Although the hereditary nature of these syndromes was predicted early on, their molecular basis was only elucidated at the end of the 20th century by means of genetic developments and the characterization of the Ras-PI3K-Akt-mTOR pathway in NF1, TSC, and CS, as well as of the hypoxia signaling pathway in VHL. This evidence concerns the gene NF1 and Cowden syndrome 1.