Advertisement

Endocrine

, Volume 52, Issue 1, pp 157–164 | Cite as

Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter’s syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men

  • Francesca PanimolleEmail author
  • Claudio Tiberti
  • Simona Granato
  • Antonella Semeraro
  • Daniele Gianfrilli
  • Antonella Anzuini
  • Andrea Lenzi
  • Antonio Radicioni
Original Article

Abstract

The aim of this study was to evaluate the frequency of humoral endocrine organ-specific autoimmunity in 47,XXY Klinefelter’s syndrome (KS) by investigating the autoantibody profile specific to type 1 diabetes (T1DM), Addison’s disease (AD), Hashimoto thyroiditis (HT), and autoimmune chronic atrophic gastritis (AG). Sixty-one adult Caucasian 47,XXY KS patients were tested for autoantibodies specific to T1DM (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs), HT (TPO Abs), AD (21-OH Abs), and AG (APC Abs). Thirty-five of these patients were not undergoing testosterone replacement therapy TRT (Group 1) and the remaining 26 patients started TRT before the beginning of the study (Group 2). KS autoantibody frequencies were compared to those found in 122 control men. Six of 61 KS patients (9.8 %) were positive for at least one endocrine autoantibody, compared to 6.5 % of controls. Interestingly, KS endocrine immunoreactivity was directed primarily against diabetes-specific autoantigens (8.2 %), with a significantly higher frequency than in controls (p = 0.016). Two KS patients (3.3 %) were TPO Ab positive, whereas no patients were positive for AD- and AG-related autoantigens. The autoantibody endocrine profile of untreated and treated KS patients was not significantly different. Our findings demonstrate for the first time that endocrine humoral immunoreactivity is not rare in KS patients and that it is more frequently directed against type 1 diabetes-related autoantigens, thus suggesting the importance of screening for organ-specific autoimmunity in clinical practice. Follow-up studies are needed to establish if autoantibody-positive KS patients will develop clinical T1DM.

Keywords

Klinefelter’s syndrome Type 1 diabetes Hypogonadism Autoimmunity 

Notes

Acknowledgments

The study was funded by the Italian Ministry of Health and the Italian Medicines Agency (AIFA): research project MRAR08Q009 on rare diseases. Author’s contribution: F.P. contributed to data collection, statistical analysis, data interpretation, wrote the manuscript; C.T. contributed to data interpretation and revised the manuscript; G.S., A.A., and A.S. contributed to data collection; L.A. and G.D. revised the manuscript; R.A. is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Thanks to Marie-Hélène Hayles for the language revision.

