Endocrine Abstracts

Peptide hormones stimulate responses in target tissues by triggering enzyme activation inside cells and thus the generation of ‘second messenger’ molecules. Two of the most important second messengers in endocrinology are cAMP, whose production is stimulated by activation of Gα_s G proteins in response to hormones such as TSH and ACTH, and phosphatidylinositol-3,4,5-trisphosphate (PIP₃), generated by phosphatidylinositol-3-kinase (PI3K) in response to hormones such as insulin and IGF1. Nearly 25 years ago postzygotic activating mutations in Gα_s, encoded by GNAS, were discovered to underlie the classical endocrinopathy McCune-Albright syndrome, which features hormone-independent activation of a variety of Ga_s-coupled peptide hormone receptors. We and others have recently added to this by discovery that somatic mosaic activating mutations in components of the PI3K pathway underlie a wide variety of overgrowth disorders, ranging from mild generalised overgrowth to severe overgrowth of only some parts of the body. A subset of patients also have severe insulin-independent hypoglycaemia. Elucidating the genetic defect underlying this group of disorders immediately affords the prospect of targeted therapy with small molecule inhibitors as well as yielding insights into the role of the PI3K pathway in humans in health and disease. An overview of the newly defined ‘PIK3CA-Related Overgrowth Spectrum’ (PROS) will be given, with discussion of the underlying mutational spectrum, cell biology and prospects for therapy.