Genotype-Phenotype Relationship in Hereditary Hemorrhagic Telangiectasia: Quality of Life and Cardiovascular Risk Evaluation.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by pathogenic variants in ENG (HHT1) and ACVRL1 (HHT2), with distinct phenotypic expressions. Background/

Objectives

This study investigates the genotype-phenotype correlations, including comparing the quality of life by phenotype, conducting a cardiovascular risk assessment, and evaluating the impact of mutation type on its clinical manifestations and prognosis.

Methods

A cross-sectional study was conducted on 85 HHT patients, stratified into HHT1 (ENG, n = 43) and HHT2 (ACVRL1, n = 42). Their clinical and biochemical parameters, arteriovenous malformations (AVMs), epistaxis severity, quality of life, and cardiovascular risk were assessed. Genetic variants were classified as truncating or non-truncating. The statistical analyses included logistic regression and survival analysis.

Results

The onset of epistaxis occurred earlier in HHT1 (log-rank p = 0.011), whereas its severity (p = 0.006) and iron deficiency were greater in HHT2 (p = 0.043). Pulmonary AVMs were significantly more frequent in HHT1 (58.1% vs. 9.5%, p < 0.01), contributing to a potential decrease in survival, despite the greater hemorrhagic burden in HHT2. Truncating mutations were independently associated with anemia (p < 0.05). Cardiovascular risk (measured using the SCORE2 scale) was low to moderate, and quality of life (measured using the EQ-5D-5L scale) was most impaired in patients with severe epistaxis (p = 0.031) or anemia (p = 0.026). Truncating mutations influence the severity of anemia independently of genotype. Limitations: The principal limitations include the small sample size and the bias generated by this being a paper based on another prospective study with a methodology designed for different objectives.

Conclusions

These findings underscore the need for personalized management strategies based on genotype and mutation type. Further prospective studies are warranted to validate these associations and optimize the risk stratification in HHT.