{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:05:03Z","timestamp":1792710303354,"version":"4.5.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Istanbul University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Pediatr"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Familial Mediterranean fever (FMF) is the most common inherited autoinflammatory disorder caused by MEFV variants. Exon 10 variants, particularly M694V, are strongly associated with severe disease, but the impact of non\u2013exon 10 variants in children remains less defined. To evaluate genotype\u2013phenotype correlations in pediatric FMF by comparing patients with homozygous exon 10, compound heterozygous exon 10, and exon 10 combined with non\u2013exon 10 variants. This single-center retrospective cohort study included 477 children fulfilling Eurofever\/PRINTO criteria between 2018 and 2025. Patients were stratified into four genotype groups. Clinical features, laboratory parameters, and treatments were compared. Disease severity was assessed with the International Severity Scoring System for FMF (ISSF). Homozygous exon 10 variants were associated with an earlier disease onset, shorter diagnostic delay, higher ISSF scores, and a markedly greater requirement for anti\u2013IL-1 therapy compared with other genotypic categories. Patients with compound exon 10 variants and those with combined exon 10\u2013non\u2013exon 10 variants exhibited broadly comparable overall disease severity, although differences were observed in selected clinical manifestations. In contrast, individuals with combined exon 10\u2013non\u2013exon 10 variants demonstrated higher attack frequency, increased inflammatory marker levels, and higher ISSF scores when compared with patients with a single exon 10 allele, supporting a modifier effect of non\u2013exon 10 variants on disease expression.<\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusion<\/jats:italic>\n                    : Pediatric FMF patients homozygous for exon 10, especially M694V, show a more severe clinical course with higher disease activity and greater biologic treatment requirements. Exon 10\u2013non\u2013exon 10 variants present with attenuated but clinically relevant phenotypes, resembling compound exon 10 carriers. These findings emphasize the prognostic importance of comprehensive MEFV genotyping in risk stratification and individualized management.\n                    <jats:table-wrap>\n                      <jats:table>\n                        <jats:tbody>\n                          <jats:tr>\n                            <jats:td align=\"left\">\n                              <jats:bold>What is Known:<\/jats:bold>\n                              \u2022\n                              <jats:italic>Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disorder, caused by MEFV gene mutations.<\/jats:italic>\n                              \u2022\n                              <jats:italic>Exon 10 mutations, particularly M694V homozygosity, are associated with more severe disease, higher attack frequency, colchicine resistance, and increased risk of complications such as amyloidosis.<\/jats:italic>\n                            <\/jats:td>\n                          <\/jats:tr>\n                          <jats:tr>\n                            <jats:td align=\"left\">\n                              <jats:bold>What is New:<\/jats:bold>\n                              \u2022\n                              <jats:italic>This is one of the largest pediatric FMF cohorts systematically stratified into homozygous exon 10, compound heterozygous exon 10, exon 10\u2013non\u2013exon 10 groups, and single exon 10 allele<\/jats:italic>\n                              \u2022\n                              <jats:italic>Exon 10\u2013non\u2013exon 10 variant combinations were associated with a clinically relevant inflammatory phenotype resembling compound exon 10 genotypes, suggesting a potential modifier role of non\u2013exon 10 variants.<\/jats:italic>\n                            <\/jats:td>\n                          <\/jats:tr>\n                        <\/jats:tbody>\n                      <\/jats:table>\n                    <\/jats:table-wrap>\n                  <\/jats:p>","DOI":"10.1007\/s00431-026-06835-4","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T06:59:23Z","timestamp":1773039563000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparative analysis of exon 10 and non-exon 10 variants in children with familial mediterranean fever: a retrospective cohort study"],"prefix":"10.1007","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-9591","authenticated-orcid":false,"given":"Bengisu","family":"Menento\u011flu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7648-1195","authenticated-orcid":false,"given":"Selen Duygu","family":"Ar\u0131k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0358-2854","authenticated-orcid":false,"given":"P\u0131nar","family":"Prencuva Aky\u00fcrek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7216-0562","authenticated-orcid":false,"given":"\u00d6zlem","family":"Akg\u00fcn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3594-7387","authenticated-orcid":false,"given":"Nuray","family":"Aktay Ayaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"issue":"1","key":"6835_CR1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/sj.ejhg.5200170","volume":"6","author":"M