Autoimmune Endocrine Disorders

  • Jennifer M. Barker


Autoimmune endocrine disorders coexist in recognized syndromes known as autoimmune polyendocrine syndromes (APS). Autosomal recessively inherited mutations in the AIRE gene cause APS-1, also known as autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED). This rare disorder is most commonly associated with the triad of mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. The much more common APS-2 is inherited in a multigenic pattern and tends to present later in life. Recognized associations include type 1 diabetes, autoimmune thyroid disease, autoimmune adrenal insufficiency, and celiac disease, among others. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is a rare autoimmune syndrome associated with mutations in the FOXp3 gene.


Autoimmune polyendocrine syndrome type 1 Autoimmune polyendocrine syndrome type 2 Hypothyroidism Hyperthyroidism Immunodysregulation polyendocrinopathy enteropathy X-linked type 1 diabetes Celiac disease Addison’s disease 


  1. 1.
    Eisenbarth GS, Type I. diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986;314(21):1360–8.CrossRefGoogle Scholar
  2. 2.
    Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69–82.CrossRefGoogle Scholar
  3. 3.
    Pociot F, Lernmark A. Genetic risk factors for type 1 diabetes. Lancet. 2016;387(10035):2331–9.CrossRefGoogle Scholar
  4. 4.
    Pugliese A, Boulware D, Yu L, Babu S, Steck AK, Becker D, et al. HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype protects autoantibody-positive relatives from type 1 diabetes throughout the stages of disease progression. Diabetes. 2016;65(4):1109–19.CrossRefGoogle Scholar
  5. 5.
    Aly TA, Ide A, Jahromi MM, Barker JM, Fernando MS, Babu SR, et al. Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci U S A. 2006;103(38):14074–9.CrossRefGoogle Scholar
  6. 6.
    Lempainen J, Laine AP, Hammais A, Toppari J, Simell O, Veijola R, et al. Non-HLA gene effects on the disease process of type 1 diabetes: from HLA susceptibility to overt disease. J Autoimmun. 2015;61:45–53.CrossRefGoogle Scholar
  7. 7.
    Rewers M, Ludvigsson J. Environmental risk factors for type 1 diabetes. Lancet. 2016;387(10035):2340–8.CrossRefGoogle Scholar
  8. 8.
    Norris JM, Barriga K, Klingensmith G, Hoffman M, Eisenbarth GS, Erlich HA, et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA. 2003;290(13):1713–20.CrossRefGoogle Scholar
  9. 9.
    Piescik-Lech M, Chmielewska A, Shamir R, Szajewska H. Systematic review: early infant feeding and the risk of type 1 diabetes. J Pediatr Gastroenterol Nutr. 2017; 64(3):454–59.CrossRefGoogle Scholar
  10. 10.
    Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293(19):2343–51.CrossRefGoogle Scholar
  11. 11.
    Elding Larsson H, Vehik K, Haller MJ, Liu X, Akolkar B, Hagopian W, et al. Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood: the environmental determinants of diabetes in the young study. Diabetes. 2016;65(7):1988–95.CrossRefGoogle Scholar
  12. 12.
    Cinek O, Stene LC, Kramna L, Tapia G, Oikarinen S, Witso E, et al. Enterovirus RNA in longitudinal blood samples and risk of islet autoimmunity in children with a high genetic risk of type 1 diabetes: the MIDIA study. Diabetologia. 2014;57(10):2193–200.CrossRefGoogle Scholar
  13. 13.
    Lund-Blix NA, Stene LC, Rasmussen T, Torjesen PA, Andersen LF, Ronningen KS. Infant feeding in relation to islet autoimmunity and type 1 diabetes in genetically susceptible children: the MIDIA study. Diabetes Care. 2015;38(2):257–63.CrossRefGoogle Scholar
  14. 14.
    Gulden E, Wong FS, Wen L. The gut microbiota and type 1 diabetes. Clin Immunol. 2015;159(2):143–53.CrossRefGoogle Scholar
  15. 15.
    Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45(7):926–33.CrossRefGoogle Scholar
  16. 16.
    Barker JM, Barriga KJ, Yu L, Miao D, Erlich HA, Norris JM, et al. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab. 2004;89(8):3896–902.CrossRefGoogle Scholar
  17. 17.
    Achenbach P, Schlosser M, Williams AJ, Yu L, Mueller PW, Bingley PJ, et al. Combined testing of antibody titer and affinity improves insulin autoantibody measurement: Diabetes Antibody Standardization Program. Clin Immunol. 2007;122(1):85–90.CrossRefGoogle Scholar
  18. 18.
