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Type I Polyglandular Autoimmune Syndrome Clinical Presentation

  • Author: Saleh A Aldasouqi, MD, FACE, ECNU; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Aug 28, 2014
 

History

Overview of clinical features

  • The 3 major components of polyglandular autoimmune (PGA) syndrome, type I, are (1) chronic mucocutaneous candidiasis, (2) hypoparathyroidism, and (3) autoimmune adrenal insufficiency.
  • The presence of all 3 components is not required to make a diagnosis; at least 2 components have to be present in an individual. Additional manifestations, including, among others, type 1A diabetes (documented autoimmune etiology), hypogonadism, pernicious anemia, malabsorption, alopecia, and vitiligo, may be present as well.
  • The first manifestation usually occurs in childhood, and the complete evolution of the 3 main diseases takes place within the first 20 years of life. Accompanying diseases continue to appear at least until the fifth decade of life.
  • Candidiasis usually is the first clinical manifestation, most often presenting in people younger than 5 years. Hypoparathyroidism occurs next, usually in people younger than 10 years. Lastly, Addison disease occurs in people younger than 15 years.
  • Overall, the 3 components occur in fairly precise chronological order, and they are present in roughly 40% of cases. As mentioned earlier, however, careful follow-up is mandatory to watch for the more dreadful manifestations, eg, adrenal insufficiency, regardless of the reportedly expected pattern of appearance.
  • The probability that multiple components of the disease will occur depends on how early the symptoms appear.
  • In a case of PGA-I reported by Bhansali and colleagues, no candidiasis was noted in an East Indian boy aged 16 years.[5]

Mucocutaneous candidiasis

  • This condition usually occurs earliest and is the most common of the 3 main diseases of PGA-I.
  • Assess any young person with moniliasis for a possible state of T-cell deficiency and PGA-I.
  • Between 50 and 100% of patients with PGA-I develop a recurrent monilial infection. Most of the lesions are limited to the skin (usually < 5% of surface area), nails, and oral and anal mucosa.[13] Esophageal involvement may be complicated by strictures and stenosis.
  • Even though the presence of candidiasis is consistent with a T-cell defect, no increased frequency of other opportunistic infections exists.
  • Because these patients have a normal B-cell response to candidal antigens, they are spared from developing disseminated candidiasis.

Hypoparathyroidism[4]

  • This is the first endocrine disease to occur during the course of PGA-I, usually developing after candidiasis and before Addison disease.
  • Antiparathyroid antibodies have been reported in 10-40% of patients with hypoparathyroidism; however, whether these are being confused with mitochondrial autoantibodies is still under debate. The pathologic significance of these antibodies is not clear.
  • Other disease states presenting with neonatal hypocalcemia (DiGeorge syndrome or congenital absence or malformation of the parathyroid) must be differentiated from PGA-I. DiGeorge syndrome results from a congenital defective disorder of the branchial clefts. It manifests as hypoparathyroidism and cutaneous candidiasis; unlike PGA-I, DiGeorge syndrome does not involve the adrenal glands.
  • More than 75% of patients develop hypoparathyroidism, which usually presents in persons younger than 10 years.
  • Clinical features may include, among others, (1) tetanic clinical symptoms, such as carpopedal spasm and paresthesias of the lips, fingers, and feet; (2) seizures; (3) laryngospasm; (4) leg cramps; (5) diffuse mild encephalopathy; (6) cataracts; and (7) papilledema. Electrocardiography may show a prolonged QT interval.

Adrenocortical failure (Addison disease)

  • Addison disease typically occurs in people aged 10-30 years (mean, 12-13 y); it usually is the third disease to appear in PGA-I.
  • Mineralocorticoid and glucocorticoid deficiencies usually arise simultaneously, but their onset can be dissociated by up to 3 years.
  • CYP21 appears to be the major autoantigen in isolated Addison disease and Addison disease associated with PGA-II. Autoantibodies to CYP17 and a side-chain cleavage enzyme (CYP11A1) have been associated with Addison disease in PGA-I.
  • Early symptoms include weakness, fatigue, and orthostatic hypotension.
  • Pigmentation usually is increased and may serve as a differentiating point from secondary hypoadrenalism (primary pituitary failure).
  • Anorexia, nausea, vomiting, diarrhea, and cold intolerance often occur.
  • Late symptoms include weight loss, dehydration, hypotension, and a small-sized heart.

