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Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM)., Aim: to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT)., Methods: parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast., Results: between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy., Conclusion: This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642-649. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular multi-organ system disorder. Its diagnostic criteria include epistaxis, telangiectases in mucocutaneous sites, arteriovenous malformations (AVMs), and familial inheritance. HHT is transmitted as an autosomal dominant condition, caused in 85% of cases by mutations in either Endoglin (ENG) or Activin receptor-like kinase (ACVRL1/ACVRL1/ALK1) genes. Pathogenic mutations have been described in exons, splice junctions and, in a few cases with ENG mutations, in the proximal promoter, which creates a new ATG start site. However, no mutations affecting transcription regulation have been described to date in HHT, and this type of mutation is rarely identified in the literature on rare diseases., Methods: Sequencing data from a family with HHT lead to single nucleotide change, c.-58G > A. The functionality and pathogenicity of this change was analyzed by in vitro mutagenesis, quantitative PCR and Gel shift assay. Student t test was used for statistical significance., Results: A single nucleotide change, c.-58G > A, in the proximal ENG promoter co-segregated with HHT clinical features in an HHT family. This mutation was present in the proband and in 2 other symptomatic members, whereas 2 asymptomatic relatives did not harbor the mutation. Analysis of RNA from activated monocytes from the probands and the healthy brother revealed reduced ENG mRNA expression in the HHT patient (p = 0.005). Site-directed mutagenesis of the ENG promoter resulted in a three-fold decrease in luciferase activity of the mutant c.-58A allele compared to wild type (p = 0.005). Finally, gel shift assay identified a DNA-protein specific complex., Conclusions: The novel ENG c.-58G > A substitution in the ENG promoter co-segregates with HHT symptoms in a family and appears to affect the transcriptional regulation of the gene, resulting in reduced ENG expression. ENG c.-58G > A may therefore be a pathogenic HHT mutation leading to haploinsufficiency of Endoglin and HHT symptoms. To the best of our knowledge, this is the first report of a pathogenic mutation in HHT involving the binding site for a transcription factor in the promoter of ENG.

Purpose of Review: Hereditary hemorrhagic telangiectasia (HHT), or Osler Weber-Rendu disease, is a rare inherited disorder of fibrovascular tissue affecting various organs. Epistaxis is the most common symptom of HHT but as the disease affects multiple organs, a multisystem and multidisciplinary approach to management is required. The purpose of this article is to provide an overview of the multidisciplinary approach to HHT for the otolaryngologist and to discuss the current pharmacologic and procedural treatment options available for HHT-related epistaxis., Recent Findings: Multidisciplinary expert guidelines have better defined what screening tests are advised for the multisystem evaluation of the HHT patient. New pharmacologic therapies including bevacizumab (Avastin) used submucosally or topically have shown promise as in-office treatment modalities. Sclerotherapy of telangiectasia, including in-office applications, has recently proven safe and effective., Summary: HHT remains a difficult disease to treat. Being aware of the common organ systems involved by the disease will help the practicing otolaryngologist to ensure the patient receives appropriate multidisciplinary care. For HHT-related epistaxis, new medical and surgical options allow for a wider range of treatments than were previously available.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that can lead to frequent and severe sequelae. Although the condition has no cure, many of its physical symptoms can be managed to improve the quality of life and lower the risk of life-threatening complications. This article discusses HHT presentation, genetic screening, diagnosis, and management. The management of HHT can involve interventional radiology techniques, particularly for patients with pulmonary arteriovenous malformations.

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant inherited disease that is usually complicated by visceral vascular malformations. Patients harboring such malformations are at increased risk of brain abscess formation, which despite advances in diagnostic and surgical methods remains a life threatening medical emergency with high mortality and morbidity rates. In the present report we describe a case of cerebral abscess due to silent pulmonary arteriovenous malformation (AVM) in a young patient previously undiagnosed for hereditary hemorrhagic telangiectasia syndrome (HHT)., Competing Interests: The authors declare no competing interest.