    Steck AK, Vehik K, Bonifacio E, Lernmark A, Ziegler AG, Hagopian WA, et al. Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: the environmental determinants of diabetes in the young (TEDDY). Diabetes Care. 2015;38(5):808–13.CrossRefGoogle Scholar
  19. 19.
    Bingley PJ, Boulware DC, Krischer JP. The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes. Diabetologia. 2016;59(3):542–9.CrossRefGoogle Scholar
  20. 20.
    Umpierrez GE, Latif KA, Murphy MB, Lambeth HC, Stentz F, Bush A, et al. Thyroid dysfunction in patients with type 1 diabetes: a longitudinal study. Diabetes Care. 2003;26(4):1181–5.CrossRefGoogle Scholar
  21. 21.
    Pesenacker AM, Wang AY, Singh A, Gillies J, Kim Y, Piccirillo CA, et al. A regulatory T-cell gene signature is a specific and sensitive biomarker to identify children with new-onset type 1 diabetes. Diabetes. 2016;65(4):1031–9.CrossRefGoogle Scholar
  22. 22.
    Xu P, Wu Y, Zhu Y, Dagne G, Johnson G, Cuthbertson D, et al. Prognostic performance of metabolic indexes in predicting onset of type 1 diabetes. Diabetes Care. 2010;33(12):2508–13.CrossRefGoogle Scholar
  23. 23.
    Helminen O, Aspholm S, Pokka T, Hautakangas MR, Haatanen N, Lempainen J, et al. HbA1c predicts time to diagnosis of type 1 diabetes in children at risk. Diabetes. 2015;64(5):1719–27.CrossRefGoogle Scholar
  24. 24.
    Triolo TM, Chase HP, Barker JM, Group D-S. Diabetic subjects diagnosed through the Diabetes Prevention Trial-Type 1 (DPT-1) are often asymptomatic with normal A1C at diabetes onset. Diabetes Care. 2009;32(5):769–73.CrossRefGoogle Scholar
  25. 25.
    Coco G, Dal Pra C, Presotto F, Albergoni MP, Canova C, Pedini B, et al. Estimated risk for developing autoimmune Addison’s disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab. 2006;91(5):1637–45.CrossRefGoogle Scholar
  26. 26.
    Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite type 1 diabetes TrialNet data. Diabetes. 2012;61(8):2066–73.CrossRefGoogle Scholar
  27. 27.
    Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35(5):463–78.CrossRefGoogle Scholar
  28. 28.
    Shikama N, Nusspaumer G, Hollander GA. Clearing the AIRE: on the pathophysiological basis of the autoimmune polyendocrinopathy syndrome type-1. Endocrinol Metab Clin N Am. 2009;38(2):273–88. vii.CrossRefGoogle Scholar
  29. 29.
    Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, et al. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab. 2001;86(10):4747–52.CrossRefGoogle Scholar
  30. 30.
    Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265(5):514–29.CrossRefGoogle Scholar
  31. 31.
    Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91(8):2843–50.CrossRefGoogle Scholar
  32. 32.
    Jaaskelainen J, Perheentupa J. Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) – a diagnostic and therapeutic challenge. Pediatr Endocrinol Rev. 2009;7(2):15–28.PubMedGoogle Scholar
  33. 33.
    Bockle BC, Wilhelm M, Muller H, Gotsch C, Sepp NT. Oral mucous squamous cell carcinoma-an anticipated consequence of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J Am Acad Dermatol. 2010;62(5):864–8.CrossRefGoogle Scholar
  34. 34.
    Laakso SM, Kekalainen E, Heikkila N, Mannerstrom H, Kisand K, Peterson P, et al. In vivo analysis of helper T cell responses in patients with autoimmune polyendocrinopathy – candidiasis – ectodermal dystrophy provides evidence in support of an IL-22 defect. Autoimmunity. 2014;47(8):556–62.CrossRefGoogle Scholar
  35. 35.
    Meloni A, Furcas M, Cetani F, Marcocci C, Falorni A, Perniola R, et al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. 2008;93(11):4389–97.CrossRefGoogle Scholar
  36. 36.
    Wolff AS, Sarkadi AK, Marodi L, Karner J, Orlova E, Oftedal BE, et al. Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood. J Clin Immunol. 2013;33(8):1341–8.CrossRefGoogle Scholar
  37. 37.
    Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J Autoimmun. 1999;13(1):143–8.CrossRefGoogle Scholar
  38. 38.
    Smigoc Schweiger D, Mendez A, Kunilo Jamnik S, Bratanic N, Bratina N, Battelino T, et al. High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease. Autoimmunity. 2016;49(4):240–7.CrossRefGoogle Scholar
  39. 39.
    Gutierrez-Achury J, Romanos J, Bakker SF, Kumar V, de Haas EC, Trynka G, et al. Contrasting the genetic background of type 1 diabetes and celiac disease autoimmunity. Diabetes Care. 2015;38(Suppl 2):S37–44.CrossRefGoogle Scholar