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

References

  1. 1.
    F. Lanfranco, A. Kamischke, M. Zitzmann et al., Klinefelter’s syndrome. Lancet 364, 273–283 (2004)CrossRefPubMedGoogle Scholar
  2. 2.
    A.F. Radicioni, E. De Marco, D. Gianfrilli et al., Strategies and advantages of early diagnosis in Klinefelter’s syndrome. Mol. Hum. Reprod. 6, 434–440 (2010)CrossRefGoogle Scholar
  3. 3.
    A. Bojesen, S. Juul, N.H. Bikebaek et al., Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J. Clin. Endocrinol. Metab. 88, 622–626 (2006)CrossRefGoogle Scholar
  4. 4.
    A.H. Sawalha, J.B. Harley, R. Hal Scofield, Autoimmunity and Klinefelter’s syndrome: when men have two X chromosomes. J. Autoimmun. 33(1), 31–34 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    L.A. Abramowitz, S. Olivier-Van Stichelen, J.A. Hanover, Chromosome imbalance as a driver of sex disparity in disease. J. Genomics 2, 77–88 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    M. Cutolo, A. Sulli, S. Capellino et al., Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 13(9), 653–658 (2004)CrossRefGoogle Scholar
  7. 7.
    N.J. Olsen, W.J. Kovacs, Gonadal steroids and immunity. Endocr. Rev. 17, 369–384 (1996)PubMedGoogle Scholar
  8. 8.
    C. Oktenli, Z. Yesilova, I.H. Kocar et al., Study of autoimmunity in Klinefelter’s syndrome and idiopathic hypogonadotropic hypogonadism. J. Clin. Immuno. 22, 137–143 (2002)CrossRefGoogle Scholar
  9. 9.
    A.M.B. Bjørn, A. Bojesen, C.H. Gravholt, P. Laurberg, Hypothyroidism secondary to hypothalamic-pituitary dysfunction may be part of the phenotype in klinefelter syndrome: a case-control study. J. Clin. Endocrinol. Metab. 94(7), 2478–2481 (2006)CrossRefGoogle Scholar
  10. 10.
    G.S. Eisenbarth, Update in type 1 diabetes. J. Clin. Endocrinol. Metab. 92, 2403–2417 (2007)CrossRefPubMedGoogle Scholar
  11. 11.
    M. Knip, H. Siljander, Autoimmune mechanisms in type 1 diabetes. Autoimmun. Rev. 7, 550–557 (2008)CrossRefPubMedGoogle Scholar
  12. 12.
    O. Winqvist, F.A. Karlsson, O. Kämpe, 21-Hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet 339(8809), 1559–1562 (1992)CrossRefPubMedGoogle Scholar
  13. 13.
    J. Bednarek, J. Furmaniak, N. Wedlock et al., Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison’s disease. FEBS Lett. 309(1), 51–55 (1992)CrossRefPubMedGoogle Scholar
  14. 14.
    A.P. Weetman, Chronic autoimmune thyroiditis, in Werner and Ingbar’s the thyroid: a fundamental and clinical text, 8th edn., ed. by L.E. Braverman, R.D. Utiger (Lippincott Williams & Wilkins, Philadelphia, 2000), pp. 721–732Google Scholar
  15. 15.
    R.G. Strickland, I. Mackay, A reappraisal of the nature and significance of chronic atrophic gastritis. Am. J. Dig. Dis. 18, 426–440 (1973)CrossRefPubMedGoogle Scholar
  16. 16.
    C. Tiberti, L. Yu, F. Lucantoni et al., Detection of four diabetes specific autoantibodies in a single radioimmunoassay: an innovative high-throughput approach for autoimmune diabetes screening. Clin. Exp. Immunol. 166(3), 317–324 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    P. Vardi, S.A. Dib, M. Tuttleman et al., Competitive insulin autoantibody RIA: prospective evaluation of subjects at high risk for development of Type 1 diabetes mellitus. Diabetes 36, 1286–1291 (1987)CrossRefPubMedGoogle Scholar
  18. 18.
    C.E. Grubin, T. Daniels, B. Toivola et al., A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 37, 344–350 (1994)CrossRefPubMedGoogle Scholar
  19. 19.
    C. Törn, P.W. Mueller, M. Schlosser et al., Diabetes antibody standardization program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2. Diabetologia 51, 846–852 (2008)CrossRefPubMedGoogle Scholar
  20. 20.
    C. Tiberti, A. Verrienti, B. Fiore et al., IA-2 combined epitope assay: a new, highly sensitive approach to evaluate IA-2 humoral autoimmunity in type 1 diabetes. Clin. Immunol. 115, 260–267 (2005)CrossRefPubMedGoogle Scholar
  21. 21.
    J.M. Wenzlau, K. Juhl, L. Yu et al., The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc. Natl. Acad. Sci. USA. 104, 17040–17045 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    V. Lampasona, M. Schlosser, P.W. Mueller, A.J.K. Williams, J.M. Wenzlau, J.C. Hutton, P. Achenbach, Participating Laboratories, Diabetes antibody standardization program: first proficiency evaluation of assays for autoantibodies to zinc transporter 8. Clin. Chem. 57(12), 1693–1702 (2011)CrossRefPubMedGoogle Scholar
