Clinical Case of X-Linked Lymphoproliferative Syndrome Burdened with Hemophagocytic Lymphohistiocytosis and Crohn's Disease

Background. X-linked lymphoproliferative (XLP) syndrome is hereditary disease with the incidence of 1-3 per 1 million born boys. This clinical case demonstrates a rare picture of XLP type 2 manifestation without prior Epstein-Barr virus.

Clinical case description. Boy D., 15 years old, was admitted to Morozovskaya Children's City Hospital with complaints on fever, abdominal pain, loose stools, weight loss. The past medical history included hemophagocytic syndrome (remission) and acute erythema nodosum. We have performed several studies: abdominal ultrasound (hepatomegaly, dynamic changes in the intestine: parts of the small intestine were enlarged and walls were thickened, mass peristalsis, walls of transverse colon and descending colon are thickened up to 5 mm, mesenteric lymphadenopathy), rectosigmoidoscopy (high-activity ulcerative proctosigmoiditis corresponds to Crohn's disease), biochemical and clinical blood tests (active hemophagocytic syndrome), coagulogram (secondary hypocoagulation), myelogram (no data on hemoblastosis or aplastic condition). Virological blood tests (CMV, EBV, HHV-VI): negative. Laboratory and instrumental tests have revealed recurrence of hemophagocytic syndrome and Crohn's disease. The child was consulted by rheumatologist, hematologist, gastroenterologist, geneticist, neurologist, and clinical pharmacologist. The primary immune deficiency disease was suspected in this patient due to his medical history. Molecular genetic study was performed (deletion including the XIAP gene was revealed) and the diagnosis of primary immune deficiency was verified: X-linked lymphoproliferative syndrome type 2. Thus, allogeneic haematopoietic stem cell transplantation (HSCT) was performed.

Conclusion. XLP diagnosis and management require multidisciplinary approach. The early diagnosis is crucial due to the high risk of secondary complications development that can significantly worsen the disease's prognosis. Allogeneic HSCT is the only effective treatment for the disease. 

1. 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. doi: https://doi.org/10.1182/blood-2010-06-284935

2. Roppelt AA, Yukhacheva DV, Myakova NV, et al. X-Linked lymphoproliferative syndrome types 1 and 2. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Haematology/Oncology and Immunopathology. 2016;15(1):17–26. (In Russ). doi: https://doi.org/10.20953/1726-1708-2016-1-17-26

3. Schuster V, Steppberger K, Borte M. Manifestations of X-linked lymphoproliferative disease without prior Epstein-Barr exposure. Blood. 2001;98(6):1986–1987. doi: https://doi.org/10.1182/blood.v98.6.1986

4. Aguilar C, Lenoir C, Lambert N, 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):1131–1141.e9. doi: https://doi.org/10.1016/j.jaci.2014.04.031

5. Li FY, Chaigne-Delalande B, Rao VK, et al. Clinical utility gene card for: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN). Eur J Hum Genet. 2015;23(6). doi: https://doi.org/10.1038/ejhg.2014.179

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

7. 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. doi: https://doi.org/10.3109/15513819109065466

8. Picard С, Bobby Gaspar H, Al-Herz W, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2017;38(1):96–128. doi: https://doi.org/10.1007/s10875-017-0464-9

9. Marsh RA, Madden L, Kitchen BJ, 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):1079–1082. doi: https://doi.org/10.1182/blood-2010-01-256099

10. Latour S, Aguilar C. XIAP deficiency syndrome in humans. Semin Cell Dev Biol. 2015;39:115–123. doi: https://doi.org/10.1016/j.semcdb.2015.01.015

11. 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 (XLP2/ XIAP deficiency). Blood. 2011;117(5):1522–1529. doi: https://doi.org/10.1182/blood-2010-07-298372

12. Rigaud S, Fondanèche MC, Lambert N, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444(7115):110–114. doi: https://doi.org/10.1038/nature05257

13. Worthey EA, Mayer AN, Syverson GD, 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):255–262. doi: https://doi.org/10.1097/GIM.0b013e3182088158

14. Balashov D, Shcherbina A, Maschan M, et al. SingleCenter Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRαβ and CD19 Depletion in Children with Primary Immunodeficiency Syndromes. Biol Blood Marrow Transplant. 2015;21(11):1955–1962. doi: https://doi.org/10.1016/j.bbmt.2015.07.008

15. Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front Immunol. 2018;9:666. doi: https://doi.org/10.3389/fimmu.2018.00666

16. 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. doi: https://doi.org/10.1016/j.jim.2010.08.010

17. Kuzmenko NB, Varlamova TV, Mersiyanova IV, et al. Molecular genetic diagnosis of primary immunodeficiencies. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Haematology/ Oncology and Immunopathology. 2016;15(1):10–16. (In Russ). doi: https://doi.org/10.20953/1726-1708-2016-1-10-16

18. Volodin NN, Kasatkin VN, Tseitlin GY, et al. Strategy of medical, psychological and social rehabilitation for children with haematological and oncological diseases. Oncohematology. 2015;10(1):7–15. (In Russ). doi: https://doi.org/10.17650/1818-8346-2015-1-7-15