Title :

Safety and efficacy of low-dose sirolimus in the pik3ca-related overgrowth spectrum

Author(s) :

Parker, Victoria E. R. [Auteur]
Keppler-Noreuil, Kim M. [Auteur]
Faivre, Laurence [Auteur]
Luu, Maxime [Auteur]
Oden, Neal L. [Auteur]
De Silva, Leena [Auteur]
Sapp, Julie C. [Auteur]
Andrews, Katrina [Auteur]
Bardou, Marc [Auteur]
Chen, Kong Y. [Auteur]
Darling, Thomas N. [Auteur]
Gautier, Elodie [Auteur]
Goldspiel, Barry R. [Auteur]
Hadj-Rabia, Smail [Auteur]
Harris, Julie [Auteur]
Kounidas, Georgios [Auteur]
Kumar, Parag [Auteur]
Lindhurst, Marjorie J. [Auteur]
Loffroy, Romaric [Auteur]
Martin, Ludovic [Auteur]
Phan, Alice [Auteur]
Rother, Kristina I. [Auteur]
Widemann, Brigitte C. [Auteur]
Wolters, Pamela L. [Auteur]
Coubes, Christine [Auteur]
Pinson, Lucile [Auteur]
Willems, Marjolaine [Auteur]
Vincent, Catherine [Auteur]
Vabres, Pierre [Auteur]
Semple, Robert K. [Auteur]
Biesecker, Leslie G. [Auteur]

Journal title :

Genetics in medicine . official journal of the American College of Medical Genetics

Abbreviated title :

Genet. Med.

Publication date :

2018-10-01

ISSN :

1530-0366

Keyword(s) :

overgrowth
PIK3CA
sirolimus
mosaicism

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille

Collections :

• Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364

Submission date :

2021-09-02T07:02:01Z