{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:07:12Z","timestamp":1789589232235,"version":"build-2803163510"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Klinikum der Universit\u00e4t M\u00fcnchen"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study aimed to assess the detection rate and spectrum of pathogenic variants (PVs) and candidate variants (variants of uncertain significance, VUS) in AVM patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this retrospective multicenter cohort study, tissue and blood samples were collected from 114 patients with extracranial AVMs during treatment or when clinically indicated, for dedicated molecular genetic analyses. PVs (solved) and VUS were detected by targeted sequencing on DNA using gene panels analyzing genes suspected to be associated with AVMs. Unsolved cases were further categorized into unrestricted and restricted, with the latter reflecting methodological limitations. Subgroup analyses were carried out based on affected genes to explore associated genotype\u2013phenotype correlations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PVs were identified in 80.7% (92\/114) and VUS in 5.3% (6\/114), resulting in a total detection rate of 86.0% (98\/114). Unsolved cases accounted for 11.4% (13\/114) including 6\/13 (46.2%) with methodological restrictions. Somatic PVs were most frequent in KRAS (21.1%, 24\/114),\n                      <jats:italic>MAP2K1<\/jats:italic>\n                      (17.5%, 20\/114),\n                      <jats:italic>HRAS<\/jats:italic>\n                      (8.8%, 10\/114), and\n                      <jats:italic>BRAF<\/jats:italic>\n                      (7.9%, 9\/114). Germline variants were found in\n                      <jats:italic>RASA1<\/jats:italic>\n                      (7.0%, 8\/114),\n                      <jats:italic>PTEN<\/jats:italic>\n                      (5.3%, 6\/114), and\n                      <jats:italic>EPHB4<\/jats:italic>\n                      (3.5%, 4\/114). In a few cases, somatic variants in\n                      <jats:italic>RASA1<\/jats:italic>\n                      (1.8%, 2\/114) and\n                      <jats:italic>PTEN<\/jats:italic>\n                      (2.6%, 3\/114) were identified. Additional PVs occurred in\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      (3.5%, 4\/114),\n                      <jats:italic>SOS1<\/jats:italic>\n                      (2.6%, 3\/114),\n                      <jats:italic>GNAQ<\/jats:italic>\n                      (1.8%, 2\/114), and\n                      <jats:italic>RIT1, RAF1<\/jats:italic>\n                      , and\n                      <jats:italic>GNA14<\/jats:italic>\n                      (each 0.9%, 1\/114). Within the RAS\/MAPK pathway,\n                      <jats:italic>RAS<\/jats:italic>\n                      variants (\n                      <jats:italic>KRAS<\/jats:italic>\n                      ,\n                      <jats:italic>HRAS<\/jats:italic>\n                      ) were linked to more severe clinical stages (65.6% vs. 40.0%\n                      <jats:italic>MAP2K1 and 37.5<\/jats:italic>\n                      %\n                      <jats:italic>BRAF<\/jats:italic>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.027) and higher relapse rates (55.6% vs. 43.8%\n                      <jats:italic>MAP2K1 and 0<\/jats:italic>\n                      %\n                      <jats:italic>BRAF<\/jats:italic>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.049). Germline variants showed a distinct distribution pattern with more syndromic presentations (61.1% vs. 15.6%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) compared to mosaic variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Broad and sensitive testing enables a high detection rate of causative variants in AVMs. PVs and VUS detected reveal a broader genetic spectrum than previously recognized. Somatic\n                      <jats:italic>RAS<\/jats:italic>\n                      PVs were associated with more advanced disease stages and higher relapse rates than\n                      <jats:italic>MAP2K1<\/jats:italic>\n                      and\n                      <jats:italic>BRAF<\/jats:italic>\n                      variants, while germline variants were more frequently linked to syndromic patterns.