SMAD4 and hereditary hemorrhagic telangiectasia: Three genes are causally related to HHT: the ENG gene encoding endoglin, a co-receptor of the TGFβ family (HHT1), the ACVRL1 gene encoding ALK1 (activin receptor-like kinase 1), a type I receptor of the TGFβ family (HHT2), and the SMAD4 gene, encoding a transcription factor critical for this signaling pathway.