Hereditary Haemorrhagic Telangiectasia Spectrum of ALK1/ENG Mutation

Abstract 5066

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by two common criteria: angiodysplastic mucocutaneous telangiectasies, and epistaxis; hematemesis, melena, hemoptysis, stroke and visceral artero-venous malformation (AVMv) have also been associated with a significant risk of morbidity and mortality; HHT is divided into two forms: HHT-1 which is caused by a mutation in ENG (endoglin) gene mapping on chromosome 9q33–34, and HHT-2 which is caused by a mutation in ALK1 (activin receptor-like kinase 1) gene mapping on the pericentromeric region of chromosome 12q12–13.

Endoglin is an homodimeric disulphide-linked integral membrane glycoprotein (CD105) expressed on endothelial cells of all vessels; it binds TGF-beta 1 and 3, and it is very important to mediate vascular remodelling, the increase of blood flow, cellular migration and adhesion, extracellular matrix synthesis, through the modulation on endothelial cells, smooth muscle cells, fibroblasts and pericytes.

ALK1 increases in response to vessel wall stress or injury, and has a specific role in the differentiation of new vessels.

The majority of mutations in both genes are null, nonsense or splite-site and are non coding; the spectrum of mutations that have been reported of the two genes are short insertions, deletions, or missense and are present with a high level of consanguinity; homozygous patients with these mutations have severe haemorrhages.

We have identified on chromosome 12 a large deletion in exon 7, (8.4 kbp long fragment) of ALK1 encoding for the extracellular ligand-bindig domain involved in the TGF-beta/kinase activity signalling pathway, and in exon 8 (6.4 kbp long fragment) of ALK1 encoding serine-threonine kinase activity. The latter was a 28-year-old woman showing skin telangiectasies, recurrent and significant nosebleeds; the typical puntiform telangiectasies were evident since the age of 16, she also demonstrated with gastrointestinal endoscopy numerous gastric telangiectasies; abdominal and thoracic CT were performed and pulmonary involvement was present with a single artero-venous malformation and minimal respiratory symptoms (dyspnea, cyanosis); on the other hand, MRN did not revealed any cerebrovascular damage.

Mutations that disrupt ALK1 affect endothelial cells development and the process of angiogenesis; they are associated with mild clinical manifestation, and it has been observed that pulmonary arteriovenous malformations occur less frequently.