Autoimmune Polyglandular Syndromes

Mark A. Sperling; Anna Angelousi; Mabel Yau

Autoimmune Polyglandular Syndromes

Review

In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

2024 Jul 21.

Authors

Mark A. Sperling¹, Anna Angelousi², Mabel Yau³

Book Editors

Kenneth R Feingold¹, Bradley Anawalt², Marc R Blackman³, Alison Boyce⁴, George Chrousos⁵, Emiliano Corpas⁶, Wouter W de Herder⁷, Ketan Dhatariya⁸, Kathleen Dungan⁹, Johannes Hofland¹⁰, Sanjay Kalra¹¹, Gregory Kaltsas¹², Nitin Kapoor¹³, Christian Koch¹⁴, Peter Kopp¹⁵, Márta Korbonits¹⁶, Christopher S Kovacs¹⁷, Wendy Kuohung¹⁸, Blandine Laferrère¹⁹, Miles Levy²⁰, Elizabeth A McGee²¹, Robert McLachlan²², Maria New²³, Jonathan Purnell²⁴, Rakesh Sahay²⁵, Amy S Shah²⁶, Frederick Singer²⁷, Mark A Sperling²⁸, Constantine A Stratakis²⁹, Dace L Trence³⁰, Don P Wilson³¹

Affiliations

¹ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY 10029, Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh
² Assistant Professor, 1st Department of Internal Medicine, Unit of Endocrinology, National and Kapodistrian University of Athens, Goudi, 11527
³ Assistant Professor of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY 10029

Book Affiliations

¹ Professor of Medicine Emeritus, University of California, San Francisco, CA
² Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
³ Sr. Physician Scientist, Washington DC VA Medical Center; Professor of Medicine & Rehabilitation Medicine, Georgetown University; Clinical Professor of Medicine, Biochemistry and Molecular Medicine, George Washington University; and Professor of Medicine (Part-time), Johns Hopkins University
⁴ Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
⁵ Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
⁶ M.D. Ph.D in Gerontology. Honorary Professor of Medicine, Universidad de Alcalá, Madrid. Consultant in Endocrinology, Hospital HLA Guadalajara (Spain).
⁷ Professor of Endocrine Oncology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
⁸ Consultant in Diabetes, Endocrinology and General Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.
⁹ Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
¹⁰ Consultant Endocrinologist, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
¹¹ Consultant Endocrinologist, Department of Endocrinology, Bharti Hospital, Karnal, India
¹² Professor of General Medicine-Endocrinology, 1st Department of Propaedeutic Medicine, National and Kapodistrian University of Athens, Athens, Greece
¹³ Professor of Endocrinology, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College & Hospital, Vellore, Tamil Nadu, India, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Australia.
¹⁴ Professor, The University of Tennessee Health Science Center, Memphis, Tennessee
¹⁵ Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
¹⁶ Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
¹⁷ University Research Professor and Professor of Medicine (Endocrinology and Metabolism), Obstetrics & Gynecology, and BioMedical Sciences, at Memorial University of Newfoundland in St. John’s, Newfoundland, Canada.
¹⁸ Director of the Division of Reproductive Endocrinology at Boston Medical Center and an Associate Professor of Obstetrics and Gynecology at the Boston University School of Medicine
¹⁹ Professor of Medicine, New York Nutrition Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Consultant endocrinologist at University Hospitals of Leicester and Honorary Associate Professor at Leicester University
²¹ Professor of Obstetrics and Gynecology at the University of Vermont and Director of the Division of Reproductive Endocrinology and Infertility. Burlington, Vermont
²² Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
²³ Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Chief of the Adrenal Steroid Disorders Program, Icahn School of Medicine, Mount Sinai School of Medicine, New York, NY
²⁴ Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
²⁵ Professor and Head of Department of Endocrinology, Osmania Medical College and Osmania General Hospital, Hyderabad, India.
²⁶ Professor of Pediatrics, The University of Cincinnati, Department of Pediatrics and Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, OH, USA
²⁷ Director of the Endocrine/Bone Disease Program, Saint Johns Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
²⁸ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY. Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh.
²⁹ CSO, ELPEN, Inc. & Director, Research Institute, Athens, Greece & Senior Investigator, Human Genetics & Precision Medicine, FORTH (ITE), Heraklion, Greece. Emeritus Scientific Director & Senior Investigator, NICHD, NIH, Bethesda, MD, USA
³⁰ Professor of Medicine, Emeritus, University of Washington, Seattle, WA
³¹ Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX

PMID: 25905375
Bookshelf ID: NBK279152

Excerpt

The autoimmune polyglandular syndromes (APS) are clusters of endocrine abnormalities that occur in discreet patterns in subjects with immune dysregulation and that permit treatment and anticipation of associated systemic or other hormonal deficiencies. Three major entities are recognized, APS1, APS2 and APS3; the rare X-linked syndrome of immune-dysregulation, poly-endocrinopathy, and enteropathy due to mutations in the FOXP3 gene also qualifies as an APS. An additional increasingly described category occurs in patients treated with immunoregulatory agents such as checkpoint inhibitors for cancer, so that tumor antigens that have evaded recognition can now be targeted, but at the expense of activating autoimmunity with adverse effects on various endocrine tissues. APS1 is a syndrome characterized by chronic muco-cutaneous candidiasis, hypoparathyroidism, primary adrenal insufficiency, as well as ectodermal dystrophy and a host of other endocrine and non-endocrine tissue involvement in autoimmune destructive processes. The underlying cause is a homozygous inactivating mutation in the autoimmune regulator gene AIRE which permits the intra-thymic expression of ectopic antigens normally expressed only in specific peripheral tissues (e.g. insulin), so that T-cells as they mature within the thymus and acquire a receptor for the self- antigen are eliminated (negative selection), thereby avoiding autoimmunity. Studies demonstrate that in addition to the classical homozygous mutations, single gene dominant mutations in AIRE also play an important role in autoimmune regulation and its disorders. Recent studies demonstrate that tissue damage in APS1 due to AIRE mutations is mediated via the JAK-STAT signaling cascade and involves interferon gamma. Inhibiting the JAK-STAT signaling cascade via the monoclonal antibody, ruxolitinib, improves clinical and biochemical manifestations in both a murine model and human patients, offering promise for dramatic improvement in prognosis and clinical outcomes for affected patients. Larger studies in affected patients are awaited with interest. APS2 and APS3 are both due to mutations in the HLA DQ/DR regions which regulate antigen presentation to T-cell receptors; however, their genetic profile is more complex. APS2 is characterized by type 1 diabetes mellitus (T1DM), Addison Disease, and hypothyroidism, whereas APS3 is similar but without Addison disease. In keeping with other autoimmune disorders, these entities are more frequent in females, whereas APS1 has no sexual predominance. The recent emergence of autoimmune endocrinopathies in patients treated with checkpoint immunoregulatory agents for cancer add a new dimension to considerations of autoimmune polyendocrinopathy syndromes. Rapid progress in the immunology and genetics of these entities offers the promise of potential amelioration and eventual reversal via genetic manipulation before organ damage is established. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

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