Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically heterogeneous disorder involving at least two loci; HHT 1 mapping to chromosome 9 q 34.1 (ENG) and HHT 2 mapping to chromosome 12 q 31 (ALK-1). OBJECTIVE: To evaluate and describe the diversity of clinical manifestations in a Danish population of HHT patients with known HHT 1 or HHT 2 subtype. DESIGN: Prospective clinical examination with genetic evaluation and follow-up. SETTING: Investigation centre was Odense University Hospital. All HHT patients in the County of Fyn were included. METHODS: HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for PAVM and neurological evaluation. Blood tests were performed for analysis of disease-causing mutation, and clinical manifestations in the HHT subtypes were compared. The survival of the patients was studied in the follow-up period. RESULTS: Included in the study were 73 HHT patients representing 18 families. In 14 of the families we identified a disease-causing mutation. Thirty-nine patients (from 10 families) had HHT1 and 16 HHT patients from four families had HHT2. CONCLUSION: Amongst patients with HHT1 genotype the prevalence of PAVM was higher than amongst HHT patients with HHT2 genotype. HHT1 patients had experienced more severe GI bleeding than HHT2 patients. There was no significant difference in severity of epistaxis or age at debut. Finally the mortality over a 90-month observation period was not significantly increased.

Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a rare disorder with one per 6000-10,000 affected individuals in the general Caucasian population. HHT is genetically heterogeneous, involving at least two loci HHT1 mapping to chromosome 9q34.1 and HHT2 mapping to chromosome 12q31. The loci have been identified as endoglin (ENG) and activin receptor-like kinase 1 (ALK1). In order to gain knowledge of the genotype distribution and prevalence in the Danish population and to establish a reproducible and sensitive molecular genetic test method, we developed a denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci. Twenty-five Danish HHT families were tested. A total of eight new as well as seven previously reported mutations were identified. A founder mutation was characterized present in seven families and possibly introduced around 350 years ago. In one individual, a presumed spontaneous mutation was characterized. The method developed proved to be very sensitive for mutation detection in both ENG and ALK1. Genetic screening in HHT families facilitates an early treatment strategy for silent HHT manifestations in first degree relatives.

[Percutaneous transluminal embolization of pulmonary arteriovenous malformations]. / Perkutan transluminal embolisation af pulmonale arteriovenøse malformationer.

OBJECTIVE: The aim was to evaluate the effect of embolisation of pulmonary arteriovenous malformations (PAVM), as estimated by contrast echocardiography, arterial blood-gas analyses and functional level, and further to evaluate procedure-related and late complications. PATIENTS AND METHODS: Seventeen patients were treated on 25 occasions for a total of 48 PAVM. Fifteen patients had hereditary haemorrhagic telangiectasia (HHT). Chest X-ray, pulmonary angiography, contrast echocardiography, arterial blood-gas analyses, and functional level were analysed before and after embolisation of PAVM. The mean follow-up period was 22 months. RESULTS: Contrast intensity at contrast echocardiography decreased from median 4.0 (range 2-4) before embolisation to 1.5 after embolisation. PaO2 breathing 100% oxygen increased from mean 271 mm Hg before embolisation to 480 mm Hg after embolisation. The shunt was reduced from mean 24% before to 12% after embolisation. Most of the patients experienced an increased functional level after embolisation, and the median functional level (NYHA) increased from NYHA 2.5 to 1.2. No primary or secondary device migration, no cerebral insults, and no mortality was noted. CONCLUSION: Embolisation is a well-established method of treating PAVM, with a significant effect on oxygenation of the blood. It is a minimally invasive, lung-preserving treatment with high affectiveness and low morbidity and mortality. Patients with HHT should be screened for PAVM as a high percentage of these have PAVM.

Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.

Mutations in the ENG gene on chromosome 9 (HHT 1) and in the ALK-1 gene on chromosome 12 (HHT 2) have been reported as causes of hereditary hemorrhagic telangiectasia (HHT). HHT 1 has been correlated with a higher prevalence of pulmonary arteriovenous malformations than HHT 2. Other distinct phenotype-genotype correlations have not been described. The prevalence of HHT in the county of Fyn, Denmark, was 15.6 per 100,000 on January 1, 1995. All living patients and their first-degree relatives were invited to attend a detailed clinical examination and blood was drawn for mutation analysis. In two families mutations were identified in exon 8 of the ALK-1 gene. In family 6 we found a T1193A mutation. In this family a high prevalence of PAVM and severe GI bleeding was documented, while in family 8 with a C1120T mutation no individuals with PAVM were identified and only one patient had a history of severe GI bleeding. No mutations in the endoglin locus were found in either family.

