{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T01:39:18Z","timestamp":1787189958746,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T00:00:00Z","timestamp":1642636800000},"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>Background<\/jats:title><jats:p>STAT1 gain-of-function (GOF) is a primary immune dysregulatory disorder marked by wide infectious predisposition (most notably chronic mucocutaneous Candidiasis), autoimmunity, vascular disease and malignant predisposition. While atopic features have been described in some STAT1 GOF patients, they are not considered a predominant feature of the disease. Additionally, while eosinophilic gastrointestinal infiltration has been reported in some cases, this has always been described in the context of pre-existing oropharyngeal and\/or esophageal Candidiasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical cases<\/jats:title><jats:p>Herein, we report 3 members of a multi-generational family diagnosed with STAT1 GOF caused by a novel mutation in the N-terminal domain, c.194A&amp;gt;C (p.D65A). The proband presented initially with a long-standing history of treatment-refractory eosinophilic esophagitis (EoE) without preceding gastrointestinal tract fungal infections, and her mother was diagnosed with esophagitis as well.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>EoE has been previously associated with alterations to STAT6 and STAT3 signaling pathways. The current report expands the possible association between JAK\/STAT-related disorders and EoE, suggesting that EoE could be a primary disease manifestation of STAT1 GOF, even in the absence of oropharyngeal and\/or esophageal Candidiasis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.801832","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T06:44:18Z","timestamp":1642661058000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Case Report: Eosinophilic Esophagitis in a Patient With a Novel STAT1 Gain-of-Function Pathogenic Variant"],"prefix":"10.3389","volume":"13","author":[{"given":"Ori","family":"Scott","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Sharfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harjit","family":"Dadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Vong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Garkaby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Abrego Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Willett Pachul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Nelles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Nahum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaim M.","family":"Roifman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/ni.3691","article-title":"Mechanisms and Consequences of Jak\u2013STAT Signaling in the Immune System","volume":"18","author":"Villarino","year":"2017","journal-title":"Nat Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.03.013","article-title":"The JAK-STAT Pathway at Twenty","volume":"36","author":"Stark","year":"2012","journal-title":"Immunity"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00029","article-title":"Canonical and Non-Canonical Aspects of JAK\u2013STAT Signaling: Lessons From Interferons for Cytokine Responses","volume":"8","author":"Majoros","year":"2017","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01135","article-title":"A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses","volume":"9","author":"Michalska","year":"2018","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ng1097","article-title":"Impaired Response to Interferon-Alpha\/Beta and Lethal Viral Disease in Human STAT1 Deficiency","volume":"33","author":"Dupuis","year":"2003","journal-title":"Nat Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.8.5078","article-title":"Human Complete Stat-1 Deficiency is Associated With Defective Type I and II IFN Responses In Vitro But Immunity to Some Low Virulence Viruses In Vivo","volume":"176","author":"Chapgier","year":"2006","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-330571","article-title":"Severe Impairment of IFN-Gamma and IFN-Alpha Responses in Cells of a Patient With a Novel STAT1 Splicing Mutation","volume":"118","author":"Vairo","year":"2011","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-280586","article-title":"A Novel Form of Human STAT1 Deficiency Impairing Early But Not Late Responses to Interferons","volume":"116","author":"Kong","year":"2010","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-010-9480-8","article-title":"Novel STAT1 Alleles in a Patient With Impaired Resistance to Mycobacteria","volume":"31","author":"Kristensen","year":"2011","journal-title":"J Clin Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110958","article-title":"Gain-Of-Function Human STAT1 Mutations Impair IL-17 Immunity and Underlie Chronic Mucocutaneous Candidiasis","volume":"208","author":"Liu","year":"2011","journal-title":"J Exp Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMoa1100102","article-title":"STAT1 Mutations in Autosomal Dominant Chronic Mucocutaneous Candidiasis","volume":"365","author":"van de Veerdonk","year":"2011","journal-title":"N Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-679902","article-title":"Heterozygous STAT1 Gain-of-Function Mutations Underlie an Unexpectedly Broad Clinical Phenotype","volume":"127","author":"Toubiana","year":"2016","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.654406","article-title":"Clinical Relevance of Gain-And Loss-Of-Function Germline Mutations in STAT1: A Systematic Review","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.09.032","article-title":"Fatal Combined Immunodeficiency Associated With Heterozygous Mutation in STAT1","volume":"133","author":"Sharfe","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.11.054","article-title":"Dominant Gain-of-Function STAT1 Mutations in FOXP3 Wild-Type Immune Dysregulation\u2013Polyendocrinopathy\u2013Enteropathy\u2013X-Linked\u2013Like Syndrome","volume":"131","author":"Uzel","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.rmed.2017.03.018","article-title":"Autosomal Dominant Gain of Function STAT1 Mutation and Severe Bronchiectasis","volume":"126","author":"Breuer","year":"2017","journal-title":"Respir Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s10875-015-0214-9","article-title":"The Extended Clinical Phenotype of 26 Patients With Chronic Mucocutaneous Candidiasis Due to Gain-of-Function Mutations in STAT1","volume":"36","author":"Depner","year":"2016","journal-title":"J Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"87","DOI":"10.14785\/lpsn-2014-0004","article-title":"A