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X-linked lymphoproliferative syndrome

MedGen UID:
107498
•Concept ID:
C0549463
•
Neoplastic Process
Synonym: Lymphoproliferative Disease, X-Linked
SNOMED CT: XLPS - X-linked lymphoproliferative syndrome (77121009); Duncan's syndrome (77121009); X-linked lymphoproliferative syndrome (77121009); Purtilo syndrome (77121009); Familial fatal Epstein-Barr infection (77121009); Severe susceptibility to Epstein-Barr infection (77121009)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
•Concept ID:
C1845977
•
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
See: This record
X-linked recessive inheritance (Orphanet)
 
Related genes: SH2D1A, XIAP
 
Monarch Initiative: MONDO:0010627
Orphanet: ORPHA2442

Disease characteristics

Excerpted from the GeneReview: X-Linked Lymphoproliferative Disease
X-linked lymphoproliferative disease (XLP) in general is characterized by an inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, dysgammaglobulinemia, and lymphoproliferative disease (malignant lymphoma). The condition primarily affects males. XLP has two recognizable subtypes, XLP1 (due to pathogenic variants in SH2D1A) and XLP2 (due to pathogenic variants in XIAP). HLH / fulminant infectious mononucleosis is the most common presentation regardless of subtype. HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal. Death is generally secondary to liver failure or multisystem organ dysfunction. In those with XLP1, dys- or hypogammaglobulinemia can lead to varying degrees of humoral immune dysfunction associated with bronchiectasis and recurrent respiratory infections that, if untreated, may result in death. Lymphoproliferative disease (malignant lymphoma) and other lymphoproliferative diseases are specific to XLP1 and often develop in childhood, usually following EBV exposure. Rarer findings in those with XLP1 can include aplastic anemia, vasculitis, and lymphoid granulomatosis. Males with XLP2 are more likely to have HLH without EBV infection, recurrent episodes of HLH (which is not typically seen in those with XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis and perirectal abscesses or fistulae. Rarely, individuals with XLP2 and inflammatory bowel disease have been reported to develop inflammatory liver disease, which can progress to fatal liver failure. Transient hypogammaglobulinemia has been rarely observed in those with XLP2. To date, neither lymphoproliferative disease nor common variable immunodeficiency has been reported in males with XLP2. Heterozygous females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation favoring the X chromosome with the pathogenic variant who develop HLH, inflammatory bowel disease, and erythema nodosum. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
Authors:
Lauren Meyer  |  Melissa Hines  |  Kejian Zhang, et. al.   view full author information

Additional description

From MedlinePlus Genetics
X-linked lymphoproliferative disease (XLP) is a disorder of the immune system and blood-forming cells that is found almost exclusively in males. More than half of individuals with this disorder experience an exaggerated immune response to the Epstein-Barr virus (EBV). EBV is a very common virus that eventually infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, EBV remains in certain immune system cells (lymphocytes) called B cells. However, the virus is generally inactive (latent) because it is controlled by other lymphocytes called T cells that specifically target EBV-infected B cells.

People with XLP may respond to EBV infection by producing abnormally large numbers of T cells, B cells, and other lymphocytes called macrophages. This proliferation of immune cells often causes a life-threatening reaction called hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis causes fever, destroys blood-producing cells in the bone marrow, and damages the liver. The spleen, heart, kidneys, and other organs and tissues may also be affected. In some individuals with XLP, hemophagocytic lymphohistiocytosis or related symptoms may occur without EBV infection.

About one-third of people with XLP experience dysgammaglobulinemia, which means they have abnormal levels of some types of antibodies. Antibodies (also known as immunoglobulins) are proteins that attach to specific foreign particles and germs, marking them for destruction. Individuals with dysgammaglobulinemia are prone to recurrent infections.

Cancers of immune system cells (lymphomas) occur in about one-third of people with XLP.

Without treatment, most people with XLP survive only into childhood. Death usually results from hemophagocytic lymphohistiocytosis.

