Family phenotypic profile in hereditary hemorrhagic telangiectasia: genotype-phenotype correlation in a pediatric Italian population.

Abstract

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, hereditary, autosomal dominant vascular disease, characterized by visceral arteriovenous malformations (AVMs), mucocutaneous telangiectasias and epistaxis. While symptomatic medical and surgical therapies are used in the management of pediatric patients, data comparing phenotypic presentation between genetically related individuals (e.g., parent-child pairs) remain limited.

Aims and methods: We conducted a single-center retrospective study involving pediatric patients with genetically confirmed HHT and their affected parents at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy. The aim of our study was to assess genotype-phenotype correlation and intrafamilial HHT-phenotypic variability. Clinical, laboratory, imaging, and therapeutic data were collected between May 2022 and May 2023. Variables including presence of AVMs, epistaxis, telangiectasias, anemia, and need for interventions were compared between children and their parents.

Results: The study included 11 children (mean age 11.8 years) and 9 adults (mean age 47 years), all exhibiting ENG or ACVRL1 variants. While epistaxis was common in both cohorts (91% in children vs. 100% in adults), mucocutaneous telangiectasias and AVMs were more prevalent in adults. AVMs were more frequently detected in adults, especially among ENG carriers. Notably, phenotype concordance between parent-child pairs with the same mutation was observed in only 3 up to 9 families (33.3%), with substantial intrafamilial variability in AVM distribution and disease severity.

Conclusions: Our findings confirm the variable expressivity of HHT, even among first-degree relatives sharing the same pathogenic variant. No consistent overlap was observed between parent and child phenotypes, reinforcing the need for individualized pediatric screening and follow-up. Early genetic testing remains essential to prevent complications and guide appropriate management.