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Background: Hereditary hemorrhagic telangiectasia (HHT, Rendu- Osler-Weber disease, or Osler's disease for short) is a systemic disease that can severely impair the quality of life and that requires interdisciplinary treatment. Among rare diseases, it is relatively common, with a prevalence of approximately 1/5000., Methods: This review is based on publications retrieved by a selective literature search, including the two international guidelines on clinically relevant aspects of HHT., Results: On average, about two decades elapse between the initial symptoms and the diagnosis of HHT. 95% of patients have nosebleeds; these usually begin before age 20 but can occur at any time, from infancy to old age. The diagnosis is usually made on clinical grounds on the basis of the characteristic telangiectases, a positive family history, and possible involvement of the gastrointestinal tract, lungs, liver, and brain. Nosebleeds can sometimes be reduced by outpatient measures including counseling on keeping the nose moist (expert consensus), self-application of a nasal packing (which improves the quality of life, according to an online survey), and the prescription of tranexamic acid (reduction of nosebleeds from 17.3% [5.5; 27.6] to 54%). In particular, screening (expert consensus) for pulmonary vascular malformations (frequency 10-50%) can prevent many adverse outcomes. If pulmonary vascular malformations cannot be ruled out, antibiotic prophylaxis is recommended before medical procedures that can cause bacteremia (expert consensus)., Conclusion: Broad awareness of the condition, early diagnosis, and interdisciplinary treatment improve the quality of life and ultimate outcome of persons with HHT. Nevertheless, there are few options supported by good evidence for the appropriate treatment of this rare, often serious disease..

Hereditary hemorrhagic telangiectasia (HHT) type 2 is an autosomal dominant disease in which one allele of the ACVRL1 gene is mutated. Patients exhibit disturbances in TGF-beta/BMP-dependent angiogenesis and, clinically, often present with severe nosebleeds as well as a reduced quality of life. The aim of our study was to use CRISPR/Cas9 to knockout ACVRL1 in normal induced pluripotent stem cells (iPSCs) and evaluate the effects on TGF-beta- and BMP-related gene expression as well as angiogenesis. The CRISPR/Cas9 knockout of the ACVRL1 gene was carried out in previously characterized wild-type ( ACVRL1 wt/wt ) iPSCs. An HHT type 2 iPS cell line was generated via a single-allele knockout ( ACVRL1 wt/mut ) in wild-type ( ACVRL1 wt/wt ) iPSCs, resulting in a heterozygous 17 bp frameshift deletion in the ACVRL1 gene [NG_009549.1:g.13707_13723del; NM_000020.3:c.1137_1153del]. After the generation of embryoid bodies (EBs), endothelial differentiation was induced via adding 4 ng/mL BMP4, 2% B27, and 10 ng/mL VEGF. Endothelial differentiation was monitored via immunocytochemistry. An analysis of 151 TGF-beta/BMP-related genes was performed via RT-qPCR through the use of mRNA derived from single iPS cell cultures as well as endothelial cells derived from EBs after endothelial differentiation. Differential TGF-beta/BMP gene expression was observed between ACVRL1 wt/wt and ACVRL1 wt/mut iPSCs as well as endothelial cells. EBs derived from CRISPR/Cas9-designed ACVRL1 mutant HHT type 2 iPSCs, together with their isogenic wild-type iPSC counterparts, can serve as valuable resources for HHT type 2 in vitro studies.

Hereditary haemorrhagic telangiectasia is a rare systemic autosomal dominantly inherited disorder of the fibrovascular tissue with a wide variety of clinical manifestations. Diagnosis is based on the clinical Curaçao criteria or molecular genetic testing. Dilated vessels can develop into telangiectases or larger vascular malformations in various organs, calling for an interdisciplinary approach. Epistaxis and gastrointestinal bleeding can result from these vascular defects. Various conservative and interventional treatments have been described for these conditions. However, no optimal therapy exists. Treatment can become especially difficult due to progressive anaemia or when anticoagulant or anti-thrombotic therapy becomes necessary. Screening for pulmonary arteriovenous malformations (PAVM) should be performed in all confirmed and suspected patients. Treatment by percutaneous transcatheter embolotherapy and antibiotic prophylaxis is normally effective for PAVM. Cerebral or hepatic vascular malformations and rare manifestations need to be evaluated on a case-by-case basis to determine the best course of action for treatment., (© 2015 John Wiley & Sons Ltd.)