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-026-04874-0","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T01:15:30Z","timestamp":1776302130000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Detection rate and mutational landscape in extracranial arteriovenous malformations: a cohort study"],"prefix":"10.1186","volume":"24","author":[{"given":"Vanessa F.","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denny","family":"Schanze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Brill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius H.","family":"Loeser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wibke","family":"Uller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Doppler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zlem","family":"Cangir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Hengst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Vielsmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Pech","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Obereisenbuchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Schirren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Sint","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Puhr-Westerheide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan","family":"Deniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob B. W.","family":"Wei\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"H\u00e4berle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Hartel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Fr\u00f6ba-Pohl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Haehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annegret","family":"Holm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter B.","family":"Sporns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Scherf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Ricke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Lassmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Seidensticker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter A.","family":"Wohlgemuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie A.","family":"Kimm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Zenker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Wildgruber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich G.","family":"Kapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the APOLLON Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"2","key":"4874_CR1","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1055\/a-1728-5686","volume":"42","author":"VF Schmidt","year":"2022","unstructured":"Schmidt VF, Olivieri M, H\u00e4berle B, Masthoff M, Deniz S, Sporns PB, et al. Interventional Treatment Options in Children with Extracranial Vascular Malformations. Hamostaseologie. 2022;42(2):131\u201341.","journal-title":"Hamostaseologie"},{"issue":"10","key":"4874_CR2","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1007\/s00270-021-02926-x","volume":"44","author":"VF Schmidt","year":"2021","unstructured":"Schmidt VF, Masthoff M, Goldann C, Deniz S, \u00d6cal O, H\u00e4berle B, et al. Percutaneous Sclerotherapy of Venous Malformations of the Hand: A Multicenter Analysis. Cardiovasc Intervent Radiol. 2021;44(10):1543\u201350.","journal-title":"Cardiovasc Intervent Radiol"},{"issue":"5","key":"4874_CR3","doi-asserted-by":"publisher","first-page":"486","DOI":"10.5152\/dir.2022.21644","volume":"28","author":"VF Schmidt","year":"2022","unstructured":"Schmidt VF, Masthoff M, Goldann C, Ehrl D, Deniz S, \u00d6cal O, et al. Image-guided embolization of arteriovenous malformations of the hand using Ethylene-vinyl Alcohol Copolymer. Diagn Interv Radiol. 2022;28(5):486\u201394.","journal-title":"Diagn Interv Radiol"},{"issue":"1","key":"4874_CR4","doi-asserted-by":"publisher","DOI":"10.1186\/s40348-021-00132-w","volume":"8","author":"VF Schmidt","year":"2021","unstructured":"Schmidt VF, Masthoff M, Czihal M, Cucuruz B, H\u00e4berle B, Brill R, et al. Imaging of peripheral vascular malformations - current concepts and future perspectives. Mol Cell Pediatr. 2021;8(1):19.","journal-title":"Mol Cell Pediatr"},{"issue":"8","key":"4874_CR5","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.033287","volume":"13","author":"VF Schmidt","year":"2024","unstructured":"Schmidt VF, Kapp FG, Goldann C, Huthmann L, Cucuruz B, Brill R, et al. Extracranial vascular anomalies driven by RAS\/MAPK variants: spectrum and genotype-phenotype correlations. J Am Heart Assoc. 