Undergrowth Of First Toe In PiK3CA-Related Overgrowth Spectrum (PROS)

Background: PIK3CA-related overgrowth syndrome (PROS) include a heterogeneous group of disorders characterized by segmental overgrowth secondary to somatic mosaic activating vari-ants in PIK3CA. Segmental undergrowth is more uncommon and has been less studied but pathogenic variants in PIK3CA have also been found. With this in mind, we have noticed a group of patients with PROS that present an undergrowth component associated with their focal overgrowth.Methods: Retrospective review of patients with PROS presenting overgrowth of the lower limb and undergrowth of the ipsilateral first toe was performed.Results: Six patients were included, 4 female and 2 male with a median age of 16.8 years. All patients presented a PROS phenotype with overgrowth of the lower limb and undergrowth of ipsilateral first toe. A PIK3CA pathogenic variant was confirmed in all patients. Patients under-went multiple treatments, currently all are receiving alpelisib with a mean duration of 15.8 months (1e39) and partial response in lipomatosis and vascular anomalies but no response in over-growth and undergrowth so far.Conclusions: Pathogenic variants in the same gene can create different phenotypes depend-ing on the time and place of the mutation. There is little information regarding opposing phenot-pyes in the same patient with PROS. The presence of undergrowth in our series might be explained by genetic, embryogenic, maternal, or placental factors but needs to be further investigated.