In conclusion, our findings demonstrate that isolated macrodactyly is predominantly caused by mosaic variants in PIK3CA or AKT1. We also show that patients with macrodactyly deformities of the upper limbs tend to carry PIK3CA variants with mutations outside the helical domain, while patients with deformities in the lower limbs have PIK3CA variants with mutations in the helical domain. This evidence concerns the gene AKT1 and megalodactyly.