Characterization of coordinated growth in macrodactyly caused by somatic mosaic activating mutations in PIK3CA

Abstract

ABSTRACTLocalized somatic overgrowth disorders that occur during development can be debilitating, and most often require surgical intervention. Although underlying genetic changes associated with overgrowth have been identified in the majority of cases, the cause of the dysregulated growth and its presentation is unknown. Here we detail current work on a specific overgrowth disorder, macrodactyly, in which overgrowth is localized and shows integration with developmental patterning of the limb, providing coordination of the resulting overgrowth structure. We provide clinical analysis of presentation of macrodactyly in a cohort of patients and provide experimental evidence for nerve and vascular-biased regulation of growth. We provide the first animal model that recapitulates macrodactyly and provide evidence that genetic modifiers may underlie the development of this disorder. The unique presentation of macrodactyly provides a framework to identify the causes and regulatory activities that shape hyperplastic signals that lead to integrated patterning in overgrowth. Use of our experimental model suggests potential for genetic modifiers as important for the particular presentation of this disorder over other PIK3CA-related growth disorders.