{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:31:20Z","timestamp":1787315480237,"version":"build-2736575974"},"reference-count":42,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T00:00:00Z","timestamp":1712188800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,3,15]]},"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by\n                      <jats:italic>SMAD4<\/jats:italic>\n                      pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of\n                      <jats:italic>SMAD4<\/jats:italic>\n                      variants followed in an HHT reference centre to further delineate the phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Thirty-three participants from 15 families, out of 1114 patients with HHT, had an\n                      <jats:italic>SMAD4<\/jats:italic>\n                      variant (3%).\n                    <\/jats:p>\n                    <jats:p>Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Cura\u00e7ao criteria. Complication frequencies were as follows: epistaxis (n=27\/33, 82%), cutaneous telangiectases (n=19\/33, 58%), pulmonary arteriovenous malformations (n=17\/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7\/18, 39%), digestive angiodysplasia (n=13\/22, 59%). No cerebral AVMs were diagnosed.<\/jats:p>\n                    <jats:p>\n                      Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass\n                      <jats:italic>et al<\/jats:italic>\n                      for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.\n                    <\/jats:p>\n                    <jats:p>Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We describe a large cohort of\n                      <jats:italic>SMAD4<\/jats:italic>\n                      variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with\n                      <jats:italic>SMAD4<\/jats:italic>\n                      gene variants and justify systematic cardiac ultrasound and skeletal complications screening.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2023-109632","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T13:20:23Z","timestamp":1712236823000},"page":"734-740","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Phenotypic characterisation of\n                    <i>SMAD4<\/i>\n                    variant carriers"],"prefix":"10.1136","volume":"61","author":[{"given":"Claire","family":"Caillot","sequence":"first","affiliation":[{"name":"Service de G\u00e9n\u00e9tique et Centre de r\u00e9f\u00e9rence pour la maladie de Rendu-Osler, Femme-M\u00e8re-Enfants Hospital, Hospices Civils de Lyon, Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Christophe","family":"Saurin","sequence":"additional","affiliation":[{"name":"Service de Gastroenterologie, H\u00f4pital E. Herriot, Hospices Civils de Lyon, Lyon, France"},{"name":"P\u00f4le Sant\u00e9 Publique, Hospices Civils de Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Hervieu","sequence":"additional","affiliation":[{"name":"Institut de Pathologie Est, Hospices Civils de Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Faoucher","sequence":"additional","affiliation":[{"name":"Service de g\u00e9n\u00e9tique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France"},{"name":"Universit\u00e9 Claude Bernard Lyon 1, Villeurbanne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Reversat","sequence":"additional","affiliation":[{"name":"Service de g\u00e9n\u00e9tique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France"},{"name":"Universit\u00e9 Claude Bernard Lyon 1, Villeurbanne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyne","family":"Decullier","sequence":"additional","affiliation":[{"name":"P\u00f4le Sant\u00e9 Publique, Hospices Civils de Lyon, Lyon, France"},{"name":"Universit\u00e9 Claude Bernard Lyon 1, Villeurbanne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Poncet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Claude Bernard Lyon 1, Villeurbanne, France"},{"name":"Service de Chirurgie Digestive, H\u00f4pital E. Herriot Lyon, Hospices Civils de Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Bailly","sequence":"additional","affiliation":[{"name":"Biosant\u00e9 Lab, Unit U1292, Health Department of IRIG, CEA de Grenoble, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Giraud","sequence":"additional","affiliation":[{"name":"Service de g\u00e9n\u00e9tique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8834-5526","authenticated-orcid":false,"given":"Sophie","family":"Dupuis-Girod","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique et Centre de r\u00e9f\u00e9rence pour la maladie de Rendu-Osler, Femme-M\u00e8re-Enfants Hospital, Hospices Civils de Lyon, Bron, France"},{"name":"Biosant\u00e9 Lab, Unit U1292, Health Department of IRIG, CEA de 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