eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoproliferative Syndrome, X-linked: Differential Diagnoses & Workup

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, 2009

Differential Diagnoses

Aplastic Anemia
Lymphoma, Diffuse Large Cell
Hepatitis
Lymphoma, High-Grade Malignant Immunoblastic
Hypogammaglobulinemia
Lymphoma, Malignant Small Noncleaved
Infectious Mononucleosis
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell

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.

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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