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Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum

  • Parker, Victoria E. R.1
  • Keppler-Noreuil, Kim M.2
  • Faivre, Laurence3
  • Luu, Maxime4
  • Oden, Neal L.5
  • De Silva, Leena1
  • Sapp, Julie C.2
  • Andrews, Katrina1
  • Bardou, Marc4
  • Chen, Kong Y.6
  • Darling, Thomas N.7
  • Gautier, Elodie3
  • Goldspiel, Barry R.8
  • Hadj-Rabia, Smail9
  • Harris, Julie1
  • Kounidas, Georgios1
  • Kumar, Parag8
  • Lindhurst, Marjorie J.2
  • Loffroy, Romaric10
  • Martin, Ludovic11
  • And 11 more
  • 1 Institute of Metabolic Science, University of Cambridge, Cambridge, UK , Cambridge (United Kingdom)
  • 2 National Institutes of Health, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA , Bethesda (United States)
  • 3 CHU Dijon-Bourgogne et Université de Bourgogne, Centres de références Anomalies du Développement et Anomalies Dermatologiques Rares, Equipe GAD UMR1231 et FHU TRANSLAD, Dijon, France , Dijon (France)
  • 4 Centre d’Investigation Clinique INSERM 1432, Centre Hospitalier Universitaire de Dijon, Dijon, Bourgogne, France , Dijon (France)
  • 5 The EMMES Corporation, Rockville, MD, USA , Rockville (United States)
  • 6 National Institutes of Health, Section on Pediatric Diabetes and Metabolism, National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD, USA , Bethesda (United States)
  • 7 Uniformed Services University of the Health Sciences, Department of Dermatology, Bethesda, MD, USA , Bethesda (United States)
  • 8 National Institutes of Health, Pharmacy Department, NIH Clinical Center, Bethesda, MD, USA , Bethesda (United States)
  • 9 Université Paris Descartes - Sorbonne Paris Cité, INSERM U1163, Institut Imagine, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Department of Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Paris, France , Paris (France)
  • 10 Dijon University Hospital, Department of Interventional Radiology, Dijon, France , Dijon (France)
  • 11 University Hospital Center of Angers, Department of Dermatology, Angers, France , Angers (France)
  • 12 Claude Bernard-Lyon 1 University and Hospices Civils de Lyon, Department of Dermatology, Lyon, France , Lyon (France)
  • 13 National Institutes of Health, NCI, CCR, Pediatric Oncology Branch, Bethesda, MD, USA , Bethesda (United States)
  • 14 Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Département de Génétique Médicale, Montpellier, France , Montpellier (France)
  • 15 Service de Génétique médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France , Lille (France)
  • 16 Queen’s Medical Research Institute, University of Edinburgh, Centre for Cardiovascular Science, Edinburgh, UK , Edinburgh (United Kingdom)
Published Article
Genetics in Medicine
Springer Nature
Publication Date
Oct 01, 2018
DOI: 10.1038/s41436-018-0297-9
Springer Nature


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.

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