{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:35:27Z","timestamp":1785818127279,"version":"3.56.0"},"reference-count":26,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T00:00:00Z","timestamp":1569801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to <jats:italic>RB1<\/jats:italic> germline mutations with high penetrance, but rare <jats:italic>RB1<\/jats:italic> low\u2010penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft\u2010tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in <jats:italic>RB1<\/jats:italic> germline mutation carriers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Unexpectedly, genetic testing identified a low\u2010penetrance germline mutation in <jats:italic>RB1<\/jats:italic> [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in <jats:italic>RB1<\/jats:italic> low\u2010penetrance mutation carriers without prior Rb.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a <jats:italic>RB1<\/jats:italic>\u2010related hereditary predisposition syndrome linked to <jats:italic>RB1<\/jats:italic> low\u2010penetrance germline mutations. In these families, careful screening of primary non\u2010Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole\u2010body MRI screening might be a complementary strategy for unaffected carrier relatives in these families.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.913","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T05:32:33Z","timestamp":1569907953000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Osteosarcoma without prior retinoblastoma related to <i>RB1<\/i> low\u2010penetrance germline pathogenic variants: A novel type of <i>RB1<\/i>\u2010related hereditary predisposition syndrome?"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8967-7004","authenticated-orcid":false,"given":"Marion","family":"Imbert\u2010Bouteille","sequence":"first","affiliation":[{"name":"Medical Genetics Department CHU Montpellier, Univ Montpellier Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Gauthier\u2010Villars","sequence":"additional","affiliation":[{"name":"Department of Tumour Biology Institut Curie, University Paris Descartes Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Leroux","sequence":"additional","affiliation":[{"name":"Medical Genetics Department CHU Grenoble Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Meunier","sequence":"additional","affiliation":[{"name":"National Centre for Rare Diseases, Hereditary Retinal and Optic Nerve Disorders CHU Montpellier, Univ Montpellier Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology Institut Curie, University Paris Descartes Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Lumbroso\u2010Le Rouic","sequence":"additional","affiliation":[{"name":"Department of Ocular Oncology Institut Curie Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Lejeune","sequence":"additional","affiliation":[{"name":"Medical Genetics Department CHRU Lille Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Capucine","family":"Delnatte","sequence":"additional","affiliation":[{"name":"Oncogenetics Institut de Canc\u00e9rologie de l'Ouest site Ren\u00e9 Gauducheau Saint Herblain France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Abadie","sequence":"additional","affiliation":[{"name":"Oncogenetics Institut de Canc\u00e9rologie de l'Ouest site Ren\u00e9 Gauducheau Saint Herblain France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Pujol","sequence":"additional","affiliation":[{"name":"Medical Genetics Department CHU Montpellier, Univ Montpellier Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Houdayer","sequence":"additional","affiliation":[{"name":"Department of Tumour Biology Institut Curie, University Paris Descartes Paris France"},{"name":"Genetics Department, F76000 and Normandy Univ, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine Rouen University Hospital Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Corsini","sequence":"additional","affiliation":[{"name":"Medical Genetics Department CHU Montpellier, Univ Montpellier Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2004.03.023"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(16)30147-4"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.10.014"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djq416"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10333-x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2018.07.017"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.03.003"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-011-9505-3"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102264"},{"key":"e_1_2_7_11_1","first-page":"1122","article-title":"Molecular etiology of low\u2010penetrance retinoblastoma in two pedigrees","volume":"52","author":"Dryja T. 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