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

Abstract

Purpose: 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). Methods: 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. Results: Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P Ͻ 0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P Ͻ 0.001), as were cerebral abscesses (7.5 vs. 0.8%, P ϭ 0.002).Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P ϭ 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 Ͻ 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. Conclusion: This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies. Genet Med 2007:9(1):14-22.

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…Pulmonary AVMs are more common in HHT1 than HHT2, [22][23][24][25][26][27] though in the relatively small number of SMAD4 patients described, the prevalence of PAVMs may be higher still. 127 HHT1 patients are also more commonly affected by cerebral AVMs, [23][24][25][26] and by microscopic intrapulmonary shunting.…”

“…122 Individual series describe ENG or ACVRL1 predominance. [22][23][24][25][26][27] It is not known whether these reflect genuine geographical variation, or the clinical referral practice of the relevant HHT centres, since there are differences in patterns of HHT between families with HHT1, HHT2, and JPHT (see below). Blood Reviews _ HHT 2010_ Shovlin 10 …”

“…Many hundreds of different mutations have been described in HHT families, with no common mutation identified ( 21 , summarised in 3 ). The mutated gene has some Blood Reviews _ HHT 2010_ Shovlin 4 influence on the resultant HHT phenotype, [22][23][24][25][26][27] although more profound variation in disease expression is seen between members of the same family.…”

“…In one series, positive contrast echocardiography reflecting intrapulmonary shunting was found in 85% of HHT1 patients, and 35% of HHT2 patients 52 compared to 7% of a control normal population. 47 Patients with HHT2 have a higher prevalence of hepatic AVMs, 23,[25][26][27] and of severe disease due to hepatic AVMs 27,70 . A single series suggests HHT2 patients may have more pancreatic AVMs 9 , and develop dermal telangiectasia earlier than in HHT1.…”

Hereditary haemorrhagic telangiectasia: a clinical and scientific review

“…Both sets of considerations differ with the precise anatomy and location of the AVM. Other important considerations are that cerebral AVMs are more common in HHT1 families [31][32][33][34][35][36] , and that the lifelong risk of haemorrhage is higher for younger patients because of their longer predicted lifespan.…”