Dewalle","year":"1998","unstructured":"Dewalle M, Domingo C, Rozenbaum M, Ben-Chetrit E, Cattan D, Bernot A et al (1998) Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF). Eur J Hum Genet 6(1):95\u201397","journal-title":"Eur J Hum Genet"},{"issue":"7","key":"6835_CR2","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/sj.ejhg.5200658","volume":"9","author":"I Touitou","year":"2001","unstructured":"Touitou I (2001) The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 9(7):473\u2013483","journal-title":"Eur J Hum Genet"},{"key":"6835_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119584","author":"M Lancieri","year":"2023","unstructured":"Lancieri M, Bustaffa M, Palmeri S, Prigione I, Penco F, Papa R et al (2023) An update on familial Mediterranean fever. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms24119584","journal-title":"Int J Mol Sci"},{"issue":"3","key":"6835_CR4","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/nrrheum.2013.174","volume":"10","author":"S Ozen","year":"2014","unstructured":"Ozen S, Bilginer Y (2014) A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol 10(3):135\u2013147","journal-title":"Nat Rev Rheumatol"},{"issue":"8","key":"6835_CR5","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1002\/art.1780340806","volume":"34","author":"D Zemer","year":"1991","unstructured":"Zemer D, Livneh A, Danon YL, Pras M, Sohar E (1991) Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum 34(8):973\u2013977","journal-title":"Arthritis Rheum"},{"issue":"1","key":"6835_CR6","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s00296-019-04366-w","volume":"40","author":"S Eren Akarcan","year":"2020","unstructured":"Eren Akarcan S, Dogantan S, Edeer Karaca N, Aksu G, Kutukculer N (2020) Successful management of colchicine resistant familial Mediterranean fever patients with a standardized canakinumab treatment protocol: a case series and literature review. Rheumatol Int 40(1):161\u2013168","journal-title":"Rheumatol Int"},{"issue":"6","key":"6835_CR7","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.ard.2025.01.028","volume":"84","author":"S Ozen","year":"2025","unstructured":"Ozen S, Sag E, Oton T, Gul A, Sieiro Santos C, Bayraktar D et al (2025) EULAR\/PReS endorsed recommendations for the management of familial Mediterranean fever (FMF): 2024 update. Ann Rheum Dis 84(6):899\u2013909","journal-title":"Ann Rheum Dis"},{"issue":"8","key":"6835_CR8","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1136\/annrheumdis-2019-215048","volume":"78","author":"M Gattorno","year":"2019","unstructured":"Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I et al (2019) Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78(8):1025\u20131032","journal-title":"Ann Rheum Dis"},{"key":"6835_CR9","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2022.146447","volume":"827","author":"B Kirnaz","year":"2022","unstructured":"Kirnaz B, Gezgin Y, Berdeli A (2022) MEFV gene allele frequency and genotype distribution in 3230 patients\u2019 analyses by next generation sequencing methods. Gene 827:146447","journal-title":"Gene"},{"issue":"1","key":"6835_CR10","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1086\/302459","volume":"65","author":"C Cazeneuve","year":"1999","unstructured":"Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P et al (1999) MEFV-gene analysis in armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet 65(1):88\u201397","journal-title":"Am J Hum Genet"},{"key":"6835_CR11","unstructured":"Available from: https:\/\/infevers.umai-montpellier.fr\/web\/search.php?n=1"},{"issue":"6","key":"6835_CR12","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1136\/annrheumdis-2015-208671","volume":"75","author":"E Demirkaya","year":"2016","unstructured":"Demirkaya E, Acikel C, Hashkes P, Gattorno M, Gul A, Ozdogan H et al (2016) Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis 75(6):1051\u20131056","journal-title":"Ann Rheum Dis"},{"issue":"4","key":"6835_CR13","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1097\/RHU.0000000000001953","volume":"29","author":"H Kisaoglu","year":"2023","unstructured":"Kisaoglu H, Baba O, Kalyoncu M (2023) Genotype-phenotype associations of children with familial Mediterranean fever in a cohort consisting of M694V mutation and implications for colchicine-resistant disease. J Clin Rheumatol 29(4):207\u2013213","journal-title":"J Clin Rheumatol"},{"key":"6835_CR14","doi-asserted-by":"publisher","first-page":"805919","DOI":"10.3389\/fped.2021.805919","volume":"9","author":"K Ozturk","year":"2021","unstructured":"Ozturk K, Coskuner T, Baglan E, Sonmez HE, Yener GO, Cakmak F et al (2021) Real-life data from the largest pediatric familial mediterranean fever cohort. Front Pediatr 9:805919","journal-title":"Front Pediatr"},{"issue":"5","key":"6835_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2025.105888","volume":"92","author":"E Tunce","year":"2025","unstructured":"Tunce E, Atamyildiz Ucar S, Sozeri B (2025) Different arthritis patterns in pediatric familial Mediterranean fever: focus on exon 10 biallelic pathogenic genotypes. Joint Bone Spine 92(5):105888","journal-title":"Joint Bone Spine"},{"issue":"5","key":"6835_CR16","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1007\/s10067-022-06082-6","volume":"41","author":"PO