Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations.
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.
Berg
J
J
Department of Medical and Molecular Genetics, GKT School of Medicine, King's College London, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK. jonathan.berg@kcl.ac.uk
Porteous
M
M
Reinhardt
D
D
Gallione
C
C
Holloway
S
S
Umasunthar
T
T
Lux
A
A
McKinnon
W
W
Marchuk
D
D
Guttmacher
A
A
D030201:Activin Receptors, Type I / Q000235:genetics*; D030301:Activin Receptors, Type II; D000368:Aged; D015703:Antigens, CD; D001165:Arteriovenous Malformations / Q000235:genetics; D002536:Cerebral Arteries / Q000473:pathology; D004252:DNA Mutational Analysis; D000071063:Endoglin; D004844:Epistaxis / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011652:Pulmonary Circulation / Q000235:genetics; D011956:Receptors, Cell Surface; D011795:Surveys and Questionnaires; D016019:Survival Analysis; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000401:mortality; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II