Human growth results from an increase in cell size, cell division and amount of interstitium and is determined by the complex interplay of genetic and environmental factors. Over the last 14 years our group has been studying growth through the genetic interrogation of rare individuals presenting with syndromic overgrowth defined as an increased height and/or head circumference, compared to the age-related peer group, in combination with an intellectual disability. In the years since the studys inception we have defined the molecular and phenotypic spectra associated with Sotos syndrome and, more recently using a trio based exome sequencing approach, have identified the overgrowth genes EZH2 (Weaver syndrome); DNMT3A (DNMT3A overgrowth syndrome) and the PP2A subunit genes, PPP2R5B/C/D. It is noteworthy that many of the overgrowth gene family either encode members of the PI3K/mTOR growth regulatory pathway (PTEN, PP2A subunits, PIK3CA, PIK3R2, AKT1) or are components of the epigenetic arsenal determining chromatin modelling and gene expression (NSD1, EZH2 and DNMT3A). In addition, somatic mutations affecting many of the overgrowth genes have also been implicated in the development of malignancies. However, to date only a minority of overgrowth syndromes have been associated with an increased tumour susceptibility. Further, longitudinal clinical studies are underway to clarify associated tumour susceptibilities and the range of medical complications associated with Sotos syndrome, Weaver syndrome, the DNMT3A overgrowth syndrome and the PP2A subunit gene conditions.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology