Mutations in the SMAD4 gene, which is normally an essential effector of the aforementioned TGF-β signaling pathway, are detected in less than 2% of cases with clinical suspicion of HHT and determine an increased risk of juvenile polyposis syndrome (juvenile polyposis/HHT overlap syndrome) [6]. This evidence concerns the gene TGFB1 and hereditary hemorrhagic telangiectasia.