open access

Vol 13, No 1 (2022)
Review paper
Published online: 2022-05-09
Get Citation

Hematological manifestations of X-linked lymphoproliferative disease

Natalia Aleksandra Dułak1, Jadwiga Juwa2, Rafał Trzciński1, Alan Majeranowski3, Ninela Irga-Jaworska4
DOI: 10.5603/HCP.a2022.0002
·
Hematology in Clinical Practice 2022;13(1):1-6.
Affiliations
  1. Saint Vincent de Paul Hospital, Gdynia, Poland
  2. University Clinical Centre, Gdańsk, Poland
  3. Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland, Dębinki 1 Street, 80-211 Gdańsk, Poland
  4. Department of Paediatrics, Haemathology and Oncology, Medical University of Gdansk

open access

Vol 13, No 1 (2022)
REVIEW ARTICLES
Published online: 2022-05-09

Abstract

X-linked lymphoproliferative disease (XLP) is a rare genetic disorder that occurs predominantly in boys. There are two types of the disease, each with different clinical and genetic characteristics. XLP1 is caused by the mutation in the SH2D1A gene and XLP2 is associated with the mutation in XIAP/BIRC gene. Genetic defects lead to the dysfunction of the immune system. Additionally, Epstein-Bárr virus infection plays a major role in the development of the disease. Clinical manifestation varies significantly, even among family members who carry the same mutation. The disease most often manifests with haemophagocytic lymphohistiocytosis, dysgammaglobulinemia, fulminant infectious mononucleosis, splenomegaly, and B-cell lymphomas localized near the ileocecal valve, and colitis. Differential diagnosis should primarily consider more frequent disorders with an impaired immunological response. XLP is a fatal disease, but with the development of new treatment options, patients’ life expectancy has increased significantly. Currently, the only definitive treatment is an early allogeneic hematopoietic stem cell transplantation. The onset of severe symptoms before transplantation largely reduces the patient’s chances of therapeutic success. As a result, it is crucial to make an early diagnosis. New therapies that include enzyme inhibition, gene therapy, and gene editing are very promising. Patients and their families should be provided with genetic counselling and the possibility of preimplantation diagnostics.

Abstract

X-linked lymphoproliferative disease (XLP) is a rare genetic disorder that occurs predominantly in boys. There are two types of the disease, each with different clinical and genetic characteristics. XLP1 is caused by the mutation in the SH2D1A gene and XLP2 is associated with the mutation in XIAP/BIRC gene. Genetic defects lead to the dysfunction of the immune system. Additionally, Epstein-Bárr virus infection plays a major role in the development of the disease. Clinical manifestation varies significantly, even among family members who carry the same mutation. The disease most often manifests with haemophagocytic lymphohistiocytosis, dysgammaglobulinemia, fulminant infectious mononucleosis, splenomegaly, and B-cell lymphomas localized near the ileocecal valve, and colitis. Differential diagnosis should primarily consider more frequent disorders with an impaired immunological response. XLP is a fatal disease, but with the development of new treatment options, patients’ life expectancy has increased significantly. Currently, the only definitive treatment is an early allogeneic hematopoietic stem cell transplantation. The onset of severe symptoms before transplantation largely reduces the patient’s chances of therapeutic success. As a result, it is crucial to make an early diagnosis. New therapies that include enzyme inhibition, gene therapy, and gene editing are very promising. Patients and their families should be provided with genetic counselling and the possibility of preimplantation diagnostics.

Get Citation

Keywords

X-linked lymphoproliferative disease, X-linked recessive, immunodeficiency, hematopoietic stem cell transplantation, haemophagocytic lymphohistiocytosis

About this article
Title

Hematological manifestations of X-linked lymphoproliferative disease

Journal

Hematology in Clinical Practice

Issue

Vol 13, No 1 (2022)

Article type

Review paper

Pages

1-6

Published online

2022-05-09

Page views

1903

Article views/downloads

168

DOI

10.5603/HCP.a2022.0002

Bibliographic record

Hematology in Clinical Practice 2022;13(1):1-6.

