HHT have variants of unknown significance or no detectable mutations in any of the above-listed genes suggesting involvement of alternative pathways and mechanisms. De novo mutations in HHT are rare but have been reported. One series of 126 patients found only 3 patients with de novo mutations. 20 Although HHT1 and HHT2 are both related to TGF-β signaling defects, the phenotype is slightly different with increased incidence of PAVMs, brain AVMs, and gastrointestinal bleeding in HHT1, whereas HHT2 has increased incidence of liver vascular malformations and high output cardiac failure. Epistaxis tends to be seen equally in both the phenotypes. The classic HHT-associated vascular lesions are telangiectasias and AVMs. Telangiectasias are focal dilations of postcapillary venules, which connect with dilated arterioles in the absence of an intervening capillary bed. Thus, these represent the smallest forms of direct arteriovenous communications. Telangiectasias can be found in many locations, including the skin, pulmonary vasculature, gastrointestinal tract, liver, and other visceral organs. 21 Larger AVMs start out as telangiectasias and are likely a result of continued vascular remodeling and inappropriate endothelial cell proliferation responses. 22 The development of vascular lesions in HHT can be understood via a haploinsufficiency model with reduced signaling in the ENG-and activin receptor-like kinase type 1–mediated TGF-β pathways and preserved signaling through alternative TGF-β pathways. Activin receptor-like kinase type 1 and endoglin are involved in balancing the activation phase and resolution phases of angiogenesis. 23, 24 The activation phase involves a proangiogenic stimulus, which increases endothelial cell layer permeability, basement membrane degradation, and sprouting of endothelial cells. Lumen formation from endothelial sprouts then occurs followed by the resolution phase, which entails vessel maturation and basement membrane reconstruction. AVMs in this setting are not congenital but considered to develop early in infancy when arteriovenous maturation occurs and vessels are continuously being developed. 25 It is conceivable that the ENG and ACVR1 mutations also result in a hyper response to proangiogenic stimuli. 22 One recent mouse study demonstrated that the absence of endoglin results in developing vessels having delayed remodeling of capillary plexuses, increased endothelial cell proliferation, and local venous enlargement, thus resulting in arteriovenous shunt formation. 22 The triggering event leading to the formation of these AVMs in humans remains unknown although several mechanisms have been proposed, including inflammation/infection, endoluminal shear stress, and hypoxemia.