• Gabriel Morin and Guillaume Canaud.
• Université de Paris, Paris, France.
• Br. Med. Bull. 2021 Dec 16; 140 (1): 36-49.

Introduction Or BackgroundMosaic overgrowth syndromes (OS) are a proteiform ensemble of rare diseases displaying asymmetric overgrowth involving any tissue type, with degrees of severity ranging from isolated malformation to life-threatening conditions such as pulmonary embolism. Despite discordant clinical presentations, all those syndromes share common genetic anomalies: somatic mutations of genes involved in cell growth and proliferation. The PI3K-AKT-mTOR signaling pathway is one of the most prominent regulators of cell homeostasis, and somatic oncogenic mutations affecting this pathway are responsible for mosaic OS. This review aims to describe the clinical and molecular characteristics of the main OS involving the PI3K-AKT-mTOR pathway, along with the treatments available or under development.Sources Of DataThis review summarizes available data regarding OS in scientific articles published in peer-reviewed journals.Areas Of AgreementOS care requires a multidisciplinary approach relying on clinical and radiological follow-up along with symptomatic treatment. However, no specific treatment has yet shown efficacy in randomized control trials.Areas Of ControversyClinical classifications of OS led to frequent misdiagnosis. Moreover, targeted therapies directed at causal mutated proteins are developing in OSs through cancer drugs repositioning, but the evidence of efficacy and tolerance is still lacking for most of them.Growing PointsThe genetic landscape of OS is constantly widening and molecular classifications tend to increase the accuracy of diagnosis, opening opportunities for targeted therapies.Areas Timely For Developing ResearchOS are a dynamic, expanding field of research. Studies focusing on the identification of genetic anomalies and their pharmacological inhibition are needed.© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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