A 5-year-old boy was admitted due to shortness of breath. Blood gas analysis showed hypoxemia. However, thoracic and abdominal CT, brain MRI, and MR angiography were all normal. A Tc-MAA pulmonary scintigraphy revealed right-to-left shunting of the blood. Further genetic analysis showed the mutations in the activin receptor-like kinase 1 gene, and a diagnosis of hereditary hemorrhagic telangiectasia was made.

Objective: To determine whether patients with hereditary haemorrhagic telangiectasia were being screened according to international guidelines, and to review recent evidence in order to provide up-to-date guidelines for the initial systemic management of hereditary haemorrhagic telangiectasia., Methods: A retrospective case note analysis was conducted, assessing patients in terms of screening for: genetics, cerebral arteriovenous malformations, pulmonary and hepatic arteriovenous malformations, and gastrointestinal telangiectasia. Databases searched included Medline, the Cumulative Index to Nursing and Allied Health Literature, and Embase., Results: Screening investigations were most frequently performed for hepatic arteriovenous malformations and least frequently for genetics. Recent data suggest avoiding routine genetic and cerebral arteriovenous malformation screening because of treatment morbidities; performing high-resolution chest computed tomography for pulmonary arteriovenous malformation screening; using capsule endoscopy (if possible) to reduce complications from upper gastrointestinal endoscopy; and omitting routine liver enzyme testing in favour of Doppler ultrasound., Conclusion: Opportunities for systemic arteriovenous malformation screening are frequently overlooked. This review highlights the need for screening and considers the form in which it should be undertaken.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).

Hereditary hemorrhagic telangiectasia is a rare, autosomal dominant genetic disease that causes abnormal growth of blood vessels and, subsequently, life-threatening arteriovenous malformations in vital organs. Epistaxis may be one of the initial clues that a patient has more serious, generalized arteriovenous malformations. Recommended treatment involves careful evaluation to determine the severity and risk of spontaneous rupture of the malformations and the management of various signs and symptoms. The disease remains undiagnosed in many patients, and health care providers may miss the diagnosis until catastrophic events happen in multiple family members. Prompt recognition of hereditary hemorrhagic telangiectasia and early intervention can halt the dangerous course of the disease. Critical care nurses can assist with early diagnosis within families with this genetic disease, thus preventing early death and disability., (©2016 American Association of Critical-Care Nurses.)

A 72-year-old female patient presented with increasing dyspnea of unclear origin classified as New York Heart Association stage III (NYHA III). Using transesophageal echocardiography a patent foramen ovale (PFO) and right heart failure could be diagnosed. Right heart catheterization revealed a large left to right shunt due to an arteriovenous malformation in the liver. Because of additional telangiectasia of the lips the presumptive diagnosis was Rendu-Osler-Weber disease. Typical nosebleeds and other symptoms of the disease were lacking and only two out of four Curaçao criteria were positive; therefore, genetic testing was performed, which verified the clinical diagnosis. Off-label use of the angiogenesis inhibitor bevacizumab was initiated as the therapeutic strategy and led to an improvement in the symptomatic dyspnea.

Hereditary hemorrhagic telangiectasia (HHT), or Osler- Weber-Rendu syndrome, is a rare genetic disorder with autosomal dominant inheritance, characterized by recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations (AVMs), which may lead to severe complications. The diagnosis of HHT is often delayed due to the rarity of the disease, and the variety of clinical manifestations. The management of HHT includes systematic screening for visceral AVMs at regular intervals, preventive interventions to reduce the risk of complications, and symptomatic measures. A multidisciplinary standardized program in specialised centers may improve the management of patients with HHT.

Background: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death., Method: We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands)., Results: Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years)., Conclusion: Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

Objective: To determine the role of Gja5 that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model., Approach and Results: We identified GJA5 as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the Acvrl1(+/-) mutant mice that develop lesions similar to those in patients with HHT2 and generated Acvrl1(+/-); Gja5(EGFP/+) mice. Gja5 haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in Acvrl1(+/-) mice. At the molecular level, we found that reduced Gja5 in Acvrl1(+/-) mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in Acvrl1(+/-); Gja5(EGFP/+) mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults., Conclusions: We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events-heterozygosity, loss of heterozygosity, and angiogenic stimulation-are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development., (© 2016 American Heart Association, Inc.)

