Three major genes are causally related to HHT: the ENG gene encoding the co-receptor endoglin (ENG/HHT1) [200]; the ACVRL1 gene encoding ALK1 [201,202,203] causing HHT2; and the MADH4 gene (SMAD4) (HHT3), a critical intracellular mediator in BMP and TGF-β signalling pathways [202,204] (Figure 3). This evidence concerns the gene SMAD4 and hereditary hemorrhagic telangiectasia.