Abstract
Background
Females with Turner syndrome (TS) are prone to develop autoimmune diseases (AIDs). The X chromosome contains several immune-related genes. Growth hormone (GH) and estrogens modulate the immune system. We aimed to clarify whether the loss of a specific X chromosome gene locus and the administration of GH and estradiol facilitate the development of AIDs in TS females.
Methods
Retrospective data on clinical course, AIDs, karyotype and treatment were analyzed from a cohort of 286 Czech females with TS (current age 2.8–43.3 years; median age 18.7 years). The karyotypes were sorted using two different classification systems: a mosaicism-focused and an isochromosome (isoXq)-focused approach. Karyotype subgroups with a significantly higher prevalence of AIDs were further evaluated. Data of common therapies were correlated with the prevalence of AIDs.
Results
The most frequent AIDs were autoimmune thyroid disease (AITD; 37.4%; n = 107) and celiac disease (CD; 8.7%; n = 25). All karyotype subgroups were prone to develop AIDs. Females with an isolated Xp deletion had a significantly higher prevalence of AITD and CD compared to all other individuals with TS (AITD: 66.0% vs. 31.5%, p < 0.0001; CD: 17.4% vs. 7.2%; p = 0.04, respectively). We observed no link between the mean age at initiation as well as the duration of GH and/or estrogen administration and the occurrence of AIDs.
Conclusions
Isolated Xp deletion contributes to the development of AIDs in TS patients. The haploinsufficiency of genes located in Xpter-p11.2 may explain this observation. Common therapies used in TS do not modify the risk of AIDs.
Acknowledgments
We would like to thank Michaela Vernerova who contributed to data collection. Research on Turner syndrome was supported by a grant from the Czech Health Research Council (AZV No. NV 17-29111A).
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Czech Health Research Council, NV 17-29111A.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med 2004;351:1227–38.10.1056/NEJMra030360Search in Google Scholar PubMed
2. Jørgensen KT, Rostgaard K, Bache I, Biggar RJ, Nielsen NM, et al. Autoimmune diseases in women with Turner’s syndrome. Arthritis Rheum 2010;62:658–66.10.1002/art.27270Search in Google Scholar PubMed
3. Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syndrome in women with Turner’s syndrome – the association with karyotype. Clin Endocrinol (Oxf) 2001;55:223–6.10.1046/j.1365-2265.2001.01296.xSearch in Google Scholar PubMed
4. Bonamico M, Pasquino AM, Mariani P, Danesi HM, Culasso F, et al. Prevalence and clinical picture of celiac disease in Turner syndrome. J Clin Endocrinol Metab 2002;87:5495–8.10.1210/jc.2002-020855Search in Google Scholar PubMed
5. Bianchi I, Lleo A, Gershwin ME, Invernizzi P. The X chromosome and immune associated genes. J Autoimmun 2012;38:187–92.10.1016/j.jaut.2011.11.012Search in Google Scholar PubMed
6. Ivarsson SA, Ericsson UB, Nilsson K, Gustafsson J, Hagenäs L, et al. Thyroid autoantibodies, Turner’s syndrome and growth hormone therapy. Acta Peadiatr 1995;84:63–5.10.1111/j.1651-2227.1995.tb13485.xSearch in Google Scholar PubMed
7. Bakalov VK, Gutin L, Cheng CM, Zhou J, Sheth P, et al. Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency. J Autoimmun 2012;38:315–21.10.1016/j.jaut.2012.01.015Search in Google Scholar PubMed PubMed Central
8. Grossi A, Crinò A, Luciano R, Lombardo A, Cappa M, et al. Endocrine autoimmunity in Turner syndrome. Ital J Pediatr 2013;39:79.10.1186/1824-7288-39-79Search in Google Scholar PubMed PubMed Central
9. Chiovato L, Larizza D, Bendinelli G, Tonacchera M, Marinó M, et al. Autoimmune hypothyroidism and hyperthyroidism in patients with Turner’s syndrome. Eur J Endocrinol 1996;134:568–75.10.1530/eje.0.1340568Search in Google Scholar PubMed
10. Livadas S, Xekouki P, Fouka F, Kanaka-Gantenbein C, Kaloumenou I, et al. Prevalence of thyroid dysfunction in Turner’s syndrome: a long-term follow-up study and brief literature review. Thyroid 2005;15:1061–6.10.1089/thy.2005.15.1061Search in Google Scholar PubMed
11. Radetti G, Mazzanti L, Paganini C, Bernasconi S, Russo G, et al. Study group for TS. Frequency, clinical and laboratory features of thyroiditis in girls with Turner’s syndrome. Acta Paediatr 1995;84:909–12.10.1111/j.1651-2227.1995.tb13791.xSearch in Google Scholar PubMed
12. El-Mansoury M, Bryman I, Berntorp K, Hanson C, Wilhelmsen L, et al. Hypothyroidism is common in Turner syndrome: results of a five-year follow-up. J Clin Endocrinol Metab 2005;90:2131–5.10.1210/jc.2004-1262Search in Google Scholar PubMed
