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]}

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]

Differential Diagnoses

Jin YY, Zhou W, Tian ZQ, Chen TX. Variable clinical phenotypes of X-linked lymphoproliferative syndrome in China: Report of five cases with three novel mutations and review of the literature. Hum Immunol. 2016 Aug. 77 (8):658-66. [QxMD MEDLINE Link].
Lyu X, Guo Z, Li Y, Fan R, Song Y. Identification of a novel nonsense mutation in SH2D1A in a patient with X-linked lymphoproliferative syndrome type 1: a case report. BMC Med Genet. 2018 Apr 12. 19 (1):60. [QxMD MEDLINE Link]. [Full Text].
Zhang JY, Chen SC, Chen YY, Li SY, Zhang LL, Shen YH, et al. Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing. PLoS One. 2017. 12 (2):e0172173. [QxMD MEDLINE Link]. [Full Text].
U.S. National Library of Medicine. X-linked lymphoproliferative disease. Genetic Home Reference. Available at https://ghr.nlm.nih.gov/condition/x-linked-lymphoproliferative-disease#statistics. May 17, 2021; Accessed: January 22, 2022.
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. 2011 Jan 6. 117(1):53-62. [QxMD MEDLINE Link].
Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front Immunol. 2018. 9:666. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link].
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. 1999 Jun 15. 162(12):6981-5. [QxMD MEDLINE Link]. [Full Text].
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. 1998 Oct 1. 395(6701):462-9. [QxMD MEDLINE Link].
Bárcena P, Jara-Acevedo M, Tabernero MD, López A, Sánchez ML, García-Montero AC, et al. Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality. Oncotarget. 2015 Nov 6. [QxMD MEDLINE Link].
Rigaud S, Fondanèche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006 Nov 2. 444(7115):110-4. [QxMD MEDLINE Link].
Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011 Feb 3. 117(5):1522-9. [QxMD MEDLINE Link].
Zhang K, Wakefield E, Marsh R, Adam MP, Ardinger HH, Pagon RA, et al. Lymphoproliferative Disease, X-Linked. GeneReviews [Internet]. June 30, 2016. [QxMD MEDLINE Link]. [Full Text].
Holle JR, Marsh RA, Holdcroft AM, Davies SM, Wang L, Zhang K, et al. Hemophagocytic lymphohistiocytosis in a female patient due to a heterozygous XIAP mutation and skewed X chromosome inactivation. Pediatr Blood Cancer. 2015 Jul. 62 (7):1288-90. [QxMD MEDLINE Link].
Marsh RA, Bleesing JJ, Filipovich AH. Using flow cytometry to screen patients for X-linked lymphoproliferative disease due to SAP deficiency and XIAP deficiency. J Immunol Methods. 2010 Oct 31. 362(1-2):1-9. [QxMD MEDLINE Link]. [Full Text].
Marsh RA, Bleesing JJ, Filipovich AH. Flow cytometric measurement of SLAM-associated protein and X-linked inhibitor of apoptosis. Methods Mol Biol. 2013. 979:189-97. [QxMD MEDLINE Link].
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. 2005 Feb 1. 105(3):994-6. [QxMD MEDLINE Link]. [Full Text].
Chen RY, Li XZ, Lin Q, Zhu Y, Shen YY, Xu QY, et al. Epstein-Barr virus-related hemophagocytic lymphohistiocytosis complicated with coronary artery dilation and acute renal injury in a boy with a novel X-linked inhibitor of apoptosis protein (XIAP) variant: a case report. BMC Pediatr. 2020 Oct 2. 20 (1):456. [QxMD MEDLINE Link]. [Full Text].
Bergsten E, Horne A, Aricó M, Astigarraga I, Egeler RM, Filipovich AH, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017 Dec 21. 130 (25):2728-2738. [QxMD MEDLINE Link]. [Full Text].
Faguer S, Vergez F, Peres M, Ferrandiz I, Casemayou A, Belliere J, et al. Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T-cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis. Hematol Oncol. 2016 Mar. 34 (1):55-7. [QxMD MEDLINE Link].
Ghosh S, Gaspar HB. Gene Therapy Approaches to Immunodeficiency. Hematol Oncol Clin North Am. 2017 Oct. 31 (5):823-834. [QxMD MEDLINE Link].
Rivat C, Booth C, Alonso-Ferrero M, Blundell M, Sebire NJ, Thrasher AJ. SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease. Blood. 2013 Feb 14. 121(7):1073-6. [QxMD MEDLINE Link].
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. 2005 Jul. 36(2):99-105. [QxMD MEDLINE Link].
Marsh RA, Bleesing JJ, Chandrakasan S, Jordan MB, Davies SM, Filipovich AH. Reduced-intensity conditioning hematopoietic cell transplantation is an effective treatment for patients with SLAM-associated protein deficiency/X-linked lymphoproliferative disease type 1. Biol Blood Marrow Transplant. 2014 Oct. 20 (10):1641-5. [QxMD MEDLINE Link]. [Full Text].

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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, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for 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 Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Koyamangalath Krishnan, MD, FRCP, FACP Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, 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, Royal College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

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.