[Hereditary hemorrhagic telangiectasia. A population-based study on prevalence and mortality among Danish HHT patients]. / Hereditaer haemoragisk telangiektasi. Et populations-baseret studium af praevalens og mortalitet blandt danske HHT-patienter.

Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable in severity. Early death due to complications has been described. We report an investigation of the prevalence and mortality of HHT in a Danish population, based on two cross-sectional surveys in combination with a long-term follow-up study. The prevalence of HHT in the county of Funen was 13.8 per 100,000 January 1. 1974 and 15.6 per 100,000 January 1. 1995. In the HHT group as a whole we found a slightly increased mortality, however among the HHT patients younger than 60 years at inclusion the mortality of HHT patients was twice the expected. The excess mortality was fully explained by severe HHT symptoms contributing to death. Future research should aim at identification of HHT patients at particular risk of developing severe complications.

Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT).

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease. HHT is characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. OBJECTIVE: To estimate (i) the prevalence of PAVM, and (ii) the occurrence of neurological symptoms in a geographical well-defined population of HHT patients. METHODS: HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for pulmonary arteriovenous malformations and neurological evaluation. Two groups served as controls: (i) first-degree relatives without any signs of HHT; and (ii) age- and gender-matched controls. SETTING: Odense University Hospital. SUBJECTS: HHT patients identified in a cross-sectional family survey carried out in the County of Fyn, Denmark. RESULTS: Included in the study were 169 HHT family members representing 24 families. They included both HHT patients and their first-degree relatives. The criteria of HHT were fulfilled in 75 participants; of these, 59 had a screening procedure performed, and PAVMs were demonstrated at pulmonary angiography (PA) in 18. Seven of the HHT patients had a history of cerebral stroke, compared with none of their healthy first-degree relatives. CONCLUSION: The prevalence of PAVM was 24% amongst HHT patients. The study confirmed an increased prevalence of neurological symptoms amongst HHT patients; the odds ratio was estimated to be 7.6. In order to enable prevention of these complications, screening for PAVM should become an integral part of the medical care for HHT patients.

Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disease with a high prevalence of pulmonary arteriovenous malformations (PAVMs). The first symptom of HHT may be stroke or fatal hemoptysis associated with the presence of PAVM. OBJECTIVE: To evaluate different screening methods applied for the identification of PAVMs. SETTING: Odense University Hospital. SUBJECTS: HHT patients with positive findings on contrast echocardiography (CE) who participated in a screening investigation and underwent pulmonary angiography (PA). METHODS: Different screening methods were evaluated against the results of PA. In a group of patients with positive findings on CE, we compared results of PA with the following: severity of dyspnea; results of pulse oximetry arterial oxygen saturation (SaO2) supine and upright; supine PaO2 in room air and while breathing 100% oxygen; size of arteriovenous shunt in supine position; chest radiograph; and intensity of contrast at CE. RESULTS: PA was performed in 25 HHT patients with positive findings on CE, 15 of whom had PAVM. Embolization therapy was recommended in 12 patients, and 3 patients had small PAVMs not accessible for therapy. In 10 patients, PAVM could not be demonstrated at PA. The sensitivity and specificity calculated for the screening procedures are as follows: 53% and 90%, respectively, for SaO2; 60% and 100%, respectively, for chest radiograph; 73% and 80%, respectively, for PaO2 in room air; 100% and 40%, respectively, for PaO2 breathing 100% oxygen; and 64% and 80%, respectively, for shunt measurement. CONCLUSION: Initial screening with CE followed by measurement of PaO2 while breathing 100% oxygen seemed to be the best screening procedure for identification of patients with PAVM. Screening with chest radiograph and pulse oximetry was shown to be insufficient.

Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients.