Less common clinical manifestations

  • Hypergonadotropic hypogonadism
  • Type 1 diabetes mellitus
  • Autoimmune thyroid disease (not including Graves disease)
  • Pernicious anemia
  • Chronic atrophic gastritis
  • Chronic active hepatitis
  • Enamel hypoplasia, which occasionally precedes the onset of hypoparathyroidism
  • Asplenia
  • Keratoconjunctivitis
  • Cholelithiasis
  • Malabsorption
  • Alopecia
  • Vitiligo
  • Interstitial nephritis
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Physical

Physical findings in polyglandular autoimmune (PGA) syndrome, type I, are dependent on the components of the syndrome that are clinically manifested at the time of examination.

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Causes

Genetic

  • HLA alleles are not seen in polyglandular autoimmune (PGA) syndrome, type I.
  • The postulated genetic locus is described in Pathophysiology.

Environmental

  • Precipitators of autoimmunity exist, but they continue to be elusive.
  • Postulations include the association between congenital rubella infections and type 1 diabetes mellitus or hypoparathyroidism.
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Contributor Information and Disclosures
Author

Saleh A Aldasouqi, MD, FACE, ECNU Associate Professor of Medicine, Vice Chief of Endocrinology Division, Department of Medicine, Michigan State University College of Human Medicine

Saleh A Aldasouqi, MD, FACE, ECNU is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians

Disclosure: Received honoraria from Takeda for speaking and teaching; Received honoraria from Janssen for speaking and teaching; Received honoraria from Invokana for speaking and teaching.

Coauthor(s)

Olakunle P A Akinsoto, MD, MB, BCh Consulting Staff, Family Health Center

Olakunle P A Akinsoto, MD, MB, BCh is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Medical Association

Disclosure: Nothing to disclose.

Serge A Jabbour, MD, FACP, FACE Professor of Medicine, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University

Serge A Jabbour, MD, FACP, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Thyroid Association, Endocrine Society, Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Nutrition, American Society for Bone and Mineral Research, International Society for Clinical Densitometry, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

I would like to thank Jinie Shirey at the Department of Medicine, College of Human Medicine, Michigan State University, East Lansing for manuscript assistance and preparation, and Laura Smith at the Medical Library, Sparrow Hospital, Lansing, Michigan, for assistance in reference retrieval.

References
  1. Garcia-Hernandez FJ, Ocana-Medina C, Gonzalez-Leon R, et al. Autoimmune polyglandular syndrome and pulmonary arterial hypertension. Eur Respir J. 2006 Mar. 27(3):657-8. [Medline]. [Full Text].

  2. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981 Sep. 60(5):355-62. [Medline].

  3. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004 May 13. 350(20):2068-79. [Medline].

  4. Alimohammadi M, Bjorklund P, Hallgren A, et al. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. 2008 Mar 6. 358(10):1018-28. [Medline]. [Full Text].

  5. Bhansali A, Kotwal N, Suresh V, et al. Polyglandular autoimmune syndrome type 1 without chronic mucocutaneous candidiasis in a 16 year-old male. J Pediatr Endocrinol Metab. 2003 Jan. 16(1):103-5. [Medline].

  6. Bjorses P, Halonen M, Palvimo JJ, et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am J Hum Genet. 2000 Feb. 66(2):378-92. [Medline]. [Full Text].

  7. Org T, Chignola F, Hetenyi C, et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008 Apr. 9(4):370-6. [Medline]. [Full Text].

  8. Heino M, Scott HS, Chen Q, et al. Mutation analyses of North American APS-1 patients. Hum Mutat. 1999. 13(1):69-74. [Medline].

