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Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1 ‐related hereditary predisposition syndrome?

Abstract : Background: Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low-penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft-tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in RB1 germline mutation carriers. Methods: We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma. Results: Unexpectedly, genetic testing identified a low-penetrance germline mutation in RB1 [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 In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low-penetrance mutation carriers without prior Rb. Conclusion: We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1-related hereditary predisposition syndrome linked to RB1 low-penetrance germline mutations. In these families, careful screening of primary non-Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole-body MRI screening might be a complementary strategy for unaffected carrier relatives in these families.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02376947
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Submitted on : Thursday, June 16, 2022 - 1:59:45 PM
Last modification on : Tuesday, June 21, 2022 - 3:44:54 AM

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Marion Imbert‐bouteille, Marion Gauthier‐villars, Dominique Leroux, Isabelle Meunier, Isabelle Aerts, et al.. Osteosarcoma without prior retinoblastoma related to RB1 low‐penetrance germline pathogenic variants: A novel type of RB1 ‐related hereditary predisposition syndrome?. Molecular Genetics & Genomic Medicine, 2019, 7, pp.e913. ⟨10.1002/mgg3.913⟩. ⟨hal-02376947⟩

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