Avar-Aydin","year":"2022","unstructured":"Avar-Aydin PO, Ozcakar ZB, Aydin F, Karakas HD, Cakar N, Yalcinkaya F (2022) The expanded spectrum of arthritis in children with familial Mediterranean fever. Clin Rheumatol 41(5):1535\u20131541","journal-title":"Clin Rheumatol"},{"issue":"5","key":"6835_CR17","first-page":"438","volume":"7","author":"F Demir","year":"2020","unstructured":"Demir F, Bolac GL, Merter T, Canbek S, Dogan OA, Demirkol YK et al (2020) The musculoskeletal system manifestations in children with familial Mediterranean fever. North Clin Istanb 7(5):438\u2013442","journal-title":"North Clin Istanb"},{"issue":"4","key":"6835_CR18","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1136\/annrheumdis-2014-206844","volume":"74","author":"G Giancane","year":"2015","unstructured":"Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V et al (2015) Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis 74(4):635\u2013641","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"6835_CR19","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s00296-018-4123-0","volume":"39","author":"HE Sonmez","year":"2019","unstructured":"Sonmez HE, Esmeray P, Batu ED, Arici ZS, Demir S, Sag E et al (2019) Is age associated with disease severity and compliance to treatment in children with familial Mediterranean fever? Rheumatol Int 39(1):83\u201387","journal-title":"Rheumatol Int"},{"issue":"9","key":"6835_CR20","first-page":"2014","volume":"30","author":"S Ozen","year":"2003","unstructured":"Ozen S, Bakkaloglu A, Yilmaz E et al (2003) Mutations in the gene for familial Mediterranean fever: do they predispose to inflammation? J Rheumatol 30(9):2014\u20132018","journal-title":"J Rheumatol"},{"issue":"2","key":"6835_CR21","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1136\/annrheumdis-2012-202580","volume":"73","author":"M Stoffels","year":"2014","unstructured":"Stoffels M, Szperl A, Simon A, Netea MG, Plantinga TS, van Deuren M et al (2014) MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis 73(2):455\u2013461","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"6835_CR22","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1002\/ajmg.a.20296","volume":"124A","author":"A Aldea","year":"2004","unstructured":"Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J et al (2004) A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A 124A(1):67\u201373","journal-title":"Am J Med Genet A"},{"issue":"6","key":"6835_CR23","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1002\/mgg3.336","volume":"5","author":"MM Moradian","year":"2017","unstructured":"Moradian MM, Babikyan D, Banoian D, Hayrapetyan H, Manvelyan H, Avanesian N et al (2017) Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF. Mol Genet Genomic Med 5(6):742\u2013750","journal-title":"Mol Genet Genomic Med"},{"issue":"5","key":"6835_CR24","first-page":"49","volume":"38 Suppl 127","author":"Y Endo","year":"2020","unstructured":"Endo Y, Koga T, Hara K, Furukawa K, Agematsu K, Yachie A et al (2020) The possession of exon 2 or exon 3 variants in the MEFV gene promotes inflammasome activation in Japanese patients with familial Mediterranean fever with a heterozygous exon 10 mutation. Clin Exp Rheumatol 38 Suppl 127(5):49\u201352","journal-title":"Clin Exp Rheumatol"},{"issue":"10","key":"6835_CR25","doi-asserted-by":"publisher","first-page":"4499","DOI":"10.1007\/s00431-024-05690-5","volume":"183","author":"E Orouk Awaad","year":"2024","unstructured":"Orouk Awaad E, Khoury L, van Straalen JW, Miller-Barmak A, Gazitt T, Haddad-Haloun J et al (2024) E148Q variant: a familial Mediterranean fever-causing mutation or a sequence variant? Eur J Pediatr 183(10):4499\u20134506","journal-title":"Eur J Pediatr"},{"issue":"1","key":"6835_CR26","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1007\/s10875-025-01898-8","volume":"45","author":"C Baggio","year":"2025","unstructured":"Baggio C, Oliviero F, Galozzi P, Guidea I, Doria A, Ramonda R et al (2025) Unresolved issues in familial Mediterranean fever: Is p.R202Q MEFV variant potentially pathogenetic in unleashing inflammation? J Clin Immunol 45(1):104","journal-title":"J Clin Immunol"}],"container-title":["European Journal of Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06835-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00431-026-06835-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00431-026-06835-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T07:41:25Z","timestamp":1776930085000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00431-026-06835-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,9]]},"references-count":26,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["6835"],"URL":"https:\/\/doi.org\/10.1007\/s00431-026-06835-4","relation":{},"ISSN":["1432-1076"],"issn-type":[{"value":"1432-1076","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,9]]},"assertion":[{"value":"8 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study protocol was approved by the Ethics Committee of Istanbul University (Approval No: 3429662).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants included in the study. Patients\u2019 data were treated to guarantee confidentiality.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}],"article-number":"169"}}