  9. Rosatelli MC, Meloni A, Meloni A, et al. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum Genet. 1998 Oct. 103(4):428-34. [Medline].

  10. Zlotogora J, Shapiro MS. Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet. 1992 Nov. 29(11):824-6. [Medline]. [Full Text].

  11. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. 2003 Jul. 88(7):2983-92. [Medline]. [Full Text].

  12. Iannello S, Campanile E, Cipolli D, et al. [A rare case of juvenile diabetes mellitus associated with APECED (autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy) with strong X-linked familial inheritance]. Minerva Endocrinol. 1997 Jun. 22(2):51-9. [Medline].

  13. LeBoeuf N, Garg A, Worobec S. The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Pediatr Dermatol. 2007 Sep-Oct. 24(5):529-33. [Medline].

  14. Meloni A, Furcas M, Cetani F, et al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. 2008 Nov. 93(11):4389-97. [Medline].

  15. Oftedal BE, Wolff AS, Bratland E, et al. Radioimmunoassay for autoantibodies against interferon omega; its use in the diagnosis of autoimmune polyendocrine syndrome type I. Clin Immunol. 2008 Oct. 129(1):163-9. [Medline].

  16. Ahonen P, Myllarniemi S, Sipila I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990 Jun 28. 322(26):1829-36. [Medline].

  17. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997 Dec. 17(4):399-403. [Medline].

  18. Katzung BG, ed. Basic and Clinical Pharmacology. 7th ed. Stamford, Conn: Appleton & Lange; 1998. 635-52, 706-22.

  19. Betterle C, Greggio NA, Volpato M. Clinical review 93: autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1998 Apr. 83(4):1049-55. [Medline]. [Full Text].

  20. Eisenbarth GS, Gottlieb PA. The immunoendocrinopathy syndromes. Larsen PR, Kronenberg HM, Melmed S, et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders; 2003. 1763-76.

  21. Halonen M, Eskelin P, Myhre AG, et al. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab. 2002 Jun. 87(6):2568-74. [Medline]. [Full Text].

  22. Hannigan NR, Jabs K, Perez-Atayde AR, et al. Autoimmune interstitial nephritis and hepatitis in polyglandular autoimmune syndrome. Pediatr Nephrol. 1996 Aug. 10(4):511-4. [Medline].

  23. Hogenauer C, Meyer RL, Netto GJ, et al. Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I. N Engl J Med. 2001 Jan 25. 344(4):270-4. [Medline].

  24. Muir A, Schatz DA, Maclaren NK. Polyglandular failure syndromes. DeGroot LJ, et al, eds. Endocrinology. 3rd ed. Philadelphia, Pa: Saunders; 1995. 3013-22.

  25. Myhre AG, Halonen M, Eskelin P, et al. Autoimmune polyendocrine syndrome type 1 (APS I) in Norway. Clin Endocrinol (Oxf). 2001 Feb. 54(2):211-7. [Medline].

  26. Nieman LK. Causes of primary adrenal insufficiency (Addison's disease). www.uptodate.com. Available at http://www.utdol.com/utd/content/topic.do?topicKey=adrenal/7188&view. Accessed: May, 10, 2006.

  27. Obermayer-Straub P, Manns MP. Autoimmune polyglandular syndromes. Baillieres Clin Gastroenterol. 1998 Jun. 12(2):293-315. [Medline].

  28. Rybojad M, Abimelec P, Feuilhade M, et al. [Familial chronic mucocutaneous candidiasis associated with autoimmune polyendocrinopathy. Treatment with fluconazole: 3 cases]. Ann Dermatol Venereol. 1999 Jan. 126(1):54-6. [Medline].

  29. Soderbergh A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. 2004 Feb. 89(2):557-62. [Medline]. [Full Text].

  30. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck; 1999. 119-20.

  31. Toonkel R, Levine M, Gardner L. Erythropoietin-deficient anemia associated with autoimmune polyglandular syndrome type I. Am J Hematol. 2004 Feb. 75(2):84-8. [Medline].

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