To cite this article: Sabbà C, Pasculli G, Lenato GM, Suppressa P, Lastella P, Memeo M, Dicuonzo F, Guanti G. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007; 5: 1149-57.Summary. Background: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs), particularly in the brain (CAVMs), lungs (PAVMs), liver (HAVMs) and gastrointestinal tract (GI). The identification of a mutated ENG (HHT1) or ALK-1 (HHT2) gene now enables a genotype-phenotype correlation. Objective: To determine the incidence of visceral localizations and evaluate phenotypic differences between ENG and ALK1 mutation carriers. Methods: A total of 135 consecutive adult patients were subjected to mutational screening in ENG and ALK1 genes and instrumental tests to detect AVMs, such as chest-abdomen multislice computed tomography (MDCT), brain magnetic resonance imaging and magnetic resonance angiography (MRI/MRA), upper endoscopy, were offered to all patients, independent of presence of clinical symptoms. The 122 patients with identified mutations were enrolled in the study and genotype-phenotype correlations were established. Results: PAVMs and CAVMs were significantly more frequent in HHT1 (75% vs. 44%, P < 0.0005; 20% vs. 0%, P < 0.002, respectively) and HAVMs in HHT2 (60% vs. 84%, P < 0.01). No age difference was found for PAVMs whereas HAVMs were significantly higher in older patients in both HHT1 and HHT2. Neurological manifestations secondary to CAVMs/PAVMs were found only in HHT1 patients, whereas severe liver involvement was detected only in HHT2. Respiratory symptoms were mainly detected in HHT1. Conclusions: Our study evidences a higher visceral involvement in HHT1 and HHT2 compared with previous reports. HHT1 is more frequently associated with congenital AVM malformations, such as CAVMs and PAVMs whereas HHT2 predominantly involves the liver. The ENG gene should be first targeted for mutational screening in the presence of large PAVM in patients < 45 years.
The levels of the health-related quality of life (HR-QoL) were analyzed in hereditary hemorrhagic telangiectasia (HHT) patients. The Short Form-36 Health Survey (SF-36) was administered to 50 HHT patients and scores were compared to a cohort of 2301 normal subjects. Clinical variables were patient age, illness duration, number of epistaxis episodes in the previous year and hemoglobin levels. Physical functioning, physical role limitations, bodily pain, social functioning, emotional role limitations and the physical component scores were lower among females. In multivariable analyses increasing age was related to lower physical functioning (p < 0.04), physical role limitations (p < 0.008), bodily pain (p < 0.05) and emotional role limitations (p < 0.01), while higher hemoglobin levels improved physical functioning (p < 0.03). The number of epistaxis episodes was negatively associated with physical role limitations (p < 0.009), vitality (p < 0.002), social functioning (p < 0.001), physical component summary (p < 0.001) and bodily pain (p < 0.01). Illness duration was negatively related to the mental component summary (p < 0.004). HHT patients had a lower HR-QoL with respect to normal controls in all domains except for bodily pain. Females had lower scores for several domains. Epistaxis was the most important clinical variable.
Background: Hereditary hemorrhagic telangiectasia (HHT) is a genetic angiodysplasia affecting multiple organs. Two genes involved in the transduction of TGF-β signalling are responsible for HHT. An additional role for vascular endothelial growth factor (VEGF) has been proposed. Serum VEGF, which has been evaluated in several diseases characterized by aberrant angiogenesis, has never been measured in patients with HHT. Aims: To evaluate VEGF serum levels in HHT patients as compared to normal subjects. Materials and Methods: 32 HHT patients (age 47.7 ± 16.7 years) and a control group of 37 healthy subjects (age 48.2 ± 15.5 years) were entered in the study. Each patient underwent serum VEGF dosage using a commercial ELISA specific for the human molecule. Results: The serum level of VEGF in HHT patients was 196.3 ± 103.2 pg/ml, while it was 152.0 ± 84.1 pg/ml in the control group. Statistical analysis showed that serum VEGF was significantly higher in HHT patients than in the controls (p < 0.031). Conclusions: According to a study performed in a murine model, persistence of the activation phase of angiogenesis might be responsible for an increased production of several angiogenic factors, in particular VEGF, in HHT. Our work is the first to suggest an increased expression of VEGF in the serum of subjects with HHT in agreement with the stimulation of VEGF synthesis proposed in the murine model.
Life expectancy appears to be significantly lower in HHT patients than in their partners. Prevention of HHT complications with screening programs could increase life expectancy.
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