  40. 40.
    Barker JM, Ide A, Hostetler C, Yu L, Miao D, Fain PR, et al. Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison’s disease in a high-risk population. J Clin Endocrinol Metab. 2005;90(1):128–34.CrossRefGoogle Scholar
  41. 41.
    Meloni A, Mandas C, Jores RD, Congia M. Prevalence of autoimmune thyroiditis in children with celiac disease and effect of gluten withdrawal. J Pediatr. 2009;155(1):51-5–.e1.CrossRefGoogle Scholar
  42. 42.
    Cassio A, Ricci G, Baronio F, Miniaci A, Bal M, Bigucci B, et al. Long-term clinical significance of thyroid autoimmunity in children with celiac disease. J Pediatr. 2010;156(2):292–5.CrossRefGoogle Scholar
  43. 43.
    Sattar N, Lazare F, Kacer M, Aguayo-Figueroa L, Desikan V, Garcia M, et al. Celiac disease in children, adolescents, and young adults with autoimmune thyroid disease. J Pediatr. 2011;158(2):272–5.e1.CrossRefGoogle Scholar
  44. 44.
    (11) Children and adolescents. Diabetes Care. 2016;39(Suppl 1):S86–93.Google Scholar
  45. 45.
    Kordonouri O, Klingensmith G, Knip M, Holl RW, Aanstoot HJ, Menon PS, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Other complications and diabetes-associated conditions in children and adolescents. Pediatr Diabetes. 2014;15(Suppl 20):270–8.CrossRefGoogle Scholar
  46. 46.
    Lord S, Greenbaum CJ. Disease modifying therapies in type 1 diabetes: where have we been, and where are we going? Pharmacol Res. 2015;98:3–8.CrossRefGoogle Scholar
  47. 47.
    Michels A, Zhang L, Khadra A, Kushner JA, Redondo MJ, Pietropaolo M. Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention. Pediatr Diabetes. 2015;16(7):465–84.CrossRefGoogle Scholar
  48. 48.
    Mahon JL, Sosenko JM, Rafkin-Mervis L, Krause-Steinrauf H, Lachin JM, Thompson C, et al. The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results. Pediatr Diabetes. 2009;10(2):97–104.CrossRefGoogle Scholar
  49. 49.
    Knip M, Akerblom HK, Becker D, Dosch HM, Dupre J, Fraser W, et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA. 2014;311(22):2279–87.CrossRefGoogle Scholar
  50. 50.
    Bonifacio E, Ziegler AG, Klingensmith G, Schober E, Bingley PJ, Rottenkolber M, et al. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA. 2015;313(15):1541–9.CrossRefGoogle Scholar
  51. 51.
    Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial – Type 1. Diabetes Care. 2005;28(5):1068–76.CrossRefGoogle Scholar
  52. 52.
    Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18):1909–20.CrossRefGoogle Scholar
  53. 53.
    Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692–8.CrossRefGoogle Scholar
  54. 54.
    Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005;54(6):1763–9.CrossRefGoogle Scholar
  55. 55.
    Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, et al. B-lymphocyte depletion with rituximab and β-cell function: two-year results. Diabetes Care. 2014;37(2):453–9.CrossRefGoogle Scholar
  56. 56.
    Bin Dhuban K, Piccirillo CA. The immunological and genetic basis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Curr Opin Allergy Clin Immunol. 2015;15(6):525–32.CrossRefGoogle Scholar
  57. 57.
    Bacchetta R, Barzaghi F, Roncarolo MG. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci. 2016.
  58. 58.
    Vasiljevic A, Poreau B, Bouvier R, Lachaux A, Arnoult C, Faure J, et al. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and recurrent intrauterine fetal death. Lancet. 2015;385(9982):2120.CrossRefGoogle Scholar
  59. 59.
    Burroughs LM, Torgerson TR, Storb R, Carpenter PA, Rawlings DJ, Sanders J, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol. 2010;126(5):1000–5.CrossRefGoogle Scholar
  60. 60.
    Nademi Z, Slatter M, Gambineri E, Mannurita SC, Barge D, Hodges S, et al. Single centre experience of haematopoietic SCT for patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Bone Marrow Transplant. 2014;49(2):310–2.CrossRefGoogle Scholar
  61. 61.
    Kucuk ZY, Bleesing JJ, Marsh R, Zhang K, Davies S, Filipovich AH. A challenging undertaking: stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2016;137(3):953-5.e4.CrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.PediatricsUniversity of Colorado and Children’s Hospital ColoradoAuroraUSA

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