XLP can be divided into two types based on its genetic cause and pattern of signs and symptoms: XLP1 (also known as classic XLP) and XLP2. People with XLP2 have not been known to develop lymphoma, are more likely to develop hemophagocytic lymphohistiocytosis without EBV infection, usually have an enlarged spleen (splenomegaly), and may also have inflammation of the large intestine (colitis). Some researchers believe that these individuals should actually be considered to have a similar but separate disorder rather than a type of XLP.  https://medlineplus.gov/genetics/condition/x-linked-lymphoproliferative-disease

Professional guidelines

PubMed

Prenatal diagnosis and genetic analysis of X-linked immunodeficiency disorders.
Puck JM
Pediatr Res 1993 Jan;33(1 Suppl):S29-33; discussion S33-4. doi: 10.1203/00006450-199305001-00158. PMID: 8433872

Recent clinical studies

Etiology

Immune-mediated inflammatory diseases with chronic excess of serum interleukin-18.
Miyazawa H, Wada T
Front Immunol 2022;13:930141. Epub 2022 Jul 25 doi: 10.3389/fimmu.2022.930141. PMID: 35958573Free PMC Article
Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.
Tomomasa D, Booth C, Bleesing JJ, Isoda T, Kobayashi C, Koike K, Taketani T, Sawada A, Tamura A, Marsh RA, Morio T, Gennery AR, Kanegane H
Clin Immunol 2022 Apr;237:108993. Epub 2022 Mar 30 doi: 10.1016/j.clim.2022.108993. PMID: 35367395
Infection-induced inflammation from specific inborn errors of immunity to COVID-19.
Ku CL, Chen IT, Lai MZ
FEBS J 2021 Sep;288(17):5021-5041. Epub 2021 May 20 doi: 10.1111/febs.15961. PMID: 33971084Free PMC Article
X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic.
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
Flow cytometry-based diagnosis of primary immunodeficiency diseases.
Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T
Allergol Int 2018 Jan;67(1):43-54. Epub 2017 Jul 3 doi: 10.1016/j.alit.2017.06.003. PMID: 28684198

Diagnosis

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis.
Suzuki T, Sato Y, Okuno Y, Torii Y, Fukuda Y, Haruta K, Yamaguchi M, Kawamura Y, Hama A, Narita A, Muramatsu H, Yoshikawa T, Takahashi Y, Kimura H, Ito Y, Kawada JI
J Clin Immunol 2024 Apr 20;44(4):103. doi: 10.1007/s10875-024-01701-0. PMID: 38642164
Rare diseases presenting with hemophagocytic lymphohistiocytosis.
Kanegane H, Noguchi A, Yamada Y, Yasumi T
Pediatr Int 2023 Jan-Dec;65(1):e15516. doi: 10.1111/ped.15516. PMID: 36843347
Genomic diagnosis and care co-ordination for monogenic inflammatory bowel disease in children and adults: consensus guideline on behalf of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition.
Kammermeier J, Lamb CA, Jones KDJ, Anderson CA, Baple EL, Bolton C, Braggins H, Coulter TI, Gilmour KC, Gregory V, Hambleton S, Hartley D, Hawthorne AB, Hearn S, Laurence A, Parkes M, Russell RK, Speight RA, Travis S, Wilson DC, Uhlig HH
Lancet Gastroenterol Hepatol 2023 Mar;8(3):271-286. Epub 2023 Jan 9 doi: 10.1016/S2468-1253(22)00337-5. PMID: 36634696
Flow cytometry-based diagnosis of primary immunodeficiency diseases.
Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T
Allergol Int 2018 Jan;67(1):43-54. Epub 2017 Jul 3 doi: 10.1016/j.alit.2017.06.003. PMID: 28684198
X-linked lymphoproliferative syndrome.
Nelson DL, Terhorst C
Clin Exp Immunol 2000 Dec;122(3):291-5. doi: 10.1046/j.1365-2249.2000.01400.x. PMID: 11122230Free PMC Article

