Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations

Abstract

Background: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterised by mucocutaneous telangiectasis, epistaxis, gastrointestinal haemorrhage, and arteriovenous malformations in the lung and brain. Causative mutations for HHT have been identified in two genes, endoglin and ALK1, which encode proteins involved in serine-threonine kinase signalling in the endothelial cell. Methods: A number of people affected with HHT had completed a postal questionnaire as part of an international study to delineate the HHT phenotype. We identified questionnaires completed by subjects in whom we had identified a mutation in endoglin or ALK1. Further questionnaires were sent to families with known mutations. Data were only included from questionnaires returned by people known to carry disease causing mutations. Results: Questionnaires were completed by 83 subjects with known mutations. Of these, 49 had endoglin mutations (HHT1) and 34 had ALK1 mutations (HHT2). Subjects with HHT1 reported an earlier onset of epistaxis (p=0.01) and telangiectasis (p=0.0001) than those with HHT2. Pulmonary arteriovenous malformations were only reported in the endoglin mutation group in our study (p<0.001). Conclusions: Our questionnaire based study provides evidence that the HHT phenotype caused by mutations in endoglin (HHT1) is distinct from, and more severe than, HHT caused by mutations in ALK1 (HHT2). This has significant implications for diagnosis, screening, and treatment in the two different forms of HHT, as well as for understanding the pathogenesis of the disease.

Hepatic manifestation is associated withALK1 in hereditary hemorrhagic telangiectasia: Identification of five novelALK1 and one novelENG mutations

“…In that study, an earlier onset of epistaxis and telangiectasis was present in patients with HHT1. In addition, pulmonary arteriovenous malformations (PAVM) were only seen in HHT1 (Berg et al, 2003), which confirmed earlier observations . However, PAVMs can also be encountered in some patients with HHT2 (McDonald et al, 2000;Kjeldsen et al, 2001).…”

“…Fifty seven mutations were listed in the recent review by van den Driesche and colleagues (van der Driesche et al, 2003) while 59 further novel mutations have been published subsequently as follows: 31 mutations (Lesca et al, 2004), 17 (Cymerman et al, 2003), 4 (Lastella et al, 2003), 4 (Berg et al, 2003), 2 (Harrison et al, 2003), and 1 (Chaouat et al, 2004). Together with the one novel ENG mutation detected in this study, the total number of ENG mutations is now 117.…”

“…Among all published patients with known mutation and hepatic disease, only five were reported to carry a mutation in the ENG gene Berg et al, 2003;Cymerman et al, 2003;Harrison et al, 2003). ALK1 mutations and liver involvement was reported for single patients (Johnson et.…”

“…The presence of two disease loci provided the rationale for genotype/phenotype studies of the disease. Recently, a large questionnaire based study led Berg and colleagues to conclude that the HHT1 phenotype is distinct from, and more severe than the HHT2 phenotype (Berg et al, 2003). In that study, an earlier onset of epistaxis and telangiectasis was present in patients with HHT1.…”

“…ALK1 mutations and liver involvement was reported for single patients (Johnson et. al., 1996;Berg et al, 1997;Trembath et al, 2001), for 2 patients each (Abdalla et al, 2003a;Berg et al, 2003), for 6 unrelated patients (Olivieri et al, 2002), and for multiple familial cases (Piantanida et al, 1996;McDonald et al, 2000;Lin et al, 2001; Abdalla et al 2003b). …”