Hereditary hemorrhagic telangiectasia clinical and molecular genetics

Abstract

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber (ROW) syndrome is an autosomal dominant disease characterized by vascular malformations in multiple organ systems. HHT has an age-related penetrance and variable clinical expression. The clinical symptoms are caused by direct arteriovenous connections without an intervening capillary bed. This can result in a range of manifestations, from smaller mucocutaneous telangiectases to large visceral arteriovenous malformations (AVM). The clinical manifestations of HHT include recurrent epistaxis, multiple telangiectases, at characteristic sites (lips, oral cavity, nose, fingers, gastrointestinal telangiectases) and AVMs, mostly in the lung (PAVM), the liver (HAVM) or the brain (CAVM). The clinical diagnosis HHT is established using the Cura硯 criteria. At least three of the following four criteria are required for a certain clinical diagnosis: spontaneous and recurrent epistaxis, telangiectases at characteristic sites, visceral manifestations (gastrointestinal telangiectases, PAVM, CAVM, HAVM) and a first degree relative with HHT. In the presence of two criteria, the diagnosis is considered possible. Mutations in the endoglin (ENG) and activin A receptor type-like kinase 1 (ACVRL1) genes have been shown to be associated with HHT; mutations in ENG cause HHT1 and mutations in ACVRL1 cause HHT2. A combined syndrome of juvenile polyposis and HHT is caused by mutations in the SMAD4 gene. The molecular and genetic characterization of HHT families is performed. Once a mutation in the majority of the families is found, the identification of carriers and non-carriers is possible and the HHT subtype is clear. This combined with well described phenotypes, allows for an extensive analysis of the genotype-phenotype correlation, which is performed. Analyses are performed to establish the phenotypic differences between HHT1 and HHT2 for the AVMs, telangiectases, episaxis and gastrointestinal telangiectases. The results published in this thesis have improved the knowledge of HHT. In families suspected of HHT, a general risk profile for the different clinical manifestations can be given to probands and family members according to the type of HHT. However, the risk profile of the clinical manifestations remains population based. An explanation for the question, why the one family member is affected with all symptoms whereas the other has only epistaxis, remains open and will be focus of future research. Identifying modifier genes or environmental factors influencing the expression of the HHT genes will possibly generate a more personalized risk profile