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Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia
  1. C Olivieri1,
  2. E Mira2,
  3. G Delù2,
  4. F Pagella2,
  5. A Zambelli3,
  6. L Malvezzi2,
  7. E Buscarini3,
  8. C Danesino1
  1. 1Genetica Medica, Università di Pavia, Pavia, Italy
  2. 2Clinica Otorinolaringoiatrica, Università di Pavia, IRCCS S Matteo, Pavia, Italy
  3. 3Unità Operativa di Gastroenterologia, Ospedale Maggiore, Crema, Italy
  1. Correspondence to:
 Dr C Danesino, Genetica Medica, Via Forlanini 14, 27100 Pavia, Italy;

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Hereditary haemorrhagic telangiectasia (HHT) (OMIM 187300) is an autosomal dominant disorder caused by mutations in either of two genes, endoglin (ENG, OMIM 131195) (HHT1) and activin A receptor type II-like 1 (ACVRL1, OMIM 601284) (HHT2). Evidence for a third locus has also been reported.1

The product of the ACVRL1 gene is a type I receptor for the TGF-beta group of ligands; it is associated with the TGF-beta or activin type II receptors and the complex binds TGF-beta or activin. It is highly expressed in endothelial cells, lung, and placenta, as endoglin, mutations of which are observed in HHT1; endoglin is supposed to sequester TGF-beta and present the ligand to activin A receptor type II-like 1 plus a type II receptor.2 Mutations in ENG and ACVRL1 may cause HHT1 or HHT2, respectively, by disrupting this complex.

The clinical presentation, indistinguishable between HHT1 and HHT2, typically includes epistaxis and telangiectasia, and the diagnosis can be considered to be confirmed, according to the proposal of Shovlin et al,3 if three of the four suggested diagnostic criteria (epistaxis, telangiectasia, visceral lesions, positive family history) are present. The phenotype is highly variable and penetrance is complete by the age of 40 years.4

Arteriovenous (AV) fistulae are frequently observed in the liver (8% of patients),5 lungs (20%),6 and brain5 and may cause severe life threatening complications. Neurological complications (strokes, cerebral abscesses, seizures) may be prevented with appropriate treatment of the pulmonary arteriovenous malformations (PAVMs). A higher risk for lung involvement has been suggested in patients carrying mutations in the ENG gene,7 while in some families with a peculiar liver involvement, mutations in ACVRL1 have been described.8 The involvement of the latter gene has also been reported in a single patient with a pituitary tumour …

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