The blended phenotype of a germline RIT1 and a mosaic PIK3CA variant

Abstract

We report a patient with a germline RIT1 and a mosaic PIK3CA variant. The diagnosis of the RASopathy was confirmed by targeted sequencing following the identification of transient cardiomyopathy in a patient with PIK3CA-related overgrowth spectrum (PROS). Our observation confirms that the PIK3CA gain-of-function (GoF) variant effects dominate those of the RASopathy, and the resulting blended phenotype mostly resembles megalencephaly-capillary malformation syndrome (MCAP PROS). There appears to be interaction between RIT1 and PI3K-AKT because the latter pathway is needed for the growth-promoting activity of the first, at least in adenocarcinomas, but the details of this interaction are not known. If so, the PIK3CA somatic variant may not be just a chance event. It could also be of etiological relevance that Rit activation mediates resistance to cellular stress—that is, promotes cell survival. This anti-apoptotic effect could also make it more likely that a cell that spontaneously acquires a PIK3CA GoF variant will survive and proliferate. We aim to encourage clinicians to investigate atypical findings in individuals with PROS. If further similar cases are reported, this would suggest that the establishment of PROS mosaicism is facilitated by the background of a RASopathy.