%0 Journal Article %T Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum %+ Institute of Metabolic Science-Metabolic Research Laboratories %+ National Human Genome Research Institute (NHGRI) %+ Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon) %+ Equipe GAD (LNC - U1231) %+ FHU TRANSLAD (CHU de Dijon) %+ Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC) %+ The EMMES Corporation %+ National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda] %+ Uniformed Services University of the Health Sciences (USUHS) %+ Pharmacy Department (NIH Clinical Center National, Institutes of Health) %+ Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC) %+ Université Paris Descartes - Paris 5 (UPD5) %+ Imagine - Institut des maladies génétiques (IMAGINE - U1163) %+ Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon) %+ Département de dermatologie, CHU Angers %+ Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon %+ National Institutes of Health [Bethesda] (NIH) %+ Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier] %+ Service de Génétique Médicale [Lille] %+ Queen's Medical Researche Institute %A Parker, Victoria %A Keppler-Noreuil, Kim %A Faivre, Laurence %A Luu, Maxime %A Oden, Neal %A de Silva, Leena %A Sapp, Julie %A Andrews, Katrina %A Bardou, Marc %A Chen, Kong %A Darling, Thomas %A Gautier, Elodie %A Goldspiel, Barry %A Hadj-Rabia, Smail %A Harris, Julie %A Kounidas, Georgios %A Kumar, Parag %A Lindhurst, Marjorie %A Loffroy, Romaric %A Martin, Ludovic %A Phan, Alice %A Rother, Kristina %A Widemann, Brigitte %A Wolters, Pamela %A Coubes, Christine %A Pinson, Lucile %A Willems, Marjolaine %A Vincent-Delorme, Catherine %A Promise Working Group, - %A Vabres, Pierre %A Semple, Robert %A Biesecker, Leslie %Z IF 9.937 (2017) %< avec comité de lecture %@ 1098-3600 %J Genetics in Medicine %I Nature Publishing Group %8 2019 %D 2019 %R 10.1038/s41436-018-0297-9 %M 30270358 %K PIK3CA %K mosaicism %K overgrowth %K sirolimus %Z Life Sciences [q-bio]/Genetics/Human geneticsJournal articles %X PurposePIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth.MethodsThirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy.ResultsThirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.ConclusionThis study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS %G English %L hal-02000984 %U https://u-bourgogne.hal.science/hal-02000984 %~ UNIV-PARIS5 %~ UNIV-BOURGOGNE %~ APHP %~ UNAM %~ USPC %~ LNC-UMR866 %~ AGREENIUM %~ LNC-GAD %~ CHU-UNIV-PARIS5 %~ UNIV-PARIS %~ UP-SANTE %~ TEST3-HALCNRS %~ INSTITUT-AGRO