Giovanna Pasculli

Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers

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.

Vascular Endothelial Growth Factor Serum Levels Are Elevated in Patients with Hereditary Hemorrhagic Telangiectasia

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.

Health-related quality of life in a rare disease: hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease

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.

Brain abscess: A need to screen for pulmonary arteriovenous malformations

Background: Pulmonary arteriovenous malformations (PAVMs) are direct connections between an artery and a vein in the pulmonary circulation associated with hereditary hemorrhagic telangiectasia in up to 88% of cases. Patients with PAVMs are at increased risk of brain abscess (BA). This study aimed to provide preliminary data on the prevalence of PAVMs among BA patients. Methods: Administrative hospital discharge forms were used to identify patients with BA; possible PAVM patients were screened. Results: 126 patients with BA were identified. Two patients had undiagnosed PAVMs at the time of admission for BA. The age-adjusted incidence of BA was 6.3 cases/1 million/year, with a male:female ratio of 2.0. Conclusion: Although PAVMs are rare conditions, they play a role in the development of BA. PAVMs are usually not recognized at the time of BA, thus exposing patients to life-threatening risks.

HHT: A Rare Disease with A Broad Spectrum of Clinical Aspects

HHT is an autosomal dominant disease characterised by diffuse muco-cutaneous and visceral telangiectases in potentially all organs. Mutations in two different genes identify HHT type 1 and HHT type 2: endoglin located on chromosome 9q33-q34 and ALK-1 or ACVRL1 on chromosome 12q13, respectively. The existence of a third locus has also been hypothesised. HHT-1 is considered a more severe form of the disease with an earlier onset of epistaxis and telangiectases and a higher prevalence of pulmonary arteriovenous malformations than that found in HHT-2 subjects. Usually, a typical HHT patient has epistaxis, muco-cutaneous telangiectases and GI bleeding in later life, even though this clinical scenario represents only one of the possible HHT patterns. In fact, vascular malformations often remain silent until the onset of a severe complication, which frequently is the first clinical manifestation of HHT. The lung and brain are of particular concern because each may contain clinically silent lesions that can result in sudden morbidity and mortality. At present, awaiting the availability of genetic testing, only an expert in the clinical patterns and diagnostic imaging of HHT can permit a definite diagnosis in individuals at high risk for the disease.

Angiogenesis and hereditary hemorrhagic telangiectasia. Rendu-Osler-Weber disease.

To date much of the recent work on pathological angiogenesis has focused on inflammatory diseases, diabetes and cancer in particular. Hereditary hemorrhagic telangiectasia or Rendu-Osler-Weber disease provides an example of the genetic disorder of angiogenesis in which a multisystemic angiodysplasia is responsible for severe hemorrhage. The disease pathogenesis is partially explained by a defect in the TGF-β signaling system, although in more recent works a possible role of other vascular growth factors has been proposed. This paper provides a model of an aberrant angiogenesis in which multiple vascular growth factors could be involved in a diffuse angiodysplasia.