The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or β1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng (+/-) mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.

Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Eng(fl/fl)LysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Eng(fl/fl)LysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is an autosomal dominant inherited disease defined by the presence of epistaxis and mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in internal organs. In most families (~85%), HHT is caused by mutations in the ENG (HHT1) or the ACVRL1 (HHT2) genes. Here, we report the results of genetic testing of 113 Norwegian families with suspected or definite HHT. Variants in ENG and ACVRL1 were found in 105 families (42 ENG, 63 ACVRL1), including six novel variants of uncertain pathogenic significance. Mutation types were similar to previous reports with more missense variants in ACVRL1 and more nonsense, frameshift and splice-site mutations in ENG. Thirty-two variants were novel in this study. The preponderance of ACVRL1 mutations was due to founder mutations, specifically, c.830C>A (p.Thr277Lys), which was found in 24 families from the same geographical area of Norway. We discuss the importance of founder mutations and present a thorough evaluation of missense and splice-site variants., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hereditary haemorrhagic telangiectasia (HHT) is characterized by the development of arteriovenous malformations--enlarged shunts allowing arterial flow to bypass capillaries and enter directly into veins. HHT is caused by mutations in ALK1 or Endoglin; however, the majority of arteriovenous malformations are idiopathic and arise spontaneously. Idiopathic arteriovenous malformations differ from those due to loss of ALK1 in terms of both location and disease progression. Furthermore, while arteriovenous malformations in HHT and Alk1 knockout models have decreased NOTCH signalling, some idiopathic arteriovenous malformations have increased NOTCH signalling. The pathogenesis of these lesions also differs, with loss of ALK1 causing expansion of the shunt through proliferation, and NOTCH gain of function inducing initial shunt enlargement by cellular hypertrophy. Hence, we propose that idiopathic arteriovenous malformations are distinct from those of HHT. In this review, we explore the role of ALK1-NOTCH interactions in the development of arteriovenous malformations and examine a possible role of two signalling pathways downstream of ALK1, TMEM100 and IDs, in the development of arteriovenous malformations in HHT. A nuanced understanding of the precise molecular mechanisms underlying idiopathic and HHT-associated arteriovenous malformations will allow for development of targeted treatments for these lesions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The incidence of hereditary haemorrhagic telangiectasia (HHT - Osler-Weber-Rendu disease) in the Netherlands is 1:5000 but approximately 1:1300 in people from the Antilles. The disease is characterised by the development of telangiectasia and arteriovenous malformations (AVMs) that may result in serious morbidity and mortality., Case Description: A 31-year-old primigravid patient consulted her general practitioner at 31 1/7 weeks gestational age with dyspnoea. She was referred for further diagnostics because of suspected pulmonary embolism. A CT scan showed haemothorax and a bleeding arteriovenous malformation (AVM) in the left lung. Family history suggested the possibility of HHT. After multidisciplinary consideration, a primary caesarean section was performed, followed by embolisation of the AVM during the same surgical session. The patient had a gene mutation consistent with HHT type 2., Conclusion: Pregnant patients with HHT are at risk of serious morbidity, especially if they are not screened for AVMs. A multidisciplinary approach for such patients, with consideration of various scenarios, is highly recommended.

