{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:45:04Z","timestamp":1792111504793,"version":"4.4.0"},"reference-count":38,"publisher":"The Endocrine Society","issue":"11","funder":[{"DOI":"10.13039\/100030692","name":"Intramural Research Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100030692","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI001175"],"award-info":[{"award-number":["AI001175"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021453","name":"United States Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100021453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000016","name":"U.S. Department of Health and Human Services","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000016","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a monogenic disorder of impaired central immune tolerance classically inherited in an autosomal recessive manner and caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene, leading to chronic mucocutaneous candidiasis and multiorgan autoimmunity. Although hypoparathyroidism and adrenal insufficiency are among the most common and clinically consequential manifestations, it is increasingly recognized that several non-endocrine features\u2014including autoimmune enteritis, urticarial eruption (termed APECED rash), enamel hypoplasia, autoimmune pneumonitis, and autoimmune hepatitis\u2014often precede classical endocrinopathies, contributing to delayed diagnosis. Endocrinologists are often among the first specialists to encounter these patients and play a central role in early recognition and longitudinal care. Here, we present 5 cases that illustrate the expanding clinical spectrum of APS-1, novel genetic mechanisms, key diagnostic challenges, and emerging therapeutic approaches. These cases highlight the importance of applying expanded clinical criteria and recognizing the limitations of standard genetic testing, including the need to consider deep intronic and dominant-negative AIRE variants. Finally, evolving mechanistic insights have established APS-1 as an interferon-\u03b3-driven disease, providing a rationale for emerging targeted immunomodulatory therapies such as Janus kinase inhibition with ruxolitinib. Early diagnosis enables proactive surveillance and may allow timely initiation of disease-modifying treatment.<\/jats:p>","DOI":"10.1210\/clinem\/dgag282","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:46:56Z","timestamp":1784116016000},"page":"3277-3285","source":"Crossref","is-referenced-by-count":0,"title":["Approach to the patient with APS-1\/APECED"],"prefix":"10.1210","volume":"111","author":[{"given":"Taura","family":"Webb","sequence":"first","affiliation":[{"name":"Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Pechacek","sequence":"additional","affiliation":[{"name":"Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4994-9500","authenticated-orcid":false,"given":"Michail S","family":"Lionakis","sequence":"additional","affiliation":[{"name":"Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2026101520013100400_dgag282-B1","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2021.723532","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"9","author":"Ferre","year":"2021","journal-title":"Front Pediatr"},{"issue":"13","key":"2026101520013100400_dgag282-B2","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.88782","article-title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"1","author":"Ferre","year":"2016","journal-title":"JCI Insight"},{"issue":"8","key":"2026101520013100400_dgag282-B3","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1210\/jc.2016-1821","article-title":"A longitudinal follow-up of autoimmune polyendocrine syndrome type 1","volume":"101","author":"Bruserud","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026101520013100400_dgag282-B4","doi-asserted-by":"crossref","first-page":"e2207","DOI":"10.1210\/clinem\/dgaa140","article-title":"Patients with APECED have increased early mortality due to endocrine causes, malignancies and infections","volume":"105","author":"Borchers","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2026101520013100400_dgag282-B5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nri.2016.9","article-title":"AIRE expands: new roles in immune tolerance and beyond","volume":"16","author":"Anderson","year":"2016","journal-title":"Nat Rev Immunol"},{"issue":"5597","key":"2026101520013100400_dgag282-B6","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"2026101520013100400_dgag282-B7","article-title":"An AIREless breath: pneumonitis caused by impaired central immune tolerance","volume":"11","author":"Ferre","year":"2020","journal-title":"Front Immunol"},{"issue":"3","key":"2026101520013100400_dgag282-B8","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1002\/hep.31421","article-title":"APECED-Associated Hepatitis: clinical, biochemical, histological and treatment data from a large, predominantly American cohort","volume":"73","author":"Chascsa","year":"2021","journal-title":"Hepatology"},{"issue":"9","key":"2026101520013100400_dgag282-B9","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1210\/jc.2017-00139","article-title":"Expanding the phenotypic and genotypic landscape of autoimmune polyendocrine syndrome type 1","volume":"102","author":"Orlova","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2026101520013100400_dgag282-B10","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s40618-020-01376-5","article-title":"Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients","volume":"44","author":"Fierabracci","year":"2021","journal-title":"J Endocrinol 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patients","volume":"322","author":"Ahonen","year":"1990","journal-title":"N Engl J Med"},{"issue":"7","key":"2026101520013100400_dgag282-B14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.0030289","article-title":"Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1","volume":"3","author":"Meager","year":"2006","journal-title":"PLoS Med"},{"issue":"6","key":"2026101520013100400_dgag282-B15","doi-asserted-by":"crossref","DOI":"10.1016\/j.isci.2023.106818","article-title":"Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes","volume":"26","author":"Oftedal","year":"2023","journal-title":"iScience"},{"issue":"6","key":"2026101520013100400_dgag282-B16","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.immuni.2015.04.021","article-title":"Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune 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dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis","volume":"86","author":"Cetani","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"issue":"495","key":"2026101520013100400_dgag282-B32","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aav5597","article-title":"Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance","volume":"11","author":"Ferre","year":"2019","journal-title":"Sci Transl Med"},{"key":"2026101520013100400_dgag282-B33","article-title":"Fatal autoimmune pneumonitis requiring bilobectomy and omental flap repair in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)","volume":"33","author":"Kubala","year":"2021","journal-title":"Respir Med Case Rep"},{"issue":"1","key":"2026101520013100400_dgag282-B34","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1053\/j.gastro.2019.12.040","article-title":"Progressive small bowel obstruction in a patient with the autoimmune syndrome APECED","volume":"159","author":"Ferre","year":"2020","journal-title":"Gastroenterology"},{"issue":"6","key":"2026101520013100400_dgag282-B35","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1016\/j.jaci.2025.03.026","article-title":"Selective JAK1 inhibition remits multiorgan autoimmunity in a patient with refractory autoimmune polyendocrine syndrome type 1","volume":"155","author":"Hadjiyannis","year":"2025","journal-title":"J Allergy Clin Immunol"},{"key":"2026101520013100400_dgag282-B36","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-026-76285-x","article-title":"Prevention of irreversible autoimmune endocrinopathies in APECED with ruxolitinib","author":"Pechacek","year":"2026","journal-title":"Nat Commun"},{"issue":"1","key":"2026101520013100400_dgag282-B37","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10875-023-01629-x","article-title":"Ruxolitinib rescues multiorgan clinical 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