SummaryBackground-Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease that leads to multiregional angiodysplasia. Severe recurrent epistaxis is the most common presentation, frequently leading to severe anemia. Multiple therapeutic approaches have been tried, but they are largely palliative with variable results.We aimed to assess the efficacy of thalidomide in reducing epistaxis in patients with HHT refractory to standard therapy.

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease, with an autosomal dominant inheritance and a worldwide incidence of about 1: 5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG or ACVRL1, which code for ENDOGLIN and Activin A Receptor Type II-Like Kinase 1 (ALK1), belonging to the TGF-β/BMP signalling pathway. Typical HHT clinical features are mucocutaneous telangiectases, arteriovenous malformations, spontaneous and recurrent epistaxis, as well as gastrointestinal bleedings. An additional, but less frequent, clinical manifestation in some HHT patients is the presence of Pulmonary Arterial Hypertension (PAH). The aim of this work is to describe the functional role of a novel ENG intronic variant found in a patient affected by both HHT and PAH, in order to assess whether it has a pathogenic role. We proved that the variant lies in a novel binding-site for the transcription factor Sp1, known to be involved in the regulation of ENG and ACVRL1 transcription. We confirmed a pathogenic role for this intronic variant, as it significantly reduces ENG transcription by affecting this novel Sp1 binding-site.

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Hereditary hemorrhagic telangiectasia (HTT) is an autosomal dominant disease, most frequently caused by a mutation in either ENG or ACVRL1, which can be associated with pulmonary arterial hypertension (PAH). In this report, we describe a new unpublished ACVRL1 mutation segregating in three members of the same family, showing three different types of pulmonary hypertension (PH) in the absence of BMPR2 mutations. The first patient has a form of heritable PAH (HPAH) in the absence of hepatic arteriovenous malformations (AVMs); the second one has a severe form of portopulmonary hypertension (PoPAH) associated with multiple hepatic AVMs; the third one has hepatopulmonary syndrome (HPS) with numerous hepatic arteriovenous fistulas and a form of post-capillary PH due to high cardiac output. In summary, a single mutation in the ACVRL1 gene can be associated, in the same family, with an extreme phenotypic variability regarding not only the clinical presentation of HHT but also the type of PH in the absence of BMPR2 mutations. More studies are needed to evaluate if this variability can be explained by the presence of additional variants in other genes relevant for the pathogenesis of HHT.

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