Purpose of Review: Moyamoya and arteriovenous malformations represent, respectively, significant sources of ischemic and hemorrhagic stroke in children after the first year of life. Although rarely encountered in routine pediatric practice, the potential severe morbidity of these entities, coupled with the typical acuity of their presentation, merit ongoing awareness of current relevant diagnostic and therapeutic strategies., Recent Findings: Mutations in RNF213, ACTA2, and GUCY are implicated in moyamoya. Several common pediatric conditions - trisomy 21, sickle-cell disease, and neurofibromatosis type I - demonstrate an increased risk of moyamoya development. Advances in imaging have improved the diagnosis of moyamoya and surgical revascularization has been further supported as the primary treatment.Genetic associations with arteriovenous malformations (AVMs) are few outside of hereditary hemorrhagic telangiectasia. Within this population, the majority harbor mutations in ENG and ACVRL. Once screened, if no AVM is found, repeat scanning may not be needed for 5 years. Trauma and infection may not be 'triggers' for inducing hemorrhage in patients with untreated AVMs. If found in children, evidence supports the treatment of the AVM, ideally with surgery., Summary: Moyamoya and AVMs are rare but important causes of stroke in children. If identified, it is important to refer the children to pediatric centers with experienced neurovascular teams. Surgical revascularization of moyamoya and resection of AVMs should be strongly considered, including incidentally discovered asymptomatic disease.

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.)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominantly inherited vascular-malformation syndrome associated with gene mutations including ENG, ACVRL1 and SMAD4 gene. Clinically indistinguishable HHT1 and HHT2 are caused by mutations in ENG and ACVRL1 gene, respectively. Generally, pulmonary arteriovenous malformations (PAVMs) and pulmonary arterial hypertension (PAH) are rare manifestations of HHT related to ACVRL1 gene mutations. We described a female patient with HHT2 whose clinical features included epistaxis, mucocutaneous telangiectases, systemic AVMs and PAH. She also suffered from severe iron deficiency anemia and recurrent heart failure. A genetic mutation analysis disclosed a missense mutation in exon 7 of ACVRL1 gene in this patient and her daughter. A nonsense mutation in exon 7 of ACVRL1 gene was detected in her brother and her niece. This case supports that PAVMs and PAH can be rare manifestations of HHT2 patients.

Hereditary hemorrhagic telangiectasia (HHT) is a hereditary condition that results in vascular malformations throughout the body, which have a proclivity to rupture and bleed. HHT has a worldwide incidence of about 1:5000 and approximately 80 % of cases are due to mutations in ENG, ALK1 (aka activin receptor-like kinase 1 or ACVRL1) and SMAD4. Over 200 international clinicians and scientists met at Captiva Island, Florida from June 11-June 14, 2015 to present and discuss the latest research on HHT. 156 abstracts were accepted to the meeting and 60 were selected for oral presentations. The first two sections of this article present summaries of the basic science and clinical talks. Here we have summarized talks covering key themes, focusing on areas of agreement, disagreement, and unanswered questions. The final four sections summarize discussions in the Workshops, which were theme-based topical discussions led by two moderators. We hope this overview will educate as well as inspire those within the field and from outside, who have an interest in the science and treatment of HHT.

Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.

A 58-year-old woman presented with intermittent passage of bright red blood from the rectum, progressive fatigue, and dyspnea. Examination revealed telangiectasias on the labial mucosa and nail folds. Her mother was reported to have frequent epistaxis and similar skin lesions.

