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Genet Med. 2019 May;21(5):1189-1198. doi: 10.1038/s41436-018-0297-9. Epub 2018 Oct 1.

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

Author information

1
Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
2
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
3
Centres de références Anomalies du Développement et Anomalies Dermatologiques Rares, Equipe GAD UMR1231 et FHU TRANSLAD, CHU Dijon-Bourgogne et Université de Bourgogne, Dijon, France.
4
Centre d'Investigation Clinique INSERM 1432, Centre Hospitalier Universitaire de Dijon, Dijon, Bourgogne, France.
5
The EMMES Corporation, Rockville, MD, USA.
6
Section on Pediatric Diabetes and Metabolism, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
7
Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
8
Pharmacy Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA.
9
Department of Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Université Paris Descartes - Sorbonne Paris Cité, INSERM U1163, Institut Imagine, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
10
Department of Interventional Radiology, Dijon University Hospital, Dijon, France.
11
Department of Dermatology, University Hospital Center of Angers, Angers, France.
12
Department of Dermatology, Claude Bernard-Lyon 1 University and Hospices Civils de Lyon, Lyon, France.
13
NCI, CCR, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD, USA.
14
Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France.
15
Service de Génétique médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
16
Institute of Metabolic Science, University of Cambridge, Cambridge, UK. rsemple@ed.ac.uk.
17
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. rsemple@ed.ac.uk.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

PIK3CA; mosaicism; overgrowth; sirolimus

PMID:
30270358
PMCID:
PMC6752269
DOI:
10.1038/s41436-018-0297-9
[Indexed for MEDLINE]
Free PMC Article

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