2024;13(8):e033287.","journal-title":"J Am Heart Assoc"},{"issue":"1","key":"4874_CR6","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1161\/CIRCRESAHA.121.318145","volume":"129","author":"A Queisser","year":"2021","unstructured":"Queisser A, Seront E, Boon LM, Vikkula M. Genetic basis and therapies for vascular anomalies. Circ Res. 2021;129(1):155\u201373.","journal-title":"Circ Res"},{"issue":"1","key":"4874_CR7","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.det.2016.07.001","volume":"35","author":"N Nathan","year":"2017","unstructured":"Nathan N, Keppler-Noreuil KM, Biesecker LG, Moss J, Darling TN. Mosaic disorders of the PI3K\/PTEN\/AKT\/TSC\/mTORC1 signaling pathway. Dermatol Clin. 2017;35(1):51\u201360.","journal-title":"Dermatol Clin"},{"key":"4874_CR8","doi-asserted-by":"publisher","DOI":"10.1007\/s00270-022-03296-8","author":"VF Schmidt","year":"2022","unstructured":"Schmidt VF, Masthoff M, Vielsmeier V, Seebauer CT, Cangir \u00d6, Meyer L, et al. Clinical outcome and quality of life of multimodal treatment of extracranial arteriovenous malformations: the APOLLON study protocol. Cardiovasc Intervent Radiol. 2022. https:\/\/doi.org\/10.1007\/s00270-022-03296-8.","journal-title":"Cardiovasc Intervent Radiol"},{"issue":"7","key":"4874_CR9","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1002\/gepi.20410","volume":"33","author":"J Little","year":"2009","unstructured":"Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, et al. STrengthening the REporting of Genetic Association Studies (STREGA)\u2013an extension of the STROBE statement. Genet Epidemiol. 2009;33(7):581\u201398.","journal-title":"Genet Epidemiol"},{"key":"4874_CR10","unstructured":"ISSVA Classification of Vascular Anomalies \u00a92025 International Society for the Study of Vascular Anomalies Available at \"issva.org\/classification\" Accessed May 3rd."},{"issue":"3","key":"4874_CR11","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1097\/00006534-199809010-00006","volume":"102","author":"MP Kohout","year":"1998","unstructured":"Kohout MP, Hansen M, Pribaz JJ, Mulliken JB. Arteriovenous malformations of the head and neck: natural history and management. Plast Reconstr Surg. 1998;102(3):643\u201354.","journal-title":"Plast Reconstr Surg"},{"issue":"4","key":"4874_CR12","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1583\/05-1769.1","volume":"13","author":"SK Cho","year":"2006","unstructured":"Cho SK, Do YS, Shin SW, Kim DI, Kim YW, Park KB, et al. Arteriovenous malformations of the body and extremities: analysis of therapeutic outcomes and approaches according to a modified angiographic classification. J Endovasc Ther. 2006;13(4):527\u201338.","journal-title":"J Endovasc Ther"},{"issue":"1","key":"4874_CR13","doi-asserted-by":"publisher","first-page":"8239","DOI":"10.1038\/s41598-019-44584-7","volume":"9","author":"A Eijkelenboom","year":"2019","unstructured":"Eijkelenboom A, van Schaik FMA, van Es RM, Ten Broek RW, Rinne T, van der Vleuten C, et al. Functional characterisation of a novel class of in-frame insertion variants of KRAS and HRAS. Sci Rep. 2019;9(1):8239.","journal-title":"Sci Rep"},{"issue":"6","key":"4874_CR14","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1038\/s41591-023-02364-x","volume":"29","author":"D Li","year":"2023","unstructured":"Li D, Sheppard SE, March ME, Battig MR, Surrey LF, Srinivasan AS, et al. Genomic profiling informs diagnoses and treatment in vascular anomalies. Nat Med. 2023;29(6):1530\u20139.","journal-title":"Nat Med"},{"issue":"4","key":"4874_CR15","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1172\/JCI98589","volume":"128","author":"L Al-Olabi","year":"2018","unstructured":"Al-Olabi L, Polubothu S, Dowsett K, Andrews KA, Stadnik P, Joseph AP, et al. Mosaic RAS\/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest. 2018;128(4):1496\u2013508.","journal-title":"J Clin Invest"},{"key":"4874_CR16","doi-asserted-by":"publisher","unstructured":"Green TE, Garza D, Brown NJ, de Silva MG, Bennett MF, Tubb C, Phillips RJ, MacGregor D, Robertson SJ, Bekhor P, Simpson J, Penington AJ, Hildebrand MS. Improving genetic diagnostic yield in a large cohort of children with rare vascular anomalies or PIK3CA-related overgrowth spectrum. Genet Med Open. 2023;2:100837.