Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.

Service de Génétique Moléculaire et Médicale, Hôpital Edouard Herriot, Lyon, France, and Genetica Medica, Università di Pavia and IRCCS S. Matteo, Pavia, Italy.
Genetics in Medicine (Impact Factor: 6.44). 02/2007; 9(1):14-22. DOI: 10.1097/GIM.0b013e31802d8373
Source: PubMed

ABSTRACT Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2).
Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening.
Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2.
This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.

  • 04/2014; 104(4):256-7. DOI:10.7196/samj.7816
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular malformations. The genes known to be associated with HHT include ENG (HHT1), ACVRL1 (HHT2) and SMAD4 (JPHT). It has been reported that circulating CD34+ cell subsets repair damaged vessels. To investigate whether mobilization of these cells is present in the peripheral blood (PB) of HTT patients, we analyzed CD34+ cells, CD34+VEGFR-2+ progenitor or mature endothelial cells, and CD34+CD133+VEGFR-2− hematopoietic progenitor cells (HPCs). Cytofluorimetric analysis was performed in 150 HTT patients and 43 healthy subjects (CTRLs). In HTT patients, PB CD34+ cells were significantly increased; the frequency of endothelial cells was higher (P = 0.002), while the frequency of CD34+CD133+VEGFR-2− HPCs was lower (P = 0.00007) than in CTRLs. Results were comparable in patients with ENG or ACVRL1 gene mutation; in patients with ENG mutation, the frequency of the cell subsets inversely correlated with the age of the patients at time of sampling (CD34+), disease duration (CD34+VEGFR-2+), and age at disease onset (CD34+CD133+VEGFR-2−). In conclusion, HHT patients show an increase of circulating endothelial cells and a decrease of HPCs. In patients with ENG mutation, the frequency of CD34+ endothelial cells correlates with specific clinical characteristics suggesting that their active turnover characterizes the initial phase of the disease.
    International Journal of Hematology 12/2014; 101(1). DOI:10.1007/s12185-014-1698-4 · 1.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT), also known by the eponym Osler-Weber-Rendu syndrome, is a group of related disorders inherited in an autosomal dominant fashion and characterized by the development of arteriovenous malformations (AVM) in the skin, mucous membranes, and/or internal organs such as brain, lungs, and liver. Its prevalence is currently estimated at one in 5,000 to 8,000. Most cases are due to mutations in the endoglin (HHT1) or ACVRLK1 (HHT2) genes. Telangiectasias in nasal and gastrointestinal mucosa generally present with recurrent/chronic bleeding and iron deficiency anemia. Larger AVMs occur in lungs (~40%-60% of affected individuals), liver (~40%-70%), brain (~10%), and spine (~1%). Due to the devastating and potentially fatal complications of some of these lesions (for example, strokes and brain abscesses with pulmonary AVMs), presymptomatic screening and treatment are of utmost importance. However, due to the rarity of this condition, many providers lack an appreciation for the whole gamut of its manifestations and complications, age-dependent penetrance, and marked intrafamilial variation. As a result, HHT remains frequently underdiagnosed and many families do not receive the appropriate screening and treatments. This article provides an overview of the clinical features of HHT, discusses the clinical and genetic diagnostic strategies, and presents an up-to-date review of literature and detailed considerations regarding screening for visceral AVMs, preventive modalities, and treatment options.
    Hematology Research and Reviews 01/2014; 5:191-206. DOI:10.2147/JBM.S45295

Full-text (2 Sources)

Available from
Aug 19, 2014