Molecular mechanisms of childhood overgrowth.

This issue of the Seminar Series C is dedicated to the molecular mechanisms of childhood overgrowth and celebrates the last decade of unprecedented gene discovery. Constitutional gene disorders, somatic gene disorders and imprinting dysregulation are each considered. The constitutional overgrowth genes discussed include NSD1, EZH2, GPC3, DIS3L2, and PTEN whilst the somatic overgrowth genes include AKT3, PIK3R2, and PIK3CA. Abnormalities of imprinting, exemplified by disruption of the (epi)genetic regulation of the imprinted 11p15 gene cluster, constitutes the final section of this issue. Many of the genes discussed in this issue encode components of the PI3K/mTOR growth regulatory pathway. This signaling cascade consists of dual, parallel branches, anchored by the serine-threonine kinase, mTOR, and has diverse downstream effects including inhibition of apoptosis, activation of protein synthesis, and enhanced cell survival. Activation of the PI3K/mTOR pathway promotes growth whereas inhibition, or abrogation, results in decreased cellular growth. Despite the rapid advances of the last decade, there is still an enormous amount to discover. We hope that some of the work reviewed in this issue will facilitate the next decade's discoveries and we look forward to a 10 years as productive as the last.