Pediatric Hematology/Oncology and Immunopathology

Advanced search

X-Linked lymphoproliferative syndrome types 1 and 2 (Review of literature and clinical case reports)

Full Text:


X-Linked lymphoproliferative syndrome (XLP) is a primary immunodeficiency characterized by atypical reaction to Epstein-Barr virus (EBV), resulting in the development of hemophagocytosis, disgammaglobulinemia, and, depending on the syndrome type, malignant lymphoproliferation. Three types of XLP are known. XLP type 1 is a result of mutation in the SH2D1A gene encoding SAP adapter molecule. This XLP type is characterized by predisposition to EBV infection, hemophagocytic lymphohistiocytosis (HLH), disgammaglobulinemia, and malignant lymphoproliferation. XLP type 2 is similar to XLP type 1 by some clinical manifestations, such as predisposition to EBV infection and high risk of HLH, but differs from type 1 by the pathogenesis, development of hemorrhagic colitis, and absence of lymphomas. The clinical manifestations of XLP type 2 develop as a result of defects in XIAP gene, also known as BIRC4 gene, encoding an antiapoptotic protein. XLP type 3, caused by loss-of-function _ mutations in the gene encoding magnesium transporter 1 (MAGT1), has been recently discovered. In addition, several autosomal recessive syndromes with a similar XLP clinical manifestation - EBV-associated lymphoproliferation, with ITK, CD27, and CORO1A genes defects, are known. Clinical case reports of the most incident XLP types 1 and 2 are presented.

About the Authors

Anna A. Roppelt
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Darya V. Yukhacheva
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Natalya V. Myakova
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Nadezhda V. Smirnova
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Yuliya V. Skvortsova
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Tatyana V. Varlamova
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Elena V. Raikina
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Dmitry S. Abramov
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation

Natalya B. Ulanova
St. Petersburg State Pediatric Medical University
Russian Federation

Tatyana V. Gabrusskya
St. Petersburg State Pediatric Medical University
Russian Federation

Anna Yu. Shcherbina
Federal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry Rogachev
Russian Federation


1. Purtilo DT, Grierson HL. Methods of detection of new families with X-linked lymphoproliferative disease. Cancer Genet Cytogenet. 1991; 51(2): 143-53.

2. Aguilar C, Latour S. X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome. J Clin Immunol. 2015; 35(4): 331-8.

3. Hambleton G, Cottom DG. Familial lymphoma. Proc R Soc Med. 1969; 62(11, Pt 1): 1095.

4. Purtilo DT, Grierson HL, Davis JR, Okano M. The X-linked lymphoproliferative disease: from autopsy toward cloning the gene 1975-1990. Pediatr Pathol. 1991; 11(5): 685-710.

5. Seemayer TA, Gross TG, Egeler RM, Pirruccello SJ, Davis JR, Kelly CM, et al. X-linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr Res. 1995; 38(4): 471-8.

6. Harrington DS, Weisenburger DD, Purtilo DT. Malignant lymphoma in the X-linked lymphoproliferative syndrome. Cancer. 1987; 59(8): 1419-29.

7. Sumegi J, Huang D, Lanyi A, Davis JD, Seemayer TA, Maeda 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. 2000; 96(9): 3118-25.

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

9. Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998; 20(2): 129-35.

10. Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist KA, Genovese C, et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci USA. 1998; 95(23): 13765-70.

11. Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, et al. The X-linked lympho-proliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. 1998; 395(6701): 462-9.

12. Nagy N, Cerboni C, Mattsson K, Maeda A, Gogolak P, Sümegi J, et al. SH2D1A and SLAM protein expression in human lymphocytes and derived cell lines. Int J Cancer. 2000; 88(3): 439-47.

13. Latour S, Veillette A. Molecular and immunological basis of X-linked lymphoproliferative disease. Immunol Rev. 2003; 192: 212-24.

14. Cannons JL, Yu LJ, Hill B, Mijares LA, Dombroski D, Nichols KE, et al. SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1. Immunity. 2004; 21(5): 693-706.

15. Veillette A. Immune regulation by SLAM family receptors and SAP-related adaptors. Nat Rev Immunol. 2006; 6(1): 56-66.

16. Tangye SG. XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. J Clin Immunol. 2014; 34(7): 772-9.

17. Bottino C, Falco M, Parolini S, Marcenaro E, Augugliaro R, Sivori S, et al. NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. J Exp Med. 2001; 194(3): 235-46.

18. Hislop AD, Palendira U, Leese AM, Arkwright PD, Rohrlich PS, Tangye SG, et al. Impaired Epstein-Barr virus-specific CD8+ T-cell function in X-linked lympho-proliferative disease is restricted to SLAM family-positive B-cell targets. Blood. 2010; 116(17): 3249-57.

19. Dupré L, Andolfi G, Tangye SG, Clementi R, Locatelli F, Aricó M, et al. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood. 2005: 105(11): 4383-9.

