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

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.

Life expectancy in patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: There are few data on life expectancy in patients with hereditary haemorrhagic telangiectasia (HHT), a disorder with life-threatening complications. METHODS: Seventy HHT patients provided data on age and age at death of their HHT-affected parent, which was compared with that of the parent's non-affected partner. RESULTS: At the time of the study, 40 HHT parents (57.1%) vs. 36 (51.4%) non-HHT parents had died (p = 0.404). Median age at death was lower in HHT vs. non-HHT parents (63.2 vs. 70.0 years, respectively). The mortality of HHT parents showed an early peak in the under 50s and a late peak at 60-79 years. HHT was the main risk factor influencing life expectancy after 30 years (p < 0.05). No differences in survival probability were found in HHT patients with respect to sex (p = 0.37), or ENG vs. ALK-1 genotype (p < 0.9). DISCUSSION: 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.

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.

The need for an interdisciplinary network of investigations on HHT.

In the last years, the understanding of HHT has greatly progressed. The two genes for most on cromosomes 9 and 12 have been discovered and the existence of a third involved gene has been predicted. Recent progress in the field of genetics has allowed the identification of many gene mutation thus facilitating the characterisation of the at risk members of the same family. Complications from bleeding or shunting (pulmonary AVMs) may be sudden and life-threatening (hemothorax, haemoptysis, stroke and brain abscess). Catastrophic events are preventable by early diagnosis and treatment. Appropriate screening programmes are mandatory and multi-specialistic cooperation is needed. Special centers have been developed in the world, where physicians, who are specialised and trained in all aspects of HHT, are working to develop better therapeutic approaches for the disease and to locate new genes in view of the future potential of gene therapy for this condition.

Emergencies in hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a systemic autosomal dominant vascular disease. Although the clinical picture is that of a chronic disabling disease, vascular malformations can suddenly lead to life-threatening conditions. AIM: To assess the frequency and type of emergency acute complications in HHT. DESIGN: Retrospective case-note review. METHODS: From August 2000 to December 2004, our specialized HHT centre saw 139 patients (74 males, 65 females, mean age 45.5 years, range 14-77) with a definite diagnosis of HHT. We reviewed their clinical files and recorded all visits for acute complications (massive nosebleeds, haematemesis, melaena, haematochezia, haemothorax, haemoptysis, TIA/ischaemic stroke, haemorrhagic stroke, brain abscess). RESULTS: Fifty patients (35.9%) had at least one acute complication. There were a total of 93 visits potentially involving the emergency department. Most commonly, patients sought urgent medical attention for nosebleeds and gastrointestinal bleeding (63.4%), but there were also disorders of the brain, lung, heart and liver. DISCUSSION: Acute complications of HHT are not uncommon and can be severe and wide-ranging. Physicians should be aware of HHT and its major complications, as a prompt diagnosis is essential to direct patients to the most appropriate therapies, and to suggest screening for visceral involvement in their relatives.

Capillaroscopy of the dorsal skin of the hands in hereditary hemorrhagic telangiectasia.

BACKGROUND: Cutaneous telangiectases are manifestations of hereditary hemorrhagic telangiectasia (HHT), a dominantly inherited disorder. Telangiectases have been studied by skin biopsy, and recently by nailfold capillaroscopy. AIM: To confirm the diagnostic role of nailfold capillaroscopy, and assess the value of skin capillaroscopy of the dorsum of the hands in HHT. DESIGN: Prospective clinical investigation. METHODS: Using a Wild Heerbrugg-M650 microscope, we studied the nailfolds and dorsum of the hands of 88 patients (37 females, 51 males, mean age 39.7 +/- 18.4 years), including 85 with positive genetic testing and three with clinical diagnosis (at least three clinical criteria but a negative genetic test) and 27 controls (13 females, 14 males, mean age 38.6 +/- 19.6 years). RESULTS: Microscopic telangiectases were observed on the dorsum of the hands in 80/88 patients (91%): 77 with positive and three with negative genetic tests. No control showed vascular abnormalities. In six patients (7%), nailfold capillaroscopy showed pseudo-megacapillaries and megacapillaries; the remaining 82 (93%) and all controls, had normal capillaroscopic patterns. DISCUSSION: HHT can induce morphological changes in microcirculation that are more easily detectable on the dorsum of the hands than in the nailfold. Microscopic lesions without macroscopic telangiectases were also noted, suggesting the need for further research. Capillaroscopy may provide an additional non-invasive diagnostic criterion for HHT.

Hereditary hemorrhagic teleangiectasia (Rendu-Osler-Weber disease).

Rendu-Osler-Weber disease, or hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disorder with incomplete penetrance, characterized by vascular anomalies which may virtually develop in many organs. The prevalence varies and may range from 1/3,500 to 1/5,000 in specific regions. Two chromosal sites have been at least identified: in HHT1, mutations at chromosome 9 alter the protein endoglin and in HHT2, mutations at chromosome 12 alter the protein activine or ALK-1. Clinical manifestations include recurrent epistaxis, mucocutaneous telangiectases that bleed easily, and larger arteriovenous malformations in parenchymatous organs. Epistaxis is the first symptom, occurring in the vast majority of affected persons. The lung is the most common site for arteriovenous malformations. Brain abscess, transient ischemic attack and ischemic stroke occur exclusively in patients with pulmonary arteriovenous malformations and right-to-left shunt, which facilitates the passage of emboli into the cerebral circulation. Transcatheter embolotherapy with detachable balloons or stainless-steel coils has been used in order to occlude such malformations and to prevent such complications. At present a genetic diagnosis is possible in only a few families. The clinical diagnosis is based on 4 criteria: family history, epistaxis, mucocutaneous telangiectases and arteriovenous malformations. The diagnosis will be definite if 3 criteria are present, suspected if 2 criteria are present, unlikely if fewer than 2 criteria are present. In conclusion, the authors examine clinical features of 28 HHT patients observed in the HHT University Centre of Bari from September 2000 to May 2001.

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-beta 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.