Introduction: Epistaxis is the most frequent manifestation in hereditary hemorrhagic telangiectasia, in which no optimal treatment exists. It can lead to severe anemia and reduced quality of life. Positive effects of tranexamic acid, an antifibrinolytic drug, have been reported on epistaxis related to this disorder. We sought to evaluate the efficacy of treating nosebleeds in hereditary hemorrhagic telangiectasia with tranexamic acid., Materials and Methods: In a randomized, double-blind, placebo controlled, cross-over phase IIIB study, 1 gram of tranexamic acid or placebo was given orally 3 times daily for 3 months for a total of 6 months., Results: 22 patients were included in the intention-to-treat analysis. Hemoglobin levels, the primary outcome measure, did not change significantly (p=0.33). The secondary outcome measure was epistaxis score and patients reported a statistically significant reduction in nosebleeds, equaling a clinically relevant 54% diminution (p=0.0031), as compared to the placebo period. No severe side effects were observed., Conclusion: Tranexamic acid reduces epistaxis in patients with hereditary hemorrhagic telangiectasia. (Clinical trial registration numbers: BfArM 141 CHC 9008-001 and ClinicalTrials.gov NCT01031992)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The olfactory and gustatory functions of hereditary hemorrhagic telangiectasia (HHT) patients have not been documented by validated tests. Disorders of the nasal/oral cavity may interfere with the olfactory and gustatory functions. Fifty-four HHT patients were investigated by smell/taste tests., Methods: HHT patients provided subjective ratings in areas such as ability to perceive smell/taste. "Sniffin' Sticks" were used for smell tests, and taste strips were used for taste tests., Results: HHT patients rated their subjective olfactory and gustatory function on a visual analog scale from 0 (none) to 100 (high) as 65.3 ± 27.7 and 68.1 ± 25.1, respectively. Comparison of smell test results of HHT patients with normative data of sex- and age-matched controls from Hummel et al. revealed that HHT patients had lower threshold values, whereas there was no difference in identification and discrimination values. HHT patients were hyposmic. In the case of taste qualities, all values (sweet, sour, salty, and bitter) in HHT patients were lower than those in normative data of Mueller et al. However, HHT patients were not hypogeusic. The duration of disease, extranasal manifestation, and treatments did not significantly correlate with smell/taste test values., Conclusion: Compared with healthy people, HHT patients exhibit reduced olfactory and gustatory function; however, HHT patients are hyposmic and not hypogeusic. This chemosensory deficit may highlight an early sign of disease and has no correlation with disease severity. HHT patients should be informed about these potential disease manifestations, thus enabling them to improve their quality of life.

Background: Surgical treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT) has historically been managed with the laser procedure or the septodermoplasty procedure. For transfusion-dependent patients with severe epistaxis we have been performing the Young's procedure or surgical closure of the nostrils. The objective of this study was to report treatment of severe epistaxis related to HHT with the Young's procedure and assess patient outcome., Methods: Patients with severe iron or blood transfusion-dependent epistaxis who underwent a Young's procedure in three otolaryngology HHT centers were reviewed. Patients were evaluated for postoperative epistaxis and subjective outcome., Results: Forty-three patients underwent a Young's procedure for severe epistaxis and were observed for a mean of 34 months. The procedure was well tolerated by all patients and 30 of 36 patients (83%) experienced complete cessation of bleeding after the Young's procedure. Patients had a mean increase in hemoglobin of 4.68 g/dL after the procedure. The average Glasgow Benefit Inventory score after surgery was 43.56. No patients requested a reversal of the procedure., Conclusion: The Young's procedure is a safe and efficacious procedure with complete cessation of epistaxis in most patients with severe epistaxis and HHT.

