X-linked Lymphoproliferative Syndrome

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X-linked lymphoproliferative (XLP) syndrome is a rare recessive genetic disorder that can be divided into two types based on its genetic cause and pattern of signs and symptoms. X-linked lymphoproliferative syndrome type 1 (XLP1), also known as classic XLP, is caused by mutations in SH2D1A; XLP type 2 (XLP2) is caused by the XIAP gene. ^{[1, 2]}

XLP1 is characterized by a severe Epstein-Barr virus (EBV)–induced hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, malignant lymphoma, dysgammaglobulinemia, and common variable immunodeficiency (CVID). ^[3]  Neither malignant lymphoma nor CVID have been reported in XLP2. Patients with XLP2 are more likely to develop HLH without EBV infection, splenomegaly, and may also have inflammation of the large intestine (colitis). ^[4]

Currently, the only definitive treatment available for XLP1 patients is allogeneic hematopoietic stem cell transplant (HSCT). ^[5]  However, depending on clinical features, less aggressive treatments may be adopted, particularly if a suitable donor for transplant is not available. As symptoms may not all be present simultaneously, and they may be of varying severity, treatment options that target specific clinical phenotypes may be appropriate. ^[6]

For patient education information, see the Infections Center, as well as Mononucleosis.

X-linked lymphoproliferative (XLP) syndrome is characterized by a high susceptibility to severe infection with EBV. Hemophagocytic lymphohistiocytosis is the most common presenting feature. Other patients develop fulminant infectious mononucleosis following infection with EBV. Most succumb to hepatic necrosis and/or bone marrow failure. Those that survive manifest chronic hypogammaglobulinemia and are at risk for lymphoma and aplastic anemia.

In 1998, the gene for classic XLP syndrome 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 XLP converts normally activating signals into inhibitory signals. ^{[7, 8, 9, 10]}

An XLP syndrome caused by mutations in the inhibitor-of-apoptosis gene XIAP has also been reported. ^{[11, 12]}

Mutations in the SH2D1A and XIAP genes cause XLP syndrome. SH2D1A gene mutations cause XLP1, and XIAP gene mutations cause XLP2. ^[13]

X-linked lymphoproliferative (XLP) syndrome is rare. XLP1 is estimated to occur in about 1 in 1,000,000 males worldwide. XLP2 occurs in about 1 in 5,000,000 males. ^[4]

XLP syndrome has been reported in families of European, African, Asian, and Middle Eastern descent and no evidence exists for a racial or ethnic predilection. Because XLP syndrome is an X-linked disorder, nearly all patients are male. However, a case of a heterozygous female who became symptomatic due to skewed X-chromosome inactivation has been reported. ^{[13, 14]}

The overall mortality of XLP1 has decreased significantly since 1995, from 75 to 29%. This is largely due to improved chemotherapy protocols and stem cell transplantion, as well as improved monitoring and supportive care. ^[6]  Mortality is most often related to HLH (70%), lymphoma (12%), and complications of transplantation (12%). ^[13]

The mean age at death for XLP2 has been reported as 16 years with mortality due to HLH (30%), complications of HCT (30%), colitis (23%), liver failure (8%), and pneumonia (8%). However, approximately 43% of patients with XLP2 reach adulthood. Of note, some males with a pathogenic variant in XIAP are asymptomatic and their long-term prognosis is unknown. ^[13]

Stem cell transplantation has significantly prolonged the survival of these patients. In a report by Booth et al of 43 patients who underwent transplantation compared with 48 patients who did not, survival was 81.4% for transplanted patients compared with 62.5% for untransplanted patients. ^[5]  Follow-up ranged from 4 to 148 months. Patients with a history of hemophagocytic lymphohistiocytosis had an inferior survival, 50% if transplanted and only 18.8% if not transplanted. The outcome was best for older patients (especially older than 15 years) with a matched sibling donor and no prior history of hemophagocytic lymphohistiocytosis.

Almost a third of patients with XLP1 develop lymphoma, with the most common form being abdominal B cell non-Hodgkin lymphoma in both EBV-positive and EBV-negative patients. Prognosis for those patients has dramatically improved over the decades due to improved  lymphoma chemotherapy protocols. ^[6]

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. [Medline].

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. [Medline]. [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. [Medline]. [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. November 2014; Accessed: April 25, 2018.

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. [Medline].

Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front Immunol. 2018. 9:666. [Medline]. [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. [Medline].

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. [Medline]. [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. [Medline].

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. [Medline].

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. [Medline].

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. [Medline].

Zhang K, Wakefield E, Marsh R, Adam MP, Ardinger HH, Pagon RA, et al. Lymphoproliferative Disease, X-Linked. GeneReviews [Internet]. June 30, 2016. [Medline]. [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. [Medline].

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. [Medline]. [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. [Medline].

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. [Medline]. [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. [Medline]. [Full Text].

Ghosh S, Gaspar HB. Gene Therapy Approaches to Immunodeficiency. Hematol Oncol Clin North Am. 2017 Oct. 31 (5):823-834. [Medline].

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. [Medline].

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. [Medline].

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. [Medline]. [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. [Medline].

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.

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.

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.

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.

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.

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.

X-linked Lymphoproliferative Syndrome

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