Mutations in SMAD4 have been associated with juvenile polyposis syndrome and combined juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. SMAD4 is part of the SMAD gene family. To date, there has been no report in the literature of a SMAD4 pseudogene. An unusual SMAD4 duplication pattern was seen in multiple patient samples using two different duplication/deletion platforms: multiplex ligation-dependent probe amplification and chromosomal microarray. Follow-up confirmatory testing included real-time quantitative PCR and sequencing of an exon/exon junction, all results leading to the conclusion of the existence of a processed pseudogene. Examination of clinical results from two laboratories found a frequency of 0.26% (12 in 4672 cases) for this processed pseudogene. This is the first report of the presence of a processed pseudogene for SMAD4. We believe that knowledge of its existence is important for accurate interpretation of clinical diagnostic test results and for new assay designs. This study also indicates how a processed pseudogene may confound quantitative results, dependent on placement of probes and/or primers in a particular assay design, potentially leading to both false-positive and false-negative results. We also found that the SMAD4 processed pseudogene affects next-generation sequencing results by confounding the alignment of the sequences, resulting in erroneous variant calls. We recommend Sanger sequencing confirmation for SMAD4 variants., (Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder of fibrovascular tissues. Patients with HHT often develop life-threatening bleeds from telangiectasias in the nasal or gastrointestinal mucosa or from visceral arteriovenous malformations. Recurrent oral bleeds are rare presentations in these patients and are seldom reported. This report describes a rare case of 72-year-old man with a known history of HHT who presented with a recurrent life-threatening oral bleed from telangiectasia of the palate and reviews the literature for current trends of medical and dental management. This study is an effort to draw the attention of oral physicians and surgeons to such drastic complications of the disease and various current treatment modalities., (Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Recurrent epistaxis in hereditary haemorrhagic telangiectasia (HHT) patients significantly decreases their quality of life. Treatment in therapy refractory patients is limited although various options have been tested so far., Case Report: Herein, one patient is described that was treated for HHT for over 20 years with only intermediate benefits. As epistaxis duration and frequency increased continuously, bevacizumab 5 mg/kg was administered every 2 weeks. During the time of treatment (six doses) and up to 3 month afterwards clinical symptoms, blood pressure, cardiac output, pulmonary arterial hypertension (PAH), bleeding duration and frequency were assessed as criteria for treatment benefit., Results: Duration and frequency of epistaxis decreased immediately after the first application resulting in reduced need of blood transfusions. After completion of six cycles, a further decrease in frequency and duration of bleeding was noted. Cardiac output and PAH decreased or remained stable, respectively, during time and after treatment. No increase in blood pressure could be found but a significant increase in heart rate was experienced after completion of all six applications. Unfortunately, the patient died due to a cerebral abscess., Conclusion: Bevacizumab led to an improvement of HHT related epistaxis, refractory to other treatments.

Hereditary Hemorrhagic Telangiectasia syndrome (HHT) or Rendu-Osler-Weber (ROW) syndrome is an autosomal dominant vascular disorder. Two most common forms of HHT, HHT1 and HHT2, have been linked to mutations in the endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1or ALK1) genes respectively. This work was designed to examine the pathogenicity of 23 nucleotide variations in ACVRL1 gene detected in more than 400 patients. Among them, 14 missense mutations and one intronic variant were novels, and 8 missense mutations were previously identified with questionable implication in HHT2. The functionality of missense mutations was analyzed in response to BMP9 (specific ligand of ALK1), the maturation of the protein products and their localization were analyzed by western blot and fluorescence microscopy. The splicing impairment of the intronic and of two missense mutations was examined by minigene assay. Functional analysis showed that 18 out of 22 missense mutations were defective. Splicing analysis revealed that one missense mutation (c.733A>G, p.Ile245Val) affects the splicing of the harboring exon 6. Similarly, the intronic mutation outside the consensus splicing sites (c.1048+5G>A in intron 7) was seen pathogenic by splicing study. Both mutations induce a frame shift creating a premature stop codon likely resulting in mRNA degradation by NMD surveillance mechanism. Our results confirm the haploinsufficiency model proposed for HHT2. The affected allele of ACVRL1 induces mRNA degradation or the synthesis of a protein lacking the receptor activity. Furthermore, our data demonstrate that functional and splicing analyses together, represent two robust diagnostic tools to be used by geneticists confronted with novel or conflicted ACVRL1 mutations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by aberrant vascular development. Mutations in two genes, endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) are associated with HHT. The present case study revealed the molecular diagnosis in a family exhibiting the clinical features of HHT disease. The coding exon and flanking intronic regions of the ENG and ACVRL1 genes were sequenced and a novel mutation in exon 10 of ENG was observed in the family. The mutation (c.1426C>T) in exon 10 of the ENG gene caused a G476X mutation, which results in a premature stop codon and a truncated ENG protein. This finding demonstrated a novel mutation in the ENG gene in a Chinese family, which suggested that a truncated ENG protein may cause HHT. The present study established a genetic test to confirm the clinical diagnosis in individuals and provide an opportunity for early detection and management of the disease.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR = 1.48, P = 0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR = 2.66, P = 0.022), but not ACVRL1 (OR = 0.79, P = 0.52) mutations. ACVRL1 c.314-35A>G was also associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM., (© 2015 Wiley Periodicals, Inc.)

Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder associated with pulmonary AVMs (PAVMs), present in about 30-50% of patients. Dyspnea is frequently reported by about one-half of patients with PAVMs and has been related to the degree of right to left shunting. However, many HHT patients with PAVMs remain asymptomatic and those without PAVMs have been observed to have dyspnea, the cause of which has not been characterized. The study objectives were to determine the prevalence of dyspnea and its etiology in the HHT population., Methods: Retrospective review of over 1000 patients at an HHT Center of Excellence from 1997 to 2010. Patients were categorized as definite HHT if they met ≥3 clinical diagnostic criteria or had a positive genetic diagnosis. Patients were unlikely to have HHT (non-HHT) if they had 1 or fewer diagnostic criteria. Data on dyspnea prevalence (MMRC ≥ 1), PAVMs, underlying cardio-pulmonary disease, symptomatic liver venous malformations, anemia and obesity was reviewed., Results: 506 patients were categorized as having HHT, of which 202 (40%) had confirmed PAVMs. Dyspnea prevalence was 35% (178/506) vs. 18% (50/284, p < 0.0001) in the HHT and non-HHT patients, respectively. With multivariable logistic regression, the odds of dyspnea (MMRC ≥1) was 3.45 (95% CI 2.08-5.71) with the presence of PAVMs in HHT patients. Other independent predictors of dyspnea were older age, underlying cardio-pulmonary disease, anemia, and obesity., Conclusion: Prevalence of dyspnea is significant, evident in about one-third of HHT patients, often associated with PAVMs. It is important to consider other etiologies for dyspnea when assessing patients with HHT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Hereditary hemorrhagic telangiectasia (HHT) occasionally can be discovered in patients with cerebrovascular disease. Pulmonary arteriovenous malformation (PAVM) is one of the complications in HHT and occasionally is causative for life-threatening embolic stroke. Several genetic defects have been reported in patients with HHT. The broad spectrum of phenotype and intrafamilial phenotype variations, including age-at-onset of vascular events, often make an early diagnosis difficult. We present here a Japanese family with a novel intronic heterozygous mutation of ENG, which was identified using whole exome sequencing (WES). The intronic mutation, IVS3+4delAGTG, results in in-frame deletion of exon 3 and would produce a shorter ENG protein lacking the extracellular forty-seven amino acid sequences, which is located within the orphan domain. Our findings highlight the importance of the domain for the downstream signaling pathway of transforming growth factor-beta and bone morphogenesis protein superfamily receptors. Considering the phenotype variations and the available treatment for vascular complications, an early diagnosis using genetic testing, including WES, should be considered for individuals at risk of HHT., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background and Purpose: Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs)., Methods: We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis., Results: The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0-70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42-2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25-31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11-1.73%)., Conclusions: Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically., (© 2015 American Heart Association, Inc.)

