Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network

Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2).

Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening.

Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2.

This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.