Diagnosis and treatment of rare diseases are difficult. Hereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber disorder) is a relatively common rare disease. Because epistaxis is the most frequent manifestation of this disease, affected individuals often approach otorhinolaryngologists first. The latter ones often have a key position for early diagnosis and screening for visceral involvement which can prevent life-threatening complications. Treatment of epistaxis can improve quality of life of affected persons. Diagnosis and treatment of rare diseases can be complex and it can be very helpful to use information resources to ensure a correct management. Various possibilities to access these resources are presented in general and in relation to HHT., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults., Objective: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease., Methods: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches., Results: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, telangiectasia and visceral vascular manifestations. It is associated with migraine with aura due to pulmonary arteriovenous malformations (pAVMs). The aim of the study was to evaluate headache prevalence in 106 consecutive HHT patients (67 female, 39 male, age 53.5 +/- 14.5 years) and age- and gender-matched controls. An extensive clinical work-up was performed and headache prevalence was determined. Lifetime prevalence of migraine was higher in HHT patients (39.6%) than in controls (19.8%) [P < 0.001, chi(2) = 12.17, odds ratio (OR) 3.0; 95% confidence interval 1.6 < OR < 5.7]. A positive association was confirmed between HHT patients with pAVMs and migraine with aura (38.5% vs. 10%). Furthermore, HHT patients without pAVMs had a higher prevalence of migraine without aura (11.5% vs. 26.3%; chi(2) = 11.85; d.f. = 2; P = 0.003). We speculate that pathophysiological mechanisms, including dysfunction of the transforming growth factor-beta pathways and resulting vascular changes, contribute to the higher prevalence of migraine without aura in HHT patients without pAVMs.

Background: Hereditary hemorrhagic telangiectasia (HHT) is a systemic disorder of the fibrovascular tissue. Few data have been published on the frequency of ophthalmologic manifestations. The aim of this study was to assess this frequency., Methods: A prospective observational cross-sectional study was conducted in a multitude of clinical practices and in a tertiary referral center. The main outcome measure was the number of vascular malformations detected by an ophthalmologic inspection of the retina and the conjunctivae in both eyes in a random sample of patients with HHT., Results: No retinal telangiectases were observed in any of the 75 patients (150 eyes) examined. Conjunctival telangiectases were detected in 28 of 74 patients (47 of 148 eyes)., Conclusions: The prevalence of retinal telangiectases seems to be lower than 1/75 (< 1.3%). This data does not justify screening procedures to detect retinal telangiectases. Ophthalmologists should be aware of the symptoms of HHT and its systemic character.

Objective: To assess and differentiate the health-related quality of life (HR-QoL) in patients with hereditary hemorrhagic telangiectasia (HHT)., Study Design and Setting: A prospective, open, cross-sectional questionnaire-based study (including the Short Form-36 Health Survey [SF-36]) performed by a tertiary care center., Results: A total of 77 patients (36 females) were included. Except for one domain (bodily pain), the scores for all scales of the SF-36 were significantly reduced in comparison with normative data. The duration of epistaxis, the presence of hepatic involvement and gastrointestinal bleeding, and the number of visible telangiectases correlated with lower scores on several scales of the SF-36. Unexpectedly, the frequency of epistaxis did not correlate with any scale., Conclusions: The duration of epistaxis, liver involvement, gastrointestinal bleeding, and the number of visible telangiectases have a major influence on the HR-QoL in HHT whereby the frequency of epistaxis seems to play a minor role., Significance: The data presented have an impact on therapeutic decisions, medical expert opinions, and research funding.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal-dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasias and visceral arteriovenous malformations. Mutations in endoglin (ENG) and activin A receptor type II-like kinase 1 (ACVRL1 or ALK1) have been found in patients with HHT. We have screened a total of 51 unselected German index cases with the suspected diagnosis of HHT. We identified 30 different mutations in 32 cases (62.7%) by direct sequencing. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. Two of the ACVRL1 mutations were each shared by two families. An analysis of the genotype-phenotype correlation is consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in patients with ACVRL1 mutations in our collective.