INTRODUCTION: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable and include epistaxis, gastrointestinal bleeding, pulmonary arteriovenous malformations and cerebral arteriovenous malformations. Early death due to these complications has been described. DESIGN: We report a study on the prevalence and mortality of HHT in a Danish population based on two cross-sectional surveys in combination with a long-term follow-up study. SETTINGS AND SUBJECTS: Prevalent cases of HHT as of 1 January 1974 in the County of Fyn, Denmark, were identified. In 1995-97 a follow-up study of mortality was performed of the initial patient sample, and a new point prevalence rate of HHT as of 1 January 1995 was calculated. All live patients and their families were invited to attend a detailed clinical examination. RESULTS: The prevalence of HHT in the County of Fyn was 13.8 per 100,000 on 1 January 1974 and 15.6 per 100,000 on 1 January 1995. In the HHT group as a whole, we found a slightly increased mortality; however, amongst the HHT patients younger than 60 years at inclusion the mortality of HHT patients was twice the expected. The excess mortality could be fully explained by severe HHT symptoms. CONCLUSION: This study suggests that HHT is more prevalent than previously believed. In young patients the disease is associated with an excess mortality which is fully attributable to HHT. Future research should aim at the identification of HHT patients at particular risk of developing severe complications.

Embolotherapy for pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

PURPOSE: To evaluate the clinical results of embolization of pulmonary arteriovenous malformations (PAVMs) in patients with hereditary hemorrhagic telangiectasia (HHT), the Rendu-Osler-Weber syndrome. MATERIAL AND METHODS: Twelve patients in the county of Fyn, Denmark, were treated with transcatheter embolization of 20 PAVMs using 12 detachable silicone balloons and 26 steel coils. RESULTS: All PAVMs were completely occluded and we observed a significant rise in PaO2 after treatment and a significant decrease in right-to-left shunt estimated by contrast echocardiography. All patients experienced an improved functional level. One patient experienced severe pleurisy and another a rise in temperature following treatment, but otherwise no symptomatic complications were observed. CONCLUSION: Embolotherapy is a definitive treatment for PAVMs: it is very effective with a high success rate and few complications. Patients with HHT are at risk of PAVM and should be screened and treated for PAVMs when these reach a size that is associated with complications. In the detection of PAVMs, contrast echocardiography is a very sensitive method, and follow-up of these patients can be done with contrast echocardiography.

[Percutaneous transluminal embolization of pulmonary arteriovenous malformations]. / Perkutan transluminal embolisering af pulmonale arteriovenøse misdannelser.

A series of nine patients with pulmonary arteriovenous malformations (PAVM) treated with embolotherapy at Odense University Hospital is presented. In all patients the arterial oxygen tension increased after embolisation. PAVM causes right-to-left shunting, which may result in severe hypoxaemia, and, due to lack of the normal filter function of the lung, paradoxical embolism. Women are particularly at risk during pregnancy. Among patients with Hereditary Haemorrhagic Telangiectasia 15-33% also have PAVM. Embolotherapy is a safe and efficacious treatment for occlusion of PAVM. Since serious complications to the disease can be prevented, all HHT patients should be offered screening for PAVM, and treated if required.

Magnetometry of evoked fields from human peripheral nerve, brachial plexus and primary somatosensory cortex using a liquid nitrogen cooled superconducting quantum interference device.

Superconducting Quantum Interference Devices (SQUIDs) can be used to detect neuromagnetic fields evoked in the peripheral and central nervous system. Up to now, such measurements had to be based on SQUIDs with a low critical temperature (Tc) requiring liquid helium cooling. Recent improvements in high-Tc SQUID technology relying on liquid nitrogen cooling led to a significant reduction in the system's noise level. Hare, first high-Tc recordings of weak neuromagnetic fields are demonstrated. In particular, along the entire somatosensory afferent pathway including peripheral nerves, brachial plexus and primary somatosensory neocortex evoked neuromagnetic activities were detected using conventional recording parameters for bandwidth and number of averages. This opens up a wide perspective for cost-effective high-Tc magnetometry in clinical neuroscience.

Group specific component in serum and otosclerosis: no association.

An earlier Swedish study suggested a positive association between otosclerosis and the group-specific component GC*1F marker. We investigated the distribution of GC subtypes in 101 Danish patients with otosclerosis who all had surgery performed in the county of Funen. Compared to 1674 Danish controls we found no evidence of any association between markers from the GC serum protein system and otosclerosis.

Spatially Resolved Observation of Static Magnetic Flux States in YBa2Cu3O7-dgr Grain Boundary Josephson Junctions.

