Somatic mutations in overgrowth syndromes

Human overgrowth syndromes are varied in their presentation and severity among patients. The etiology of these syndromes has long been associated with genetic phenomena associated with increased paternal or maternal age. Next generation genomic methods have expedited discovery of non-heritable mutations that cause overgrowth syndromes. Many of these somatic, tissue-specific mutations activate cancer-associated cell signaling pathways, leading to aberrant cell growth. Interestingly, although the different disorders have widely varied presentations-heretofore considered distinct syndromes-the genetic etiologies converge on similar mechanisms, which raises questions as to the proper classification and nomenclature of the different diagnoses. This chapter reviews multiple overgrowth syndromes and provides an in-depth explanation of the genetic mechanisms causing their varied presentations.