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Autoimmune polyendocrine syndrome type 1
Medical condition

Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome (autoimmune polyglandular syndrome). It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherited in autosomal recessive fashion due to a defect in the AIRE gene (autoimmune regulator), which is located on chromosome 21 and normally confers immune tolerance.

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Signs and symptoms

APS-1 tends to cause severe symptoms.4 These are present from early in life, usually around 3.5 years of age.5 Common symptoms of APS-1 include:

APS-1 may also cause:

Cause

APS-1 is caused by a mutation in the AIRE gene, encoding a protein called autoimmune regulator. This is found on the 21q22.3 chromosome location, hence chromosome 21.141516 The AIRE gene may be affected by any of at least 186 mutations.17 APS-1 may be inherited in an autosomal recessive manner.18

Different mutations are more common in different geographic regions. R139X is a common mutation in Sardinia.19 R257* is a common mutation in Finland.20 Both of these mutations are nonsense mutations: the asterisk and the "X" both indicate a stop codon.21 A 13-base-pair deletion in the AIRE gene, c.967-979del13bp, has been identified in APS-1 patients in Norway, Britain22 and North America.2324

Pathophysiology

APS-1 is due to problems with immune tolerance.25 APS-1 causes considerable reactions with both interferon omega and interferon alpha.2627 There may also be a reaction against interleukin 22.28 This leads to damage to endocrine organs.29 Common problems include hypercalcaemia and nephrocalcinosis (due to a lack of calcitonin from the thyroid), and pituitary problems (such as growth hormone deficiency).30 Antibodies against NLRP5 may lead to hypoparathyroidism.

Diagnosis

Diagnosis of APS-1 is based on a number of tests, including endoscopy, a CT scan,31 a biopsy (with histological testing),32 and serum endocrine autoantibody screening.

Treatment

Autoimmune polyendocrine syndrome type 1 treatment is based on the symptoms that are presented by the affected individual. Treatments may involve hormone therapy,33 systemic antifungal treatments,3435 and immunosuppression.36 The JAK-STAT inhibitor ruxolitinib is being investigated as a treatment specifically for its normalizing effect on interferon-gamma.37

History

APS-1 may also be known as autoimmunity endocrinopathy candidiasis ectodermal dystrophy / dysplasia (APECED), autoimmune polyglandular syndrome type 1, Whitaker syndrome,38 or candidiasis-hypoparathyroidism-Addison's disease syndrome.39

See also

Further reading

References

  1. "AIRE gene". Genetics Home Reference. Archived from the original on 2017-04-05. Retrieved 2017-04-04. https://ghr.nlm.nih.gov/gene/AIRE#location ↩

  2. "APECED". Archived from the original on 2017-04-06. Retrieved 2017-04-04. https://ghr.nlm.nih.gov/condition/autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy#inheritance ↩

  3. Shoenfeld Y, Cervera R, Gershwin ME (2010-06-08). Diagnostic Criteria in Autoimmune Diseases. Springer Science & Business Media. p. 265. ISBN 9781603272858. Archived from the original on 2023-01-14. Retrieved 2020-11-05. 9781603272858 ↩

  4. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  5. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  6. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  7. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  8. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  9. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  10. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  11. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  12. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  13. Orlova, Elizaveta M; Sozaeva, Leila S; Kareva, Maria A; Oftedal, Bergithe E; Wolff, Anette S B; Breivik, Lars; Zakharova, Ekaterina Y; Ivanova, Olga N; Kämpe, Olle; Dedov, Ivan I; Knappskog, Per M (2017-07-20). "Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1". The Journal of Clinical Endocrinology & Metabolism. 102 (9): 3546–3556. doi:10.1210/jc.2017-00139. ISSN 0021-972X. PMID 28911151. S2CID 3822560. https://doi.org/10.1210%2Fjc.2017-00139 ↩

  14. "AIRE gene". Genetics Home Reference. Archived from the original on 2017-04-05. Retrieved 2017-04-04. https://ghr.nlm.nih.gov/gene/AIRE#location ↩

  15. "APECED". Archived from the original on 2017-04-06. Retrieved 2017-04-04. https://ghr.nlm.nih.gov/condition/autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy#inheritance ↩