With low-temperature scanning electron microscopy, the magnetic flux states in high critical temperature Josephson junctions have been imaged. The experiments were performed with YBa(2)Cu(3)O(7-delta) thin-film grain boundary Josephson junctions fabricated on [001] tilt SrTiO(3) bicrystals. For applied magnetic fields parallel to the grain boundary plane, which correspond to local maxima of the magnetic field dependence of the critical current, the images clearly show the corresponding magnetic flux states in the grain boundary junction. The spatial modulation of the Josephson current density by the external magnetic field is imaged directly with a spatial resolution of about 1 micrometer.

Gastrointestinal lesions in hereditary hemorrhagic telangiectasia.

Gastrointestinal bleeding is the most frequent form of bleeding after epistaxis in patients with hereditary hemorrhagic telangiectasia. As a part of an epidemiologic study, gastrointestinal telangiectases could be endoscopically demonstrated in 28 patients with hereditary hemorrhagic telangiectasia, most frequently in the upper gastrointestinal tract and predominantly in the stomach and the duodenum. The typical endoscopic finding was nodular angiomas that did not differ, with regard to form and size, from external telangiectases. However, in 15 patients some of the gastrointestinal telangiectases were surrounded by an anemic halo. A significant difference was found in the age at onset of epistaxis (median 11 yr) and of gastrointestinal bleeding (median 55.5 yr). There was no intrafamilial or interfamilial variation as to heredity and clinical manifestations. The blood group distribution in patients with hereditary hemorrhagic telangiectasia and gastrointestinal telangiectases did not differ from that of other patients with hereditary hemorrhagic telangiectasia, whereas there was a significantly higher frequency of blood group O among patients with hereditary hemorrhagic telangiectasia than among the background population.

Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia.

We reviewed all available chest X-rays of 95 patients with hereditary hemorrhagic telangiectasia (HHT). The diagnosis of pulmonary arteriovenous fistula (PF) had previously been made in 13 patients, nine of whom had been operated on. Another three cases were found in the review. The 16 patients with HHT and PF came from eight families, one of which contributed seven patients. Median observation time between the first and the latest chest X-ray examination was 11 years (range 1/2-35). Growth of the PF was seen in four patients and spontaneous regression in one. Four of the 16 patients with PF had symptoms consistent with cerebral embolism, while only two of the 79 patients without PF had such symptoms. This study is part of an epidemiological investigation of HHT--to our knowledge not carried out before. The calculated period prevalence of simultaneous HHT and PF in the decade 1964-74 in the county of Fyn (429 207 inhabitants) was 2.6 per 100 000.

Endolaryngeal devices for perioperative identification and functional testing of the recurrent nerve.

It has previously been shown that identification of the recurrent laryngeal nerves reduces the risk of injury to the nerves during thyroid surgery. To facilitate identification and to test the conductivity of the recurrent nerves we have used electrical stimulation of the nerves and simultaneous recording of the vocal cord movements with two different endolaryngeal devices. The experience gained with these devices indicates that it is possible to reduce the frequency of injury to the nerves, and the method accelerates the progress of the operation, especially in cancer surgery and repeat operations.

Histological findings following oestrogen treatment of hereditary haemorrhagic telangiectasia. A controlled double-blind investigation.

In a controlled investigation of 22 patients with hereditary haemorrhagic telangiectasia, an evaluation has been carried out of the connective tissue content of muco-substances prior to and after treatment with oral oestrogen (oestradiol valerate 4 mg. daily). The clinical condition of the patients, all of whom had haemorrhagic anaemia, was evaluated by the frequency of epistaxis and by blood analyses. No effect of treatment could be demonstrated by means of histochemical, clinical or laboratory methods.

Long-term results of dermatoplasty in the treatment of hereditary haemorrhagic telangiectasia.

Dermatoplasty for the treatment of epistaxis caused by HHT has become well established. A modification of Saunders' (1960) original dermatoplastic technique is described, which permits the nasolabial incision to be avoided. This retrospective study of the long-term effect on epistaxis caused by HHT demonstrates, in contrast to those with a short period of observation, that epistaxis can be partially controlled by means of dermatoplasty and, further, that it is impossible to eliminate completely the need for blood transfusion. In two of the patients it was found that newly formed telangiectases had occurred in the transplant 15 and 18 years post-operatively.