{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:16:11Z","timestamp":1790630171633,"version":"4.1.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Rheumatol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>To evaluate the clinical and genetic characteristics of 3 children with Haploinsufficiency of A20 (HA20). Methods:The clinical and genetic testing data of 3 children with HA20 treated at Capital Institute of Pediatrics (CIP) between August 2016 and October 2019 were retrospectively analysed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Result<\/jats:title>\n                <jats:p>Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. Regarding laboratory tests, patients were found to have elevated white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CRP and ESR was reported to be high in all the patients. The WBC was reported to be high in patient 1 and 3. Patient 2 was positive for antinuclear antibodies, anti-Sj\u00f6gren\u2019s syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that all three patients had heterozygous mutation in TNFAIP3 gene. As for the treatment, patient 1 was treated with TNF\u03b1 antagonist, patient 2 was treated with TNF \u03b1 antagonist and sulfasalazine, and patient 3 was treated with corticosteroids and thalidomide. Patients 1 and 2 were followed for four and 3 months, respectively. There was an improvement in joint and gastrointestinal symptoms; inflammatory indices and rheumatoid factor (RF) were normal, and dsDNA and Coombs test became negative. Patient 3 was treated at another hospital and showed gradual improvement in oral ulcers and perianal abscesses.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>HA20 is a single-gene auto-inflammatory disease caused by mutation in tumour necrosis factor (TNF)-\u03b1-induced protein 3 (TNFAIP3) gene. It may present as Beh\u00e7et-like syndrome and resemble various other autoimmune diseases as well. Corticosteroids and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with early-age onset or Beh\u00e7et-like syndrome to achieve early diagnosis and accurate treatment.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12969-021-00558-6","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T12:02:51Z","timestamp":1621857771000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Clinical characteristics and genetic analysis of A20 haploinsufficiency"],"prefix":"10.1186","volume":"19","author":[{"given":"Dan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-5085","authenticated-orcid":false,"given":"Gaixiu","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"issue":"9","key":"558_CR1","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.3389\/fimmu.2018.01527","volume":"4","author":"D Lawless","year":"2018","unstructured":"Lawless D, Pathak S, Scambler TE, Ouboussad L, Anwar R, Savic S. A case of adult-onset still s disease caused by a novel splicing mutation in TNFAIP3 successfully treated with tocilizumab. Front Immunol. 2018;4(9):1527. https:\/\/doi.org\/10.3389\/fimmu.2018.01527 eCollection 2018.","journal-title":"Front Immunol"},{"issue":"5","key":"558_CR2","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1136\/annrheumdis-2017-212403","volume":"77","author":"FA Aeschlimann","year":"2018","unstructured":"Aeschlimann FA, Batu ED, Canna SW, Go E, G\u00fcl A, Hoffmann P, et al. A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease. Ann Rheum Dis. 2018;77(5):728\u201335. https:\/\/doi.org\/10.1136\/annrheumdis-2017-212403 Epub 2018 Jan 9.","journal-title":"Ann Rheum Dis"},{"issue":"11","key":"558_CR3","doi-asserted-by":"publisher","first-page":"e106","DOI":"10.1097\/TP.0000000000001407","volume":"100","author":"HP Moll","year":"2016","unstructured":"Moll HP, Lee A, Peterson CR, Revuelta Cervantes J, Wojcik BM, Parulkar A, et al. A20 haploinsufficiency aggravates transplant arteriosclerosis in mouse vascular allografts: implications for clinical transplantation. Transplantation. 2016;100(11):e106\u201316. https:\/\/doi.org\/10.1097\/TP.0000000000001407.","journal-title":"Transplantation"},{"issue":"5","key":"558_CR4","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1136\/annrheumdis-2017-212403","volume":"77","author":"HP Moll","year":"2018","unstructured":"Moll HP, Lee A, Peterson CR, Revuelta Cervantes J, Wojcik BM, Parulkar A, et al. A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease. Ann Rheum Dis. 2018;77(5):728\u201335. https:\/\/doi.org\/10.1136\/annrheumdis-2017-212403 Epub 2018 Jan 9.