{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T23:38:05Z","timestamp":1768693085411,"version":"3.49.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and poikiloderma in association with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) are rare inherited syndromes resulting from biallelic pathogenic variants in <jats:italic>AIRE<\/jats:italic> and heterozygous pathogenic variants in <jats:italic>FAM111B<\/jats:italic>, respectively. The clinical diagnosis of APECED and POIKTMP rely on the development of two or more characteristic disease manifestations that define the corresponding syndromes. We discuss the shared and distinct clinical, radiographic, and histological features between APECED and POIKTMP presented in our patient case and describe his treatment response to azathioprine for POIKTMP-associated hepatitis, myositis, and pneumonitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Through informed consent and enrollment onto IRB-approved protocols (NCT01386437, NCT03206099) the patient underwent a comprehensive clinical evaluation at the NIH Clinical Center alongside exome sequencing, copy number variation analysis, autoantibody surveys, peripheral blood immunophenotyping, and salivary cytokine analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report the presentation and evaluation of a 9-year-old boy who was referred to the NIH Clinical Center with an APECED-like clinical phenotype that included the classic APECED dyad of CMC and hypoparathyroidism. He was found to meet clinical diagnostic criteria for POIKTMP featuring poikiloderma, tendon contractures, myopathy, and pneumonitis, and exome sequencing revealed a <jats:italic>de novo<\/jats:italic> c.1292T&amp;gt;C heterozygous pathogenic variant in <jats:italic>FAM111B<\/jats:italic> but no deleterious single nucleotide variants or copy number variants in <jats:italic>AIRE<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This report expands upon the available genetic, clinical, autoantibody, immunological, and treatment response information on POIKTMP.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1133387","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T06:26:40Z","timestamp":1676615200000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case report: Discovery of a de novo FAM111B pathogenic variant in a patient with an APECED-like clinical phenotype"],"prefix":"10.3389","volume":"14","author":[{"given":"Elise M. N.","family":"Ferr\u00e9","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunting","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasileios","family":"Oikonomou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Hilfanova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chyi-Chia R.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey B.","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter D.","family":"Burbelo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara E.","family":"Vazquez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark S.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amisha","family":"Barocha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theo","family":"Heller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariane","family":"Soldatos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven M.","family":"Holland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena A.","family":"Walkiewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michail S.","family":"Lionakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"B1","volume-title":"Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis","author":"Mercier","year":"1993"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.205","article-title":"CUGC for hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP)","volume":"24","author":"Kury","year":"2016","journal-title":"Eur J Hum Genet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14537","article-title":"Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases","volume":"31","author":"Arowolo","year":"2022","journal-title":"Exp Dermatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.07.005","article-title":"The cellular mechanism of aire control of T cell tolerance","volume":"23","author":"Anderson","year":"2005","journal-title":"Immunity."},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-979814","article-title":"Autoimmune polyendocrinopathy\u2013candidiasis\u2013ectodermal dystrophy (APECED)","volume":"28","author":"Perheentupa","year":"1996","journal-title":"Horm Metab Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.723532","article-title":"Autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy","volume":"9","author":"Ferre","year":"2021","journal-title":"Front Pediatr"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11113242","article-title":"In search for the missing link in APECED-like conditions: Analysis of the AIRE gene in a series of 48 patients","volume":"11","author":"Fierabracci","year":"2022","journal-title":"J Clin Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1136\/ard.61.6.554","article-title":"Classification criteria for sjogren's syndrome: a revised version of the European criteria proposed by the American-European consensus group","volume":"61","author":"Vitali","year":"2002","journal-title":"Ann Rheum Dis"},{"key":"B10","doi-asserted-by":"publisher","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":"2020","journal-title":"Hepatology."},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","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"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay5731","article-title":"Aberrant type 1 immunity drives susceptibility to mucosal fungal infections","volume":"371","author":"Break","year":"2021","journal-title":"Science."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55053","article-title":"Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-seq","volume":"9","author":"Vazquez","year":"2020","journal-title":"Elife."},{"key":"B15","doi-asserted-by":"publisher","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"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202050662","article-title":"FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease","volume":"21","author":"Hoffmann","year":"2020","journal-title":"EMBO Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s13023-015-0352-4","article-title":"Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations","volume":"10","author":"Mercier","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/MPA.0000000000000529","article-title":"FAM111B mutation is associated with inherited exocrine pancreatic dysfunction","volume":"45","author":"Seo","year":"2016","journal-title":"Pancreas."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/mus.23321","article-title":"Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"45","author":"Watanabe","year":"2012","journal-title":"Muscle Nerve"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdcr.2020.09.025","article-title":"Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis: Hepatic disease in a child with a novel pathogenic variant of FAM111B","volume":"6","author":"Dokic","year":"2020","journal-title":"JAAD Case Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.609253","article-title":"An AIREless breath: Pneumonitis caused by impaired central immune tolerance","volume":"11","author":"Ferre","year":"2020","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmr.2018.09.002","article-title":"[Pulmonary fibrosis associated with hereditary fibrosing poikiloderma caused by FAM111B mutation: A case report]","volume":"35","author":"Sanchis-Borja","year":"2018","journal-title":"Rev Mal Respir"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2006.07473.x","article-title":"Poikiloderma, tendon contracture and pulmonary fibrosis: a new autosomal dominant syndrome","volume":"155","author":"Khumalo","year":"2006","journal-title":"Br J Dermatol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.10.013","article-title":"Mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis","volume":"93","author":"Mercier","year":"2013","journal-title":"Am J Hum Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.1081166","article-title":"Function and evolution of FAM111B serine proteases","volume":"9","author":"Welter","year":"2022","journal-title":"Front Mol Biosci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.14968","article-title":"A case of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP) with the emphasis on cutaneous histopathological findings","volume":"32","author":"Kazlouskaya","year":"2018","journal-title":"J Eur Acad Dermatol Venereol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1133387\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T06:26:45Z","timestamp":1676615205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1133387\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,17]]},"references-count":27,"alternative-id":["10.3389\/fimmu.2023.1133387"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1133387","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,17]]},"article-number":"1133387"}}