Background: Hereditary hemorrhagic telangiectasia is characterized by angiodysplastic lesions. So far, knowledge is limited on the vascular architecture and rate of occult manifestation of telangiectases. Contact endoscopy has not been used for this task before., Methods: Eleven patients with hereditary hemorrhagic telangiectasia were examined with contact endoscopy to identify occult telangiectases. Sixty enoral telangiectases were studied in detail to characterize their architecture., Results: No occult telangiectases could be detected. In most cases, telangiectases consisting of a simple dilated loop were small. In contrast, most of the complex telangiectases were larger., Conclusions: Visually normal areas in patients with hereditary hemorrhagic telangiectasia did not seem to have abnormal vascularization. Simple dilated capillary loops might be precursors of telangiectases with a more complex structure. Contact endoscopy seems to be a promising tool for the in vivo monitoring of therapies and the natural course of vascular disorders in humans and in animal models., ((c) 2005 Wiley Periodicals, Inc. Head Neck 27: XXX-XXX, 2005.)

No optimal treatment modality is currently available for the treatment of recurrent epistaxis in HHT. In this review, different therapeutic concepts are discussed together with their pathophysiologic background. Patients often profess a preventive effect for nasal ointments and use packings which can be self-administered in the case of bleeding. An effective first-line treatment for physicians is the endonasal laser coagulation or argon plasma coagulation. A second line surgical procedure is septodermoplasty according to Saunders which can provide long-lasting relief if performed correctly. There have been reports on antifibrinolytic agents and hormones, but their efficacy has yet to be determined.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of the vascular connective tissue. Pulmonary arteriovenous and cerebral vascular malformations are risk factors for serious neurological complications such as paradoxical embolism and intracranial hematomas. We describe two patients with HHT and pulmonary arteriovenous malformations suffering from stroke caused by paradoxical embolism. In both cases, fistulas were successfully treated by embolisation and no further cerebral ischemic events occurred. In ischemic strokes of unknown origin, HHT should be considered as a possible diagnosis with effective treatment options.

Hereditary hemorrhagic teleangiectasia (HHT or Rendu-Osler-Weber Syndrome) is an inherited autosomal dominant disorder of the vascular connective tissue. The resulting vascular malformations can occur in virtually any organ. Nosebleeds can massively impact on the quality of life of those afflicted. However, visceral manifestations are likely to be more serious, and may be comparable with a "ticking time bomb". Most commonly affected are the vascular systems of the lungs, liver, brain and gastrointestinal tract. Screening is recommended--at least with regard to the lungs. Difficult constellations of this complex condition may be successfully managed by an interdisciplinary approach.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterised by epistaxis, telangiectases, and visceral manifestations. The two known disease types, HHT1 and HHT2, are caused by mutations in the endoglin (ENG) and ALK-1 genes, respectively. A higher frequency of pulmonary arteriovenous malformations (AVMs) has been reported for HHT1 while HHT2 is thought to be associated with a lower penetrance and milder disease manifestations. In this study, we present 10 families with an ALK-1 genotype. Visceral manifestations were detected in 24 (26%) of the 93 HHT2 patients from nine of the families and included gastrointestinal bleeding (14%), intrahepatic shunts (6%), and AVMs in the lung (4%) and brain (3%). Gastrointestinal bleeding, the most frequent visceral manifestation, was reported in six of the 10 families, mostly in patients over the age of 50. These patients also had frequent epistaxis and suffered from anaemia, often requiring blood transfusions. The identification of ALK-1 mutations in subjects with a suspected diagnosis and without clinical signs of HHT argue in favour of a molecular diagnosis. We also analysed the data published on 44 families with HHT2 and conclude that visceral manifestations occur in 26 of these families and affect 30% of HHT2 patients. This is considered an underestimate given incomplete and variable screening for lung, brain, and/or liver involvement in different clinical centres. These findings, however, stress the need for an early diagnosis of HHT that can be useful for the early control of associated visceral involvement.

