The purpose of this project is to specifically delineate the phenotype and natural history and to better understand the genetic etiology of Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the AKT/PI3K pathway. As we have recently determined the molecular cause of PS and the related disorder of fibroadipose overgrowth, our main objectives moving forward include genotype-phenotype correlations, identifying quantifiable phenotypic characteristics in patients and measuring changes in these characteristics over time, developing potential biomarkers for future therapeutic research, and using our new molecular insights to expand our understanding of both PS and related overgrowth disorders. The natural history and specific phenotypic characteristics of patients with PS and selected other overgrowth disorders will be determined by clinical assessment and longitudinal followup of a cohort of patients. Subjects will be screened for eligibility using published diagnostic criteria for PS; screening for AKT1 and other pathway gene mutations may be used in patients with overlapping phenotypes. As well, we hope to identify and thoroughly phenotype a cohort of patients with molecularly-confirmed AKT1 mutations who may be candidates for future therapeutic intervention studies. The discovery of the AKT1 activating mutation in patients with this disease provides us with a very attractive pathway toward treatment for this devastating disorder. We also propose to expand our clinical ascertainment to determine the full range of PS/AKT1 activating mutation phenotypes and to study other overlapping conditions. The etiology of these disorders will be studied using candidate gene analysis (primarily based on the PI3K/AKT pathway) and possibly exome and whole genome sequencing (done under protocol 10-HG-0065).