Keywords

X-linked lymphoproliferative disease
X-linked recessive
immunodeficiency
hematopoietic stem cell transplantation
haemophagocytic lymphohistiocytosis

Authors

Natalia Aleksandra Dułak
Jadwiga Juwa
Rafał Trzciński
Alan Majeranowski
Ninela Irga-Jaworska

References (28)
  1. Nichols KE, Ma CS, Cannons JL, et al. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol Rev. 2005; 203: 180–199.
  2. Booth C, Gilmour KC, Veys P, 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.
  3. Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene. Blood. 2001; 97(4): 1131–1133.
  4. Xu T, Zhao Q, Li W, et al. X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic. Eur J Pediatr. 2020; 179(2): 327–338.
  5. Liang JH, Zhu HY, Xu DM, et al. A new SH2D1A mutation in a female adult XLP disease with hemophagocytic lymphohistiocytosis and NK-cell leukemia. Ann Hematol. 2019; 98(12): 2829–2831.
  6. Purtilo DT. X-linked lymphoproliferative disease. Lancet. 1992; 339(8788): 312.
  7. Panchal N, Booth C, Cannons JL, et al. X-linked lymphoproliferative disease type 1: a clinical and molecular perspective. Front Immunol. 2018; 9: 666.
  8. Jin YY, Zhou W, Tian ZQ, et al. 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; 77(8): 658–666.
  9. Tangye SG. XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. J Clin Immunol. 2014; 34(7): 772–779.
  10. Filipovich AH. Gene therapy targets XLP. Blood. 2013; 121(7): 1066–1067.
  11. Ruffo E, Malacarne V, Larsen SE, et al. Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1. Sci Transl Med. 2016; 8(321): 321ra7.
  12. Velnati S, Ruffo E, Massarotti A, et al. Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening. Eur J Med Chem. 2019; 164: 378–390.
  13. Pachlopnik Schmid J, Canioni D, Moshous D, 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): 1522–1529.
  14. Blackburn PR, Lin WL, Miller DA, et al. X-linked lymphoproliferative syndrome presenting as adult-onset multi-infarct dementia. J Neuropathol Exp Neurol. 2019; 78(5): 460–466.
  15. Nelson DL, Terhorst C. X-linked lymphoproliferative syndrome. Clin Exp Immunol. 2000; 122(3): 291–295.
  16. Romaszko A, Żuber Z. Wtórny zespół hemofagocytarny. Forum Reumatologiczne. 2018; 4(3): 189–195.
  17. Balfour HH, Dunmire SK, Hogquist KA. Infectious mononucleosis. Clin Transl Immunology. 2015; 4(2): e33.
  18. Fujii SI, Shimizu K. Immune networks and therapeutic targeting of iNKT cells in cancer. Trends Immunol. 2019; 40(11): 984–997.
  19. Filipovich AH, Zhang K, Snow AL, et al. X-linked lymphoproliferative syndromes: brothers or distant cousins? Blood. 2010; 116(18): 3398–3408.
  20. Latour S, Aguilar C. XIAP deficiency syndrome in humans. Semin Cell Dev Biol. 2015; 39: 115–123.
  21. Vince N, Mouillot G, Malphettes M, et al. DEFI Study Group. Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management. Hum Immunol. 2018; 79(7): 571–577.
  22. Li FY, Chaigne-Delalande B, Su H, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014; 123(14): 2148–2152.
  23. Stepensky P, Weintraub M, Yanir A, et al. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica. 2011; 96(3): 472–476.
  24. 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; 105(3): 994–996.
  25. 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; 362(1-2): 1–9.
  26. Trottestam H, Beutel K, Meeths M, et al. Treatment of the X-linked lymphoproliferative, Griscelli and Chédiak-Higashi syndromes by HLH directed therapy. Pediatr Blood Cancer. 2009; 52(2): 268–272.
  27. Baré P, Parodi C, Malbrán A, et al. Progressive reduction of circulating B lymphocytes in patients with X-linked lymphoproliferative disease (XLP). Br J Haematol. 2017; 177(4): 648–650.
  28. Chen S, Shi W, Qian Y, et al. Preimplantation genetic testing for a Chinese family with X-linked lymphoproliferative syndrome type 1. Front Genet. 2020; 11: 550507.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.