13. Fukuda I, Hizuka N, Kurimoto M, Morita J, Tanaka S, et al. Autoimmune thyroid diseases in 65 Japanese women with Turner syndrome. Endocr J 2009;56:983–6.10.1507/endocrj.K09E-141Search in Google Scholar PubMed
14. Mortensen KH, Cleemann L, Hjerrild BE, Nexo E, Locht H, et al. Increased prevalence of autoimmunity in Turner syndrome – influence of age. Clin Exp Immunol 2009;156:205–10.10.1111/j.1365-2249.2009.03895.xSearch in Google Scholar PubMed PubMed Central
15. Gawlik A, Gawlik T, Januszek-Trzciakowska A, Patel H, Malecka-Tendera E. Incidence and dynamics of thyroid dysfunction and thyroid autoimmunity in girls with Turner’s syndrome: a long-term follow-up study. Horm Res Peadiatr 2011;76:314–20.10.1159/000331050Search in Google Scholar PubMed
16. Savino W, Smaniotto S, Binart N, Postel-Vinay MC, Dardenne M. Pleiotropic modulation of thymic functions by growth hormone: from physiology to therapy. Curr Opin Pharmacol 2010;10:434–42.10.1016/j.coph.2010.04.002Search in Google Scholar PubMed
17. Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, et al. Sex hormones influence on the immune system : basic and clinical aspects in autoimmunity. Lupus 2004;13:635–8.10.1191/0961203304lu1094oaSearch in Google Scholar PubMed
18. Gravholt CH, Andersen NH, Conway GS, Dekkers O, Geffner ME, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;177:G1–70.10.1530/EJE-17-0430Search in Google Scholar PubMed
19. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11:1185–94.10.1097/00042737-199910000-00019Search in Google Scholar PubMed
20. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2015. Available from: https://www.r-project.org/.Search in Google Scholar
21. Horacek J. Tyreopatie v gravidite. Interni Med Pro Praxi 2011;13:388–90.Search in Google Scholar
22. Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull 2017;99:39–51.10.1093/bmb/ldr030Search in Google Scholar PubMed
23. Vancikova Z, Chlumecky V, Sokol D, Horakova D, Hamsikova E, et al. The serologic screening for celiac disease in the general population (blood donors) and in some high-risk groups of adults (patients with autoimmune diseases, osteoporosis and infertility) in the Czech Republic. Folia Microbiol (Praha) 2002;47:753–8.10.1007/BF02818684Search in Google Scholar PubMed
24. Zinn AR, Tonk VS, Chen Z, Flejter WL, Gardner HA, et al. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. Am J Hum Genet 1998;63:1757–66.10.1086/302152Search in Google Scholar PubMed PubMed Central
25. Cook KD, Shpargel KB, Starmer J, Whitfield-Larry F, Conley B, et al. T follicular helper cell-dependent clearance of a persistent virus infection requires T cell expression of the histone demethylase UTX. Immunity 2015;43:703–14.10.1016/j.immuni.2015.09.002Search in Google Scholar PubMed PubMed Central
26. Thrasher BJ, Kyung Hong L, Whitmire JK, Su MA. Epigenetic dysfunction in Turner syndrome immune cells. Curr Allergy Asthma Rep 2016;16:1–8.10.1007/s11882-016-0612-ySearch in Google Scholar PubMed PubMed Central
27. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008;8:523–32.10.1038/nri2343Search in Google Scholar PubMed PubMed Central
28. Di Nunzio S, Cecconi M, Passerini L, Mcmurchy AN, Baron U, et al. Wild-type FOXP3 is selectively active in CD4+CD25hi regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood 2009;114:4138–41.10.1182/blood-2009-04-214593Search in Google Scholar PubMed
29. Blewitt ME, Vickaryous NK, Hemley SJ, Ashe A, Bruxner TJ, et al. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc Natl Acad Sci USA 2005;102:7629–34.10.1073/pnas.0409375102Search in Google Scholar PubMed PubMed Central
30. Bakalov VK, Cheng C, Zhou J, Bondy CA. X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab 2009;94:3289–96.10.1210/jc.2009-0384Search in Google Scholar PubMed PubMed Central
31. Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, et al. SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex. Nucl Acids Res 2002;30:3245–52.10.1093/nar/gkf443Search in Google Scholar PubMed PubMed Central
32. Senee V, Chelala C, Duchatelet S, Feng D, Blanc H, et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006;38:682–8.10.1038/ng1802Search in Google Scholar PubMed
33. Deng X, Berletch JB, Nguyen DK, Disteche CM. X chromosome regulation: diverse patterns in development, tissues and disease. Nat Rev Genet 2014;15:367–78.10.1038/nrg3687Search in Google Scholar PubMed PubMed Central
34. Savino W, Smaniotto S, Binart N, Postel-Vinay MC, Dardenne M. In vivo effects of growth hormone on thymic cells. Ann NY Acad Sci 2003;992:179–85.10.1111/j.1749-6632.2003.tb03148.xSearch in Google Scholar PubMed
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