. The apoptosis modulating role of SAP (SLAM associated protein) contributes to the symptomatology of the X linked lymphoproliferative disease. Cell Cycle. Oct 1 2009;8(19):3086-90. [Medline].

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

  22. 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].

  23. 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].

  24. 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].

  25. Snow AL, Marsh RA, Krummey SM, et al. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J Clin Invest. Oct 2009;119(10):2976-89. [Medline]. [Full Text].

  26. 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].

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

  28. Veillette A. SLAM-family receptors: immune regulators with or without SAP-family adaptors. Cold Spring Harb Perspect Biol. Mar 2010;2(3):a002469. [Medline]. [Full Text].

  29. 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].

  30. 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].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.