SMAD4 and hereditary hemorrhagic telangiectasia: HHT arises from mutations in ENG, ACVRL1, MADH4, or GDF2, with ENG (encoding for the Endoglin protein) and ACVRL1 (encoding for the ALK1 protein) mutations accounting for ∼85% of cases, all encoding components of the transforming growth factor beta (TGF-β) signaling pathway.