{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:17:09Z","timestamp":1790727429233,"version":"4.1.0"},"reference-count":16,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"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:p>RELA haploinsufficiency is a recently described autoinflammatory condition presenting with intermittent fevers and mucocutaneous ulcerations. The RELA gene encodes the p65 protein, one of five NF-\u03baB family transcription factors. As RELA is an essential regulator of mucosal homeostasis, haploinsufficiency leads to decreased NF-\u03baB signaling which promotes TNF-driven mucosal apoptosis with impaired epithelial recovery. Thus far, only eight cases have been reported in the literature. Here, we report four families with three novel and one previously described pathogenic variant in RELA. These four families included 23 affected individuals for which genetic testing was available in 16. Almost half of these patients had been previously diagnosed with more common rheumatologic entities (such as Behcet\u2019s Disease; BD) prior to the discovery of their pathogenic RELA variants. The most common clinical features were orogenital ulcers, rash, joint inflammation, and fever. The least common were conjunctivitis and recurrent infections. Clinical variability was remarkable even among familial cases, and incomplete penetrance was observed. Patients in our series were treated with a variety of medications, and benefit was observed with glucocorticoids, colchicine, and TNF inhibitors. Altogether, our work adds to the current literature and doubles the number of reported cases with RELA-Associated Inflammatory Disease (RAID). It reaffirms the central importance of the NF-\u03baB pathway in immunity and inflammation, as well as the important regulatory role of RELA in mucosal homeostasis. RELA associated inflammatory disease should be considered in all patients with BD, particularly those with early onset and\/or with a strong family history.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1127085","type":"journal-article","created":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T11:58:09Z","timestamp":1678103889000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Case report: Novel variants in RELA associated with familial Behcet\u2019s-like disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Jason W.","family":"An","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallavi","family":"Pimpale-Chavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia","family":"Bandeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Dedeoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bohnsack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Rosenzweig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Schnappauf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilan","family":"Dissanayake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda T.","family":"Hiraki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L.","family":"Kastner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Pelajo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald M.","family":"Laxer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivona","family":"Aksentijevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3459","article-title":"Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease","volume":"48","author":"Zhou","year":"2016","journal-title":"Nat Genet."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160724","article-title":"Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration","volume":"214","author":"Badran","year":"2017","journal-title":"J Exp Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.11.036","article-title":"RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias","volume":"141","author":"Comrie","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/art.41531","article-title":"A novel RELA truncating mutation in a familial beh\u00e7et\u2018s disease\u2013like mucocutaneous ulcerative condition","volume":"73","author":"Adeeb","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000002796","article-title":"Comprehensive targeted sequencing identifies monogenic disorders in patients with early-onset refractory diarrhea","volume":"71","author":"Uchida","year":"2020","journal-title":"JPGN"},{"key":"B6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2021.716469","article-title":"NF- kB : At the borders of autoimmunity and inflammation","volume":"12","author":"Barnabei","year":"2021","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.2MR0520-166R","article-title":"Mendelian diseases of dysregulated canonical NF-KB signaling : From immunodeficiency to inflammation","volume":"108","author":"Schnappauf","year":"2020","journal-title":"J Leukoc Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"ACMG standards and guidelines 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":"B9","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.27.046102","article-title":"Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF- \u03ba b pathway towards transcriptional activation of type-I interferon genes","author":"Barnabei","year":"2020"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212403","article-title":"A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease","volume":"77","author":"Aeschlimann","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-020-02281-1","article-title":"A20: A master regulator of arthritis","volume":"22","author":"Wu","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212403","article-title":"Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome","volume":"77","author":"Aeschlimann","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.09.038","article-title":"Haploinsufficiency of TNFAIP3 ( A20 ) by germline mutation is involved in autoimmune lymphoproliferative syndrome","volume":"139","author":"Takagi","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00399","article-title":"NF- \u03ba b pathway in autoinflammatory Diseases: Dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases","volume":"8","author":"Aksentijevich","year":"2017","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00792-3","article-title":"Death by TNF: a road to inflammation","volume":"15","author":"Van Loo","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2590","article-title":"Neonatal high bone mass with first mutation of the NF-\u03baB complex: Heterozygous De novo missense (p.Asp512Ser) RELA (Rela\/p65)","volume":"31","author":"Frederiksen","year":"2016","journal-title":"J Bone Min Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1127085\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T11:58:18Z","timestamp":1678103898000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1127085\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,28]]},"references-count":16,"alternative-id":["10.3389\/fimmu.2023.1127085"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1127085","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,28]]},"article-number":"1127085"}}