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Parker, Victoria E R; Keppler-Noreuil, Kim M; Faivre, Laurence; Luu, Maxime; Oden, Neal L; De Silva, Leena; Sapp, Julie C; Andrews, Katrina; Bardou, Marc; Chen, Kong Y; Darling, Thomas N; Gautier, Elodie; Goldspiel, Barry R; Hadj-Rabia, Smail; Harris, Julie; Kounidas, Georgios; Kumar, Parag; Lindhurst, Marjorie J; Loffroy, Romaric; Martin, Ludovic; Phan, Alice; Rother, Kristina I; Widemann, Brigitte C; Wolters, Pamela L; Coubes, Christine; Pinson, Lucile; Willems, Marjolaine; Vincent-Delorme, Catherine; Vabres, Pierre; Semple, Robert K; Biesecker, Leslie G
Genetics in medicine, 05/2019, Volume: 21, Issue: 5Journal Article
PIK3CA-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. Thirty-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. Thirty 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had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. This 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.
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