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"558_CR5","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1097\/TP.0000000000001407","volume":"28","author":"HP Moll","year":"2019","unstructured":"Moll HP, Lee A, Peterson CR, Revuelta Cervantes J, Wojcik BM, Parulkar A, et al. Autosomal dominant Hashimoto s thyroiditis with a mutation in TNFAIP3. Clin Pediatr Endocrinol. 2019;28(3):91\u20136. https:\/\/doi.org\/10.1097\/TP.0000000000001407.","journal-title":"Clin Pediatr Endocrinol"},{"key":"558_CR6","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.autrev.2018.02.012","volume":"17","author":"F Berteaua","year":"2018","unstructured":"Berteaua F, Rouvierea B, Dellucb A, Naua A, Rozenn Le Berrea C, Sarrabayd G, et al. Autosomic dominant familial Beh\u00e7et disease and haploinsufficiency A20: a review of the literature. Autoimmun Rev. 2018;17:809\u201315.","journal-title":"Autoimmun Rev"},{"issue":"5","key":"558_CR7","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1136\/annrheumdis-2016-210944","volume":"77","author":"D CJA","year":"2018","unstructured":"CJA D, Dinnigan E, Theobald R, Grainger A, Skelton AJ, Hussain R, et al. Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20). Ann Rheum Dis. 2018;77(5):783\u20136. https:\/\/doi.org\/10.1136\/annrheumdis-2016-210944 Epub 2017 Jun 28.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"558_CR8","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/s12881-019-0856-1","volume":"20","author":"GM Li","year":"2019","unstructured":"Li GM, Liu HM, Guan WZ, Xu H, Wu BB, Sun L. Expanding the spectrum of A20 haploinsufficiency in two Chinese families: cases report. BMC Med Genet. 2019;20(1):124. https:\/\/doi.org\/10.1186\/s12881-019-0856-1.","journal-title":"BMC Med Genet"},{"issue":"3","key":"558_CR9","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.rdc.2017.04.011","volume":"43","author":"H Oda","year":"2017","unstructured":"Oda H, Kastner DL. Genomics, biology, and human illness: advances in the monogenic autoinflammatory diseases. Rheum Dis Clin N Am. 2017 Aug;43(3):327\u201345. https:\/\/doi.org\/10.1016\/j.rdc.2017.04.011.","journal-title":"Rheum Dis Clin N Am"},{"issue":"1","key":"558_CR10","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s13075-019-1928-5","volume":"21","author":"N Tsuchida","year":"2019","unstructured":"Tsuchida N, Kirino Y, Soejima Y, Onodera M, Arai K, Tamura E, et al. Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Beh\u00e7et s disease. Arthritis Res Ther. 2019;21(1):137. https:\/\/doi.org\/10.1186\/s13075-019-1928-5.","journal-title":"Arthritis Res Ther"},{"issue":"4","key":"558_CR11","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1016\/j.jaci.2017.10.039","volume":"141","author":"T Kadowaki","year":"2018","unstructured":"Kadowaki T, Ohnishi H, Kawamoto N, Hori T, Nishimura K, Kobayashi C, et al. Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders. J Allergy Clin Immunol. 2018;141(4):1485\u20131488.e11. https:\/\/doi.org\/10.1016\/j.jaci.2017.10.039 Epub 2017 Dec 11.","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"558_CR12","doi-asserted-by":"publisher","first-page":"e000740","DOI":"10.1136\/rmdopen-2018-000740","volume":"4","author":"K Rajam\u00e4ki","year":"2018","unstructured":"Rajam\u00e4ki K, Keskitalo S, Sepp\u00e4nen M, Kuismin O, V\u00e4h\u00e4salo P, Trotta L, et al. Haploinsufficiency of A20 impairs protein protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation. RMD Open. 2018;4(2):e000740. https:\/\/doi.org\/10.1136\/rmdopen-2018-000740 eCollection 2018.","journal-title":"RMD Open"},{"issue":"6","key":"558_CR13","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1016\/j.jaci.2016.09.038","volume":"139","author":"M Takagi","year":"2017","unstructured":"Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, et al. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2017;139(6):1914\u201322. https:\/\/doi.org\/10.1016\/j.jaci.2016.09.038 Epub 2016 Nov 12.","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"558_CR14","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1097\/BOR.0000000000000362","volume":"29","author":"I Aksentijevich","year":"2017","unstructured":"Aksentijevich I, McDermott MF. Lessons from characterization and treatment of the inflammatory syndromes. Curr Opin Rheumatol. 2017;29(2):187\u201394. https:\/\/doi.org\/10.1097\/BOR.0000000000000362.","journal-title":"Curr Opin Rheumatol"},{"issue":"1","key":"558_CR15","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/ng.3459","volume":"48","author":"Q Zhou","year":"2016","unstructured":"Zhou Q, Wang H, Schwartz DM. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early onset autoinflammatory syndrome. Nat Genet. 