\u00a0https:\/\/doi.org\/10.1016\/j.gimo.2023.100837. PMID: 39669602; PMCID: PMC11613910.","DOI":"10.1016\/j.gimo.2023.100837"},{"issue":"3","key":"4874_CR17","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s40291-025-00770-0","volume":"29","author":"FN El Sissy","year":"2025","unstructured":"El Sissy FN, Bisdorff A, Perrier A, Guillerm E, Denis J, Favre L, et al. Identification of Somatic Genetic Variants in Superficial Vascular Malformations by Liquid Biopsy in a Cohort of 88 Patients from a French Hospital. Mol Diagn Ther. 2025;29(3):367\u201380.","journal-title":"Mol Diagn Ther"},{"issue":"6","key":"4874_CR18","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1002\/ajmg.a.63171","volume":"191","author":"PV Hernandez","year":"2023","unstructured":"Hernandez PV, King KA, Evenson MJ, Corliss MM, Schroeder MC, Heusel JW, et al. High-depth next-generation sequencing panel testing in the evaluation of arteriovenous malformations. Am J Med Genet A. 2023;191(6):1518\u201324.","journal-title":"Am J Med Genet A"},{"key":"4874_CR19","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.humpath.2024.02.004","volume":"145","author":"K Hirose","year":"2024","unstructured":"Hirose K, Hori Y, Ozeki M, Motooka D, Hata K, Tahara S, et al. Comprehensive phenotypic and genomic characterization of venous malformations. Hum Pathol. 2024;145:48\u201355.","journal-title":"Hum Pathol"},{"issue":"7","key":"4874_CR20","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1111\/jdv.19640","volume":"38","author":"MLE Stor","year":"2024","unstructured":"Stor MLE, Horbach SER, Lokhorst MM, Tan E, Maas SM, van Noesel CJM, et al. Genetic mutations and phenotype characteristics in peripheral vascular malformations: A systematic review. J Eur Acad Dermatol Venereol. 2024;38(7):1314\u201328.","journal-title":"J Eur Acad Dermatol Venereol"},{"issue":"12","key":"4874_CR21","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1002\/humu.22431","volume":"34","author":"N Revencu","year":"2013","unstructured":"Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34(12):1632\u201341.","journal-title":"Hum Mutat"},{"issue":"6","key":"4874_CR22","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1111\/jdv.18046","volume":"36","author":"FN El Sissy","year":"2022","unstructured":"El Sissy FN, Wassef M, Faucon B, Salvan D, Nadaud S, Coulet F, et al. Somatic mutational landscape of extracranial arteriovenous malformations and phenotypic correlations. J Eur Acad Dermatol Venereol. 2022;36(6):905\u201312.","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"4874_CR23","doi-asserted-by":"publisher","unstructured":"Hirose K, Hori Y, Maruyama K, Motooka D, Hata K, Tahara S, Matsui T, Nojima S, Kohara M, Imanaka-Yoshida K, Toyosawa S, Morii E. Pathogenic mechanism of extracranial arteriovenous malformations: insights from clinical, pathological, and genetic analyses. Virchows Arch. 2025.\u00a0https:\/\/doi.org\/10.1007\/s00428-025-04158-7. Epub ahead of print. PMID: 40603544.","DOI":"10.1007\/s00428-025-04158-7"},{"issue":"4","key":"4874_CR24","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1097\/PRS.0b013e3181d18070","volume":"125","author":"AS Liu","year":"2010","unstructured":"Liu AS, Mulliken JB, Zurakowski D, Fishman SJ, Greene AK. Extracranial arteriovenous malformations: natural progression and recurrence after treatment. Plast Reconstr Surg. 2010;125(4):1185\u201394.","journal-title":"Plast Reconstr Surg"},{"issue":"4","key":"4874_CR25","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1007\/s00234-014-1483-3","volume":"57","author":"B Kim","year":"2015","unstructured":"Kim B, Kim K, Jeon P, Kim S, Kim H, Byun H, et al. Long-term results of ethanol sclerotherapy with or without adjunctive surgery for head and neck arteriovenous malformations. Neuroradiology. 2015;57(4):377\u201386.","journal-title":"Neuroradiology"},{"issue":"6","key":"4874_CR26","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1002\/ajmg.a.37613","volume":"170","author":"CF Macmurdo","year":"2016","unstructured":"Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, Le J, Wallenstein MB, Milla C, et al. RASA1 somatic mutation and variable expressivity in capillary malformation\/arteriovenous malformation (CM\/AVM) syndrome. Am J Med Genet A. 2016;170(6):1450\u20134.","journal-title":"Am J Med Genet A"},{"issue":"9","key":"4874_CR27","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1136\/jmg.2007.048934","volume":"44","author":"WH Tan","year":"2007","unstructured":"Tan WH, Baris HN, Burrows PE, Robson CD, Alomari AI, Mulliken JB, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet. 2007;44(9):594\u2013602.","journal-title":"J Med Genet"},{"issue":"11","key":"4874_CR28","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1161\/CIRCULATIONAHA.116.026886","volume":"136","author":"M Amyere","year":"2017","unstructured":"Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation. 