  16. "Autoimmune Polyglandular Syndrome Type 1 (APS-1)". NIH: National Institute of Allergy and Infectious Diseases. Archived from the original on 2017-04-17. Retrieved 2017-04-16. https://www.niaid.nih.gov/diseases-conditions/autoimmune-polyglandular-syndrome-type-1-aps-1 ↩

  17. D.N. Cooper; E.V. Ball; P.D. Stenson; A.D. Phillips; K. Evans; S. Heywood; M.J. Hayden; M.M. Chapman; M.E Mort; L. Azevedo; D.S. Millar (eds.). "AIRE". The Human Gene Mutation Database. Institute of Medical Genetics in Cardiff. Archived from the original on 22 August 2023. Retrieved 22 August 2023. https://www.hgmd.cf.ac.uk/ac/gene.php?gene=AIRE ↩

  18. Pearce SH, Cheetham T, Imrie H, Vaidya B, Barnes ND, Bilous RW, Carr D, Meeran K, Shaw NJ, Smith CS, Toft AD, Williams G, Kendall-Taylor P (1998). "A Common and Recurrent 13-bp Deletion in the Autoimmune Regulator Gene in British Kindreds with Autoimmune Polyendocrinopathy Type 1". American Journal of Human Genetics. 63 (6): 1675–1684. doi:10.1086/302145. PMC 1377639. PMID 9837820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1377639 ↩

  19. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

  20. Orlova, Elizaveta M; Sozaeva, Leila S; Kareva, Maria A; Oftedal, Bergithe E; Wolff, Anette S B; Breivik, Lars; Zakharova, Ekaterina Y; Ivanova, Olga N; Kämpe, Olle; Dedov, Ivan I; Knappskog, Per M (2017-07-20). "Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1". The Journal of Clinical Endocrinology & Metabolism. 102 (9): 3546–3556. doi:10.1210/jc.2017-00139. ISSN 0021-972X. PMID 28911151. S2CID 3822560. https://doi.org/10.1210%2Fjc.2017-00139 ↩

  21. D.N. Cooper; E.V. Ball; P.D. Stenson; A.D. Phillips; K. Evans; S. Heywood; M.J. Hayden; M.M. Chapman; M.E Mort; L. Azevedo; D.S. Millar (eds.). "AIRE". The Human Gene Mutation Database. Institute of Medical Genetics in Cardiff. Archived from the original on 22 August 2023. Retrieved 22 August 2023. https://www.hgmd.cf.ac.uk/ac/gene.php?gene=AIRE ↩

  22. Pearce SH, Cheetham T, Imrie H, Vaidya B, Barnes ND, Bilous RW, Carr D, Meeran K, Shaw NJ, Smith CS, Toft AD, Williams G, Kendall-Taylor P (1998). "A Common and Recurrent 13-bp Deletion in the Autoimmune Regulator Gene in British Kindreds with Autoimmune Polyendocrinopathy Type 1". American Journal of Human Genetics. 63 (6): 1675–1684. doi:10.1086/302145. PMC 1377639. PMID 9837820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1377639 ↩

  23. Bruserud Ø, Oftedal BE, Wolff AB, Husebye ES (2016). "AIRE-mutations and autoimmune disease". Current Opinion in Immunology. 43: 8–15. doi:10.1016/j.coi.2016.07.003. PMID 27504588. /wiki/Doi_(identifier) ↩

  24. Qian G, Yan X, Xuan J, Zheng D, He Z, Shen J (2022). "A novel AIRE mutation leads to autoimmune polyendocrine syndrome type-1". Frontiers in Cell and Developmental Biology. 10. doi:10.3389/fcell.2022.948350. PMC 9441485. PMID 36072346. 948350. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9441485 ↩

  25. De Martino L, Capalbo D, Improda N, D'Elia F, Di Mase R, D'Assante R, et al. (October 2013). "APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors". Frontiers in Immunology. 4: 331. doi:10.3389/fimmu.2013.00331. PMC 3805967. PMID 24167503. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805967 ↩

  26. Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi:10.1210/jc.2011-2461. ISSN 0021-972X. PMID 22344197. https://doi.org/10.1210%2Fjc.2011-2461 ↩

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