  23. 23.
    A. Falorni, S. Chen, R. Zanchetta et al., Measuring adrenal autoantibody response: Interlaboratory concordance in the first international serum exchange for the determination of 21-hydroxylase autoantibodies. Clin. Immunol. 140, 291–299 (2011)CrossRefPubMedGoogle Scholar
  24. 24.
    G. Huber, J.J. Staub, C. Meier et al., Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J. Clin. Endocrinol. Metab. 87, 3221–3226 (2002)CrossRefPubMedGoogle Scholar
  25. 25.
    S. Whittingham, I.R. Mackay, Pernicious anemia and gastric atrophy, in The Autoimmune Diseases, ed. by N.R. Rose, I.R. Mackay (Academic Press, New York, 1985), pp. 243–266Google Scholar
  26. 26.
    M. Jang-Feng, X. Hong-Li, W. Xue—Yan et al., Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal study. Reprod. Endocrinol. 98, 1331–1335 (2012)Google Scholar
  27. 27.
    A. Bojesen, K. Kristensen, N.H. Birkebaek, J. Fedder, L. Mosekilde, P. Bennett, P. Laurberg, J. Frystyk, A. Flyvbjerg, J.S. Christiansen, C.H. Gravolt, The metabolic syndrome Is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 29, 1591–1598 (2006)CrossRefPubMedGoogle Scholar
  28. 28.
    S. Kota, K.M. Lalit, S. Jammula, S.K. Kota, D.M. Kirtikumar, Clinical profile of coexisting conditions in type 1 diabetes mellitus patients. Diabetes Metab. Syndr. 6, 70–76 (2012)CrossRefPubMedGoogle Scholar
  29. 29.
    A.L. Notkins, A. Lernmark, Autoimmune type 1 diabetes: resolved and unresolved issues. J. Clin. Invest. 108(12), 47–52 (2001)Google Scholar
  30. 30.
    X.P. Cai, L. Zhao, M. Mao, A case of Klinefelter’s syndrome with type 1 diabetes mellitus. Chin. Med. J. 125(5), 937–940 (2012)PubMedGoogle Scholar
  31. 31.
    K. Ota, T. Suehiro, Y. Ikeda, K. ArII, Y. Kumon, K. Hashimoto, Diabetes mellitus associated with Klinefelter’s syndrome: a case report and review in Japan. Intern. Med. 41(10), 842–847 (2002)CrossRefPubMedGoogle Scholar
  32. 32.
    L.I. Alves, E. Davini, M.R. Correia, R.T. Fukui, R.F. Santos, M.R. Cunha, D.M. Rocha, W.M.G. Volpini, M.E.R. Silva, Autoantibodies and high-risk HLA susceptibility markers in first-degree relatives of Brazilian patients with type 1 diabetes mellitus: a progression to disease based study. J. Clin. Immunol. 32, 778–785 (2012)CrossRefPubMedGoogle Scholar
  33. 33.
    C. Verge, E. Gianani, L. Kawasaki et al., Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45, 926–993 (1996)CrossRefPubMedGoogle Scholar
  34. 34.
    N.K. Mclaren, M.S. Lan, D. Schatz et al., Multiple autoantibodies as predictors of type 1 diabetes in a general population. Diabetologia 46(6), 873–874 (2003)CrossRefGoogle Scholar
  35. 35.
    J.M. Barker, J. Yu, L. Yu et al., Autoantibody “subspecificity” in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups. Diabetes Care 28, 850–855 (2005)CrossRefPubMedGoogle Scholar
  36. 36.
    M. Pietropaolo, R. Towns, G.S. Eisenbarth, Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes. Cold Spring Harb. Perspect. Med. 2(10), 1–18 (2012)CrossRefGoogle Scholar
  37. 37.
    O. Kordonouri, D. Deiss, T. Danne et al., Predictivity of thyroid autoantibodies for the development of thyroid disorders in children and adolescents with Type 1 diabetes. Diabet. Med. 19(6), 518–521 (2002)CrossRefPubMedGoogle Scholar
  38. 38.
    I.H. Kocar, Z. Yesilova, M. Ozata et al., The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin. Exp. Immunol. 121, 448–452 (2000)CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    J. Nielsen, K. Johansen, H. Yde, Frequency of diabetes mellitus in patients with Klinefelter’s syndrome of different chromosome constitutions and the XYY syndrome. Plasma insulin and growth hormone level after a glucose load. J. Clin. Endocrinol. Metab. 29, 1062–1073 (1969)CrossRefPubMedGoogle Scholar
  40. 40.
    J. Visootsak, J.M. Graham Jr, Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J. Rare Dis. 1, 42 (2006)CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Francesca Panimolle
    • 1
    Email author
  • Claudio Tiberti
    • 1
  • Simona Granato
    • 1
  • Antonella Semeraro
    • 1
  • Daniele Gianfrilli
    • 1
  • Antonella Anzuini
    • 1
  • Andrea Lenzi
    • 1
  • Antonio Radicioni
    • 1
  1. 1.Section of Medical Pathophysiology, Department of Experimental Medicine, Center of Rare DiseasesSapienza University of RomeRomeItaly

Personalised recommendations