2016;48(1):67\u201373. https:\/\/doi.org\/10.1038\/ng.3459.","journal-title":"Nat Genet"},{"issue":"5","key":"558_CR16","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.jbspin.2018.11.003","volume":"86","author":"I Kone-Paut","year":"2019","unstructured":"Kone-Paut I, Georgin-Laviallec S, Galeotti C, Rossi-Semerano L, Hentgen V, Savey L, et al. New data in causes of autoinflammatory diseases. Joint Bone Spine. 2019;86(5):554\u201361. https:\/\/doi.org\/10.1016\/j.jbspin.2018.11.003 Epub 2018 Nov 22.","journal-title":"Joint Bone Spine"},{"key":"558_CR17","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3389\/fimmu.2017.00399","volume":"8","author":"I Aksentijevich","year":"2017","unstructured":"Aksentijevich I, Zhou Q. NF-\u03baB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol. 2017;8:399. https:\/\/doi.org\/10.3389\/fimmu.2017.00399 eCollection 2017.","journal-title":"Front Immunol"},{"issue":"4","key":"558_CR18","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1097\/BOR.0000000000000298","volume":"28","author":"SA Chung","year":"2016","unstructured":"Chung SA, Shum AK. Rare variants, autoimmune disease, and arthritis. Curr Opin Rheumatol. 2016;28(4):346\u201351. https:\/\/doi.org\/10.1097\/BOR.0000000000000298.","journal-title":"Curr Opin Rheumatol"},{"key":"558_CR19","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.clim.2018.03.009","volume":"191","author":"C Franco-Jarava","year":"2018","unstructured":"Franco-Jarava C, Wang H, Martin-Nalda A, Alvarez SD, Garc\u00eda-Prat M, Bodet D, et al. TNFAIP3 haploinsufficiency is the cause of autoinflammatory manifestations in a patient with a deletion of 13Mb on chromosome 6. Clin Immunol. 2018;191:44\u201351. https:\/\/doi.org\/10.1016\/j.clim.2018.03.009 Epub 2018 Mar 20.","journal-title":"Clin Immunol"},{"key":"558_CR20","unstructured":"Horita N, G\u00fcl A, Aksentijevich I, Kastner D, Remmers EF. Pseudodominance of autoinflammatory disease in a single Turkish family explained by co-inheritance of haploinsufficiency of A20 and familial Mediterranean fever. Clin Exp Rheumatol. 2019; [Epub ahead of print]."},{"issue":"10","key":"558_CR21","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1093\/intimm\/dxz024","volume":"31","author":"HH Jarosz-Griffiths","year":"2019","unstructured":"Jarosz-Griffiths HH, Holbrook J, Lara-Reyna S, MF MD. TNF receptor signalling in autoinflammatory diseases. Int Immunol. 2019;31(10):639\u201348. https:\/\/doi.org\/10.1093\/intimm\/dxz024.","journal-title":"Int Immunol"},{"issue":"7","key":"558_CR22","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1093\/rheumatology\/key445","volume":"58","author":"C Papadopoulou","year":"2019","unstructured":"Papadopoulou C, Omoyinmi E, Standing A, Pain CE, Booth C, D'Arco F, et al. Monogenic mimics of Beh\u00e7et's disease in the young. Rheumatology (Oxford). 2019;58(7):1227\u201338. https:\/\/doi.org\/10.1093\/rheumatology\/key445.","journal-title":"Rheumatology (Oxford)"},{"issue":"5","key":"558_CR23","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1097\/BOR.0000000000000532","volume":"30","author":"FA Aeschlimann","year":"2018","unstructured":"Aeschlimann FA, Laxer RM. Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal involvement. Curr Opin Rheumatol. 2018;30(5):506\u201313. https:\/\/doi.org\/10.1097\/BOR.0000000000000532.","journal-title":"Curr Opin Rheumatol"},{"issue":"5","key":"558_CR24","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1097\/BOR.0000000000000424","volume":"29","author":"S Ozen","year":"2017","unstructured":"Ozen S, Acar-Ozen NP. Recent advances in childhood vasculitis. Curr Opin Rheumatol. 2017;29(5):530\u20134. https:\/\/doi.org\/10.1097\/BOR.0000000000000424.","journal-title":"Curr Opin Rheumatol"}],"container-title":["Pediatric Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-021-00558-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12969-021-00558-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12969-021-00558-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T12:04:52Z","timestamp":1621857892000},"score":1,"resource":{"primary":{"URL":"https:\/\/ped-rheum.biomedcentral.com\/articles\/10.1186\/s12969-021-00558-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,24]]},"references-count":24,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["558"],"URL":"https:\/\/doi.org\/10.1186\/s12969-021-00558-6","relation":{},"ISSN":["1546-0096"],"issn-type":[{"value":"1546-0096","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,24]]},"assertion":[{"value":"23 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration"}},{"value":"None.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"75"}}