Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that exhibits age-related penetrance and extensive clinical variability, including intra-familial variability [1]
These findings suggest that the interplay between the bone morphogenetic protein 9 (BMP9)/endoglin/ALK1 pathway and blood flow-induced mechano-transduction signals plays a critical role during development of HHT lesions [64,65,66,72,73]
The two-hit hypothesis has been widely accepted for many years as a plausible explanation for the phenotypic variability found in HHT
Summary
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that exhibits age-related penetrance and extensive clinical variability, including intra-familial variability [1]. The characteristic vascular lesions range from 1 to 2 mm punctate mucocutaneous telangiectases to arteriovenous malformations (AVMs) several centimeters in diameter within visceral organs, the lungs, liver, and brain. Hepatic vascular malformations associated with HHT typically present in later adulthood as high output heart failure, due to significantly increased blood flow through shunting pathways in the liver [10]. The clinical diagnosis of HHT is based on the Curaçao Criteria: (i) recurrent and spontaneous nosebleeds (epistaxis), (ii) cutaneous or mucosal telangiectases on the skin of the hands, lips, or face, or inside of the nose or oral cavity, (iii) visceral AVMs or telangiectases in one or more of the internal organs, including lungs, brain, liver, gastrointestinal tract, and spinal cord, and (iv) family history of HHT (i.e., first-degree relative with a definite HHT clinical or genetic diagnosis). The phenotype and age of onset of manifestations is highly variable in HHT and this variability seems to depend on HHT subtype, as well as genetic background and/or environmental triggers (second-hits) to which each individual is exposed
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