20. Palendira U, Low C, Chan A, Hislop AD, Ho E, Phan TG, et al. Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP. PLoS Biol. 2011; 9(11): e1001187.

21. Ganem D. KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest. 2010; 120(4): 939-49.

22. Griewank K, Borowski C, Rietdijk S, Wang N, Julien A, Wei DG, et al. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity. 2007; 27(5): 751-62.

23. Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature. 2008; 455(7214): 764-9.

24. Snow AL, Marsh RA, Krummey SM, Roehrs P, Young LR, Zhang K, et al. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J Clin Invest. 2009: 119(10): 2976-89.

25. Rigaud S, Fondanèche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006; 444(7115): 110-4.

26. Zhao M, Kanegane H, Ouchi K, Imamura T, Latour S, Miyawaki T. A novel XIAP mutation in a Japanese boy with recurrent pancytopenia and splenomegaly. Haematologica. 2010; 95(4): 688-9.

27. 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; 117(5): 1522-9.

28. Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011; 13(3): 255-62.

29. Ochs HD, Smith CI, Puck JM, eds. Primary immunodeficiency diseases: A molecular and genetic approach. 3rd ed. Oxford University Press: 2013.

30. Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010; 116(7): 1079-82.

31. Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006; 7(10): 988-94.

32. Gérart S, Sibéril S, Martin E, Lenoir C, Aguilar C, Picard C, et al. Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP. Blood. 2013; 121(4): 614-23.

33. Galban S, Duckett CS. XIAP as a ubiquitin ligase in cellular signaling. Cell Death Differ. 2010; 17(1): 54-60.

34. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol. 2006; 6(1): 9-20.

35. Kapoor A, Forman M, Arav-Boger R. Activation of nucleotide oligomerization domain 2 (NOD2) by human cytomegalovirus initiates innate immune responses and restricts virus replication. PLoS One. 2014; 9(3): e92704.

36. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014; 14(1): 19-23.

37. Glocker EO, Kotlarz D, Klein C, Shah N, Grimbacher B. IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci. 2011; 1246: 102-7.

38. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001; 411(6837): 599-603.

39. Yabal M, Müller N, Adler H, Knies N, Groß CJ, Damgaard RB, et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep. 2014; 7(6): 1796-808.

40. Latour S, Aguilar C. XIAP deficiency syndrome in humans. Semin Cell Dev Biol. 2015; 39: 115-23.

41. Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of Epstein-Barr virus - induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013; 162(3): 376-82.

42. Mischler M, Fleming GM, Shanley TP, Madden L, Levine J, Castle V, et al. Epstein-Barr virus - induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease: a mimicker of sepsis in the pediatric intensive care unit. Pediatrics. 2007; 119(5): 1212-8.

43. Rezaei N, Mahmoudi E, Aghamohammadi A, Das R, Nichols KE. X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma. Br J Haematol. 2010; 152(1): 13-30.

44. Aguilar C, Lenoir C, Lambert N, Bègue B, Brousse N, Canioni D, et al. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol. 2014: 134(5): 1131-41. e9.

45. Rivat C, Booth C, Alonso-Ferrero M, Blundell M, Sebire NJ, Thrasher AJ, et al. SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease. Blood. 2013; 121(7): 1073-6.

46. Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011; 475(7357): 471-6.

47. Zhou H, Clapham DE. Mammalian MagT1 andTUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc Natl Acad Sci USA. 2009; 106(37): 15750-5.

48. Li FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014; 123(14): 2148-52.

49. Ghosh S, Bienemann K, Boztug K, Borkhardt A. Interleukin-2-inducible T-cell kinase (ITK) deficiency - clinical and molecular aspects. J Clin Immunol. 2014: 34(8): 892-9.

50. Salzer E, Daschkey S, Choo S, Gombert M, Santos-Valente E, Ginzel S, et al. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27. Haematologica. 2013: 98(3): 473-8.

51. Moshous D, Martin E, Carpentier W, Lim A, Callebaut I, Canioni D, et al. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J Allergy Clin Immunol. 2013; 131(6): 1594-603.

52. Donhuijsen-Ant R, Abken H, Bornkamm G, Donhuijsen K, Grosse-Wilde H, Neumann-Haefelin D, et al. Fatal Hodgkin and non-Hodgkin lymphoma associated with persistent Epstein-Barr virus in four brothers. Ann Intern Med. 1988: 109(12): 946-52.

For citation:

Roppelt A.A., Yukhacheva D.V., Myakova N.V., Smirnova N.V., Skvortsova Yu.V., Varlamova T.V., Raikina E.V., Abramov D.S., Ulanova N.B., Gabrusskya T.V., Shcherbina A.Yu. X-Linked lymphoproliferative syndrome types 1 and 2 (Review of literature and clinical case reports). Pediatric Hematology/Oncology and Immunopathology. 2016;15(1):17-26. (In Russ.)

Views: 1180

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 1726-1708 (Print)
ISSN 2414-9314 (Online)