Background and Purpose: Hereditary hemorrhagic telangiectasia is an autosomal dominant disease that presents in 10%-20% of patients with various brain vascular malformations. We aimed to report the radiologic features (phenotype) and the genotype-phenotype correlations of brain vascular malformations in hereditary hemorrhagic telangiectasia., Materials and Methods: Demographic, clinical, genotypic, and imaging information of 75 patients with hereditary hemorrhagic telangiectasia with brain arteriovenous malformations enrolled in the Brain Vascular Malformation Consortium from 2010 to 2012 were reviewed., Results: Nonshunting, small, superficially located conglomerates of enhancing vessels without enlarged feeding arteries or draining veins called "capillary vascular malformations" were the most commonly observed lesion (46 of 75 patients; 61%), followed by shunting "nidus-type" brain AVMs that were typically located superficially with a low Spetzler-Martin Grade and a small size (32 of 75 patients; 43%). Direct high-flow fistulous arteriovenous shunts were present in 9 patients (12%). Other types of vascular malformations (dural AVF and developmental venous anomalies) were present in 1 patient each. Multiplicity of vascular malformations was seen in 33 cases (44%). No statistically significant correlation was observed between hereditary hemorrhagic telangiectasia gene mutation and lesion type or lesion multiplicity., Conclusions: Depending on their imaging features, brain vascular malformations in hereditary hemorrhagic telangiectasia can be subdivided into brain AVF, nidus-type AVM, and capillary vascular malformations, with the latter being the most common phenotype in hereditary hemorrhagic telangiectasia. No genotype-phenotype correlation was observed among patients with this condition., (© 2015 by American Journal of Neuroradiology.)

Unlabelled: Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is predominantly caused by mutations in ENG and ACVRL1, which are part of the transforming growth factor beta (TGF-β) signaling pathway. HHT is characterized by the presence of mucocutaneous telangiectases and arteriovenous malformations in visceral organs, primarily the lungs, brain and liver. The most common symptom in HHT is epistaxis originating from nasal telangiectasia, which can be difficult to prevent and can lead to severe anemia. The clinical manifestations of HHT are extremely variable, even within family members, and the exact mechanism of how endoglin and ALK1 haploinsufficiency leads to HHT manifestations remains to be identified., Objectives: The purpose of this study was to detect significantly differentially regulated genes in HHT, and try to elucidate the pathways and regulatory mechanisms occurring in the affected tissue of HHT patients, in order to further characterize this disorder and hypothesize on how telangiectases develop. By microarray technology (Agilent G3 Human GE 8x60), we performed global gene expression profiling of mRNA transcripts from HHT nasal telangiectasial (n = 40) and non-telangiectasial (n = 40) tissue using a paired design. Comparing HHT telangiectasial and non-telangiectasial tissue, significantly differentially expressed genes were detected using a paired t-test. Gene set analysis was performed using GSA-SNP. In the group of ENG mutation carriers, we detected 67 differentially expressed mRNAs, of which 62 were down-regulated in the telangiectasial tissue. Gene set analysis identified the gene ontology (GO) terms vasculogenesis, TGF-β signaling, and Wnt signaling as differentially expressed in HHT1. Altered Wnt signaling might be related to HHT pathogenesis and a greater understanding of this may lead to the discovery of therapeutic targets in HHT., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Objective: Pulmonary arterial hypertension (PAH) is a rare disease that could be inherited with an autosomal dominant pattern. Mutations in BMPR2 gene are described in over 70% of cases, although other genes are involved in lesser extend in PAH. Hereditary hemorrhagic telangiectasia (HHT) is another rare autosomal dominant disease. PAH is a rare complication of HHT that occurs in less than 1% of cases. Liver cirrhosis with portal hypertension is also associated with the presence of PAHs in 1-2% of cases., Patients: We present here a patient with HHT who developed PAH shortly after showing portal hypertension., Results: Some genes (BMPR2, ACVRL1, ENG) seem to play an important role in PAH pathogenesis. We analyzed these genes, detecting mutations in BMPR2 gene (c.1021G>A (V341L), c.327G>A (p.Q109Q)), ACVRL1 (c.313+20C>A, c.1502+7A>G) and ENG (c.498G>A (Q166Q)). The patient also had 3 polymorphisms in the TRPC6 gene (c.1-361A>T, c.1-254C>G, c.1-218C>T)., Conclusions: The study of these genes will help us to identify and track individuals susceptible for developing PAH associated with other diseases., (Copyright © 2014 Elsevier España, S.L.U. All rights reserved.)

Aims: TMEM100 was previously identified as a downstream target of activin receptor-like kinase 1 (ALK1; ACVRL1) signalling. Mutations on ALK1 cause hereditary haemorrhagic