Numerous internal diseases can express themselves in the form of ENT manifestations. Epistaxis is one of the most common emergencies seen by the ENT specialist. Possible underlying systemic etiologies may be hypertension, systemic anticoagulation or even rare entities such as hereditary hemorrhagic telangiectasia. Internal-medical conditions underlying hoarseness are usually injuries to the recurrent nerve with lesions of the thyroid gland and mediastinum being prominent. Modern electrophysiological techniques permit early prognostication of the chances of healing a vocal cord paresis. A number of surgical procedures for improving vocal problems in the treatment of irreversible paresis are available. Unclear cervical swellings prompt a wide range of possible differential diagnoses that differ dramatically in terms of both treatment and outcome. For this reason, a rational, interdisciplinary diagnostic work-up is essential. In light of the risk of delaying the diagnosis and worsening the outcome, uncritical primary sampling of such tissue must be avoided.

Background: Hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber disease) is an autosomal dominant inherited disease of the fibrovascular tissue. More than 90% of patients have recurrent nosebleeds. Therefore, ENT physicians often have a key position for diagnosis and management of the disease. Epistaxis can severely reduce the quality of life, but visceral lesions are also life threatening., Methods: This paper provides a review of the literature about the disease, its diagnosis, preventive measures, and therapy of the different manifestations., Results and Conclusions: Physicians should be especially aware of gastrointestinal telangiectases, arteriovenous malformations (AVM) of the lungs, liver, and brain. A screening is recommended at least for pulmonary AVM.

Rendu-Osler-Weber disease is an autosomally dominant inherited disease which affects the connective tissue of blood vessels. The major symptom is recurrent epistaxis for which still exists no generally recommended treatment. Treatment modalities discussed in the literature include bilateral closure of the nostrils, brachytherapy, vessel embolization, hormone therapy, dermoplasties, as well as different kinds of laser therapies. Advantages and disadvantages of single treatment modalities are discussed. Dermoplasty and laser therapy seem to be the most suitable treatment procedures currently available for recurrent epistaxis in affected patients. Treatment carried out with the argon, KTP or ND:YAG laser has proven to be suitable as initial therapy. In most cases the additional use of long-term applications of a soft nasal ointment allows a lasting successful treatment. Our experiences show that dermoplasty should be reserved for cases with continued bleeding despite laser treatment but only rarely offers a long-term cure in the sense of a total recovery from epistaxis.

Background: Epistaxis is the leading symptom of hereditary hemorrhagic teleangiectasia (HHT). Over the last years several laser systems have been used for therapy. Only a few studies have published results of Nd:YAG laser therapy evaluating a larger number of patients., Patients and Methods: From 1987 through 1996, forty-one patients with HHT were treated with a Nd:YAG laser due to recurrent epistaxis at the Department of Otorhinolaryngology of Kiel University. Thirty-two patients were followed-up over a period of at least 24 months. A centripetal technique was used for endonasal laser light application (15-25 Watts; 0.1-0.5 s), i.e., the laser light was applied from the periphery towards the center of the angiodysplasia. Intensive preoperative and postoperative nasal care with ointments was performed., Results: Bleeding frequency and intensity decreased in 30 (94%) patients. Duration of the therapeutical success differed individually and varied from seven weeks to 14 months. Repeated laser therapy was necessary in 27 of 32 patients., Conclusion: The Nd:YAG laser is a suitable tool in the treatment of epistaxis in HHT. This procedure is less traumatic, less painful, and can be repeated multiple times. Nd:YAG laser therapy and other therapeutic options cannot obtain a lasting cure of Rendu-Osler-Weber syndrome. However, in the vast majority of cases recurrent nasal bleeding as the dominant symptom can be reduced in frequency as well as in intensity.