The finding that HHT is caused by germline, loss of function mutations in either Endoglin (ENG), Activin receptor-like kinase 1 (ALK1), or Mothers against decapentaplegic homolog 4 (SMAD4) was of particular significance because all three are involved in endothelial cell specific receptor pathways of the transforming growth factor beta (TGF-β) family of ligands, suggesting that vascular endothelial cell dysfunction might be the driving force behind AVM development (56, 64, 65). This evidence concerns the gene ACVRL1 and hereditary hemorrhagic telangiectasia.