The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis

Historically, the factor(s) that stimulate vascular malformation genesis in hereditary hemorrhagic telangiectasia (HHT) has been hotly debated. Once heterozygous loss-of-function germline mutations in ENG, ACVRL1, or SMAD4 were discovered in individuals with HHT, haploinsufficiency, a 50% reduction in the encoded protein, was proposed as the molecular mechanism of HHT. However, the focal and discrete nature of HHT-associated vascular malformations suggested to others that vascular malformation genesis requires an additional, local trigger. In this review, we discuss the evidence for the Knudsonian two-hit mutation mechanism of vascular malformation pathogenesis in HHT, where the inherited, heterozygous mutation is augmented by an acquired somatic mutation in the remaining normal copy of the gene. We consider the mechanisms of HHT-vascular malformation development in the broader context of the emerging role of somatic mutations in both sporadic and inherited vascular malformations. We discuss different mechanisms of biallelic gene inactivation in HHT, difficulties with the detection of all possible mechanisms of biallelic inactivation, and issues related to the somatic mosaic nature of the lesion. We then discuss the critical importance of non-genetic factors on the pathogenesis of HHT-associated vascular malformations. Finally, we discuss the implications of the two-hit mutation mechanism for the design of novel treatments for HHT.