Therapy

Haploidentical Hematopoietic Stem Cell Transplantation for XIAP Deficiency: a Single-Center Report.
Yang J, Zhu GH, Wang B, Zhang R, Jia CG, Yan Y, Ma HH, Qin MQ
J Clin Immunol 2020 Aug;40(6):893-900. Epub 2020 Jul 5 doi: 10.1007/s10875-020-00795-6. PMID: 32627096
Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan.
Ono S, Okano T, Hoshino A, Yanagimachi M, Hamamoto K, Nakazawa Y, Imamura T, Onuma M, Niizuma H, Sasahara Y, Tsujimoto H, Wada T, Kunisaki R, Takagi M, Imai K, Morio T, Kanegane H
J Clin Immunol 2017 Jan;37(1):85-91. Epub 2016 Nov 4 doi: 10.1007/s10875-016-0348-4. PMID: 27815752Free PMC Article
Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.
Aguilar C, Lenoir C, Lambert N, Bègue B, Brousse N, Canioni D, Berrebi D, Roy M, Gérart S, Chapel H, Schwerd T, Siproudhis L, Schäppi M, Al-Ahmari A, Mori M, Yamaide A, Galicier L, Neven B, Routes J, Uhlig HH, Koletzko S, Patel S, Kanegane H, Picard C, Fischer A, Bensussan NC, Ruemmele F, Hugot JP, Latour S
J Allergy Clin Immunol 2014 Nov;134(5):1131-41.e9. Epub 2014 Jun 15 doi: 10.1016/j.jaci.2014.04.031. PMID: 24942515
Management of Epstein-Barr virus infections.
Andersson J, Ernberg I
Am J Med 1988 Aug 29;85(2A):107-15. PMID: 2841854
Immunopathology of the X-linked lymphoproliferative syndrome.
Purtilo DT
Haematol Blood Transfus 1981;26:207-14. doi: 10.1007/978-3-642-67984-1_34. PMID: 6274747

Prognosis

Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.
Tomomasa D, Booth C, Bleesing JJ, Isoda T, Kobayashi C, Koike K, Taketani T, Sawada A, Tamura A, Marsh RA, Morio T, Gennery AR, Kanegane H
Clin Immunol 2022 Apr;237:108993. Epub 2022 Mar 30 doi: 10.1016/j.clim.2022.108993. PMID: 35367395
X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic.
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome.
Aguilar C, Latour S
J Clin Immunol 2015 May;35(4):331-8. Epub 2015 Mar 4 doi: 10.1007/s10875-015-0141-9. PMID: 25737324
X chromosome linked immunodeficiency.
Schwaber J, Rosen FS
Immunodefic Rev 1990;2(3):233-51. PMID: 1981831
Mapping the X-linked lymphoproliferative syndrome.
Skare JC, Milunsky A, Byron KS, Sullivan JL
Proc Natl Acad Sci U S A 1987 Apr;84(7):2015-8. doi: 10.1073/pnas.84.7.2015. PMID: 2882515Free PMC Article

Clinical prediction guides

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis.
Suzuki T, Sato Y, Okuno Y, Torii Y, Fukuda Y, Haruta K, Yamaguchi M, Kawamura Y, Hama A, Narita A, Muramatsu H, Yoshikawa T, Takahashi Y, Kimura H, Ito Y, Kawada JI
J Clin Immunol 2024 Apr 20;44(4):103. doi: 10.1007/s10875-024-01701-0. PMID: 38642164
XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells.
Wahida A, Müller M, Hiergeist A, Popper B, Steiger K, Branca C, Tschurtschenthaler M, Engleitner T, Donakonda S, De Coninck J, Öllinger R, Pfautsch MK, Müller N, Silva M, Usluer S, Thiele Orberg E, Böttcher JP, Pfarr N, Anton M, Slotta-Huspenina JB, Nerlich AG, Madl T, Basic M, Bleich A, Berx G, Ruland J, Knolle PA, Rad R, Adolph TE, Vandenabeele P, Kanegane H, Gessner A, Jost PJ, Yabal M
Sci Immunol 2021 Nov 5;6(65):eabf7235. doi: 10.1126/sciimmunol.abf7235. PMID: 34739338
X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic.
Xu T, Zhao Q, Li W, Chen X, Xue X, Chen Z, Du X, Bai X, Zhao Q, Zhou L, Tang X, Yang X, Kanegane H, Zhao X
Eur J Pediatr 2020 Feb;179(2):327-338. Epub 2019 Nov 21 doi: 10.1007/s00431-019-03512-7. PMID: 31754776Free PMC Article
Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation.
Nishida N, Yang X, Takasaki I, Imai K, Kato K, Inoue Y, Imamura T, Miyashita R, Kato F, Yamaide A, Mori M, Saito S, Hara J, Adachi Y, Miyawaki T, Kanegane H
J Investig Allergol Clin Immunol 2015;25(3):205-13. PMID: 26182687
XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
Rigaud S, Fondanèche MC, Lambert N, Pasquier B, Mateo V, Soulas P, Galicier L, Le Deist F, Rieux-Laucat F, Revy P, Fischer A, de Saint Basile G, Latour S
Nature 2006 Nov 2;444(7115):110-4. doi: 10.1038/nature05257. PMID: 17080092

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