2017;136(11):1037\u201348.","journal-title":"Circulation"},{"issue":"2","key":"4874_CR29","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1111\/ced.14428","volume":"46","author":"M Valdivielso-Ramos","year":"2021","unstructured":"Valdivielso-Ramos M, Martin-Santiago A, Aza\u00f1a JM, Hern\u00e1ndez-Nu\u00f1ez A, Vera A, Perez B, et al. Capillary malformation-arteriovenous malformation syndrome: a multicentre study. Clin Exp Dermatol. 2021;46(2):300\u20135.","journal-title":"Clin Exp Dermatol"},{"issue":"4","key":"4874_CR30","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1111\/ijd.17504","volume":"64","author":"Y Chen","year":"2025","unstructured":"Chen Y, Liu H, Zhou J, Yang X, Jia H, Ma G, et al. Genotypes and phenotypes of capillary malformation-arteriovenous malformation: characterization and correlation analysis. Int J Dermatol. 2025;64(4):693\u2013701.","journal-title":"Int J Dermatol"},{"key":"4874_CR31","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10061460","author":"A Diociaiuti","year":"2022","unstructured":"Diociaiuti A, Rotunno R, Pisaneschi E, Cesario C, Carnevale C, Condorelli AG, et al. Clinical and molecular spectrum of sporadic vascular malformations: a single-center study. Biomedicines. 2022. https:\/\/doi.org\/10.3390\/biomedicines10061460.","journal-title":"Biomedicines"},{"issue":"10","key":"4874_CR32","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.1016\/j.jpedsurg.2023.01.047","volume":"58","author":"MM Pamp\u00edn Mart\u00ednez","year":"2023","unstructured":"Pamp\u00edn Mart\u00ednez MM, Rodr\u00edguez-Laguna L, G\u00f3mez Garc\u00eda E, Cebri\u00e1n Carretero JL, Gonz\u00e1lez Otero T, L\u00f3pez Guti\u00e9rrez JC. Genetic profile of arteriovenous anomalies of the head and neck: implications in progression and therapeutic approaches. J Pediatr Surg. 2023;58(10):2043\u20139.","journal-title":"J Pediatr Surg"},{"issue":"7","key":"4874_CR33","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1002\/humu.21492","volume":"32","author":"F Lepri","year":"2011","unstructured":"Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011;32(7):760\u201372.","journal-title":"Hum Mutat"},{"issue":"4","key":"4874_CR34","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.ijpam.2016.06.003","volume":"3","author":"I El Bouchikhi","year":"2016","unstructured":"El Bouchikhi I, Belhassan K, Moufid FZ, IraquiHoussaini M, Bouguenouch L, Samri I, et al. Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate. International Journal of Pediatrics and Adolescent Medicine. 2016;3(4):133\u201342.","journal-title":"International Journal of Pediatrics and Adolescent Medicine"},{"issue":"4","key":"4874_CR35","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1007\/s10456-024-09934-8","volume":"27","author":"FG Kapp","year":"2024","unstructured":"Kapp FG, Bazgir F, Mahammadzade N, Mehrabipour M, Vassella E, Bernhard SM, et al. Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition. Angiogenesis. 2024;27(4):739\u201352.","journal-title":"Angiogenesis"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-026-04874-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-026-04874-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-026-04874-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T08:11:33Z","timestamp":1776327093000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12916-026-04874-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4874"],"URL":"https:\/\/doi.org\/10.1186\/s12916-026-04874-0","relation":{},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]},"assertion":[{"value":"8 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Retrospective analyses were approved by the local ethics committee (University Hospital, LMU Munich, protocol no: 23\u20130337).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All patients\/legal representatives shown in the figures provided written informed consent for the use and publication of scientific data, radiological images and clinical photographs, including open access format\/creative comments licence for scientific purpose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Authors JBWW and FGK received consultation fees from Novartis. All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"248"}}