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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.

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