Mutation in the STAT1 DNA-Binding Domain Associated With Hemophagocytic Lymphohistocytosis","volume":"1","author":"Faitelson","year":"2014","journal-title":"LymphoSign J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.03.049","article-title":"Hematopoietic Stem Cell Transplantation in Patients With Gain-of-Function Signal Transducer and Activator of Transcription 1 Mutations","volume":"141","author":"Leiding","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.08.040","article-title":"Ruxolitinib Partially Reverses Functional Natural Killer Cell Deficiency in Patients With Signal Transducer and Activator of Transcription 1 (STAT1) Gain-of-Function Mutations","volume":"141","author":"Vargas-Hern\u00e1ndez","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00967","article-title":"Recurrent, Severe Aphthous Stomatitis and Mucosal Ulcers as Primary Manifestations of a Novel Stat1 Gain-of-Function Mutation","volume":"11","author":"Erd\u0151s","year":"2020","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12727","article-title":"The Clinical and Mechanistic Intersection of Primary Atopic Disorders and Inborn Errors of Growth and Metabolism","volume":"287","author":"Lyons","year":"2019","journal-title":"Immunol Rev"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/2846928","article-title":"Gain-Of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies","volume":"2017","author":"Eren Akarcan","year":"2017","journal-title":"Case Rep Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90368-9","article-title":"Defective T Cell Receptor Signaling and CD8+ Thymic Selection in Humans Lacking Zap-70 Kinase","volume":"76","author":"Arpaia","year":"1994","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1007\/s10875-019-00688-3","article-title":"Molecular and Phenotypic Characterization of Nine Patients With STAT1 GOF Mutations in China","volume":"40","author":"Chen","year":"2020","journal-title":"J Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.gastro.2003.07.007","article-title":"Intratracheal IL-13 Induces Eosinophilic Esophagitis by an IL-5, Eotaxin-1, and STAT6-Dependent Mechanism","volume":"125","author":"Mishra","year":"2003","journal-title":"Gastroenterology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e50037","DOI":"10.1371\/journal.pone.0050037","article-title":"Omeprazole Blocks STAT6 Binding to the Eotaxin-3 Promoter in Eosinophilic Esophagitis Cells","volume":"7","author":"Zhang","year":"2012","journal-title":"PloS One"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.12.6681","article-title":"A Critical Role for Eotaxin in Experimental Oral Antigen-Induced Eosinophilic Gastrointestinal Allergy","volume":"97","author":"Hogan","year":"2000","journal-title":"Proc Natl Acad Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e0157376","DOI":"10.1371\/journal.pone.0157376","article-title":"JAK-STAT6 Pathway Inhibitors Block Eotaxin-3 Secretion by Epithelial Cells and Fibroblasts From Esophageal Eosinophilia Patients: Promising Agents to Improve Inflammation and Prevent Fibrosis in EoE","volume":"11","author":"Cheng","year":"2016","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms6593","article-title":"GWAS Identifies Four Novel Eosinophilic Esophagitis Loci","volume":"5","author":"Sleiman","year":"2014","journal-title":"Nat Commun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2020.08.020","article-title":"STAT6 Variants Associate With Relapse of Eosinophilic Esophagitis in Patients Receiving Long-Term Proton Pump Inhibitor Therapy","volume":"19","author":"Mougey","year":"2021","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2016.03.023","article-title":"Eosinophilic Esophagitis Diagnosed in a Patient With Common Variable Immunodeficiency","volume":"4","author":"Chen","year":"2016","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2016.185","article-title":"Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study","volume":"111","author":"Peterson","year":"2016","journal-title":"Off J Am Coll Gastroenterol ACG"},{"key":"B34","doi-asserted-by":"publisher","first-page":"AB24","DOI":"10.1016\/j.jaci.2017.12.077","article-title":"Eosinophilic Gastrointestinal Disease in Patients With Primary Immunodeficiency","volume":"141","author":"Ruffner","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1007\/s10875-017-0429-z","article-title":"Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome","volume":"37","author":"Arora","year":"2017","journal-title":"J\u00a0Clin Immunol"},{"key":"B36","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.155.9.4454","article-title":"Mechanism of Inhibition of Eosinophil Activation by Transforming Growth Factor-Beta. Inhibition of Lyn, MAP, Jak2 Kinases and STAT1 Nuclear Factor","volume":"155","author":"Pazdrak","year":"1995","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.6.1442.bloodjournal8561442","article-title":"Interleukin-5 Signaling in Human Eosinophils Involves JAK2 Tyrosine Kinase and Stat1 Alpha","volume":"85","author":"van der Bruggen","year":"1995","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1097\/MPG.0b013e318212647a","article-title":"Immunophenotyping of Peripheral Eosinophils Demonstrates Activation in Eosinophilic Esophagitis","volume":"53","author":"Nguyen","year":"2011","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.07.020","article-title":"Jakinibs for the Treatment of Immune Dysregulation in Patients With Gain-of-Function Signal Transducer and Activator of Transcription 1 (STAT1) or STAT3 Mutations","volume":"142","author":"Forbes","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1007\/s10875-018-0519-6","article-title":"Utility of Ruxolitinib in a Child With Chronic Mucocutaneous Candidiasis Caused by a Novel STAT1 Gain-of-Function Mutation","volume":"38","author":"Bloomfield","year":"2018","journal-title":"J Clin Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24976","article-title":"Ruxolitinib-Associated Infections: A Systematic Review and Meta-Analysis","volume":"93","author":"Lussana","year":"2018","journal-title":"Am J Hematol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.801832\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T20:59:17Z","timestamp":1674507557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.801832\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,20]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2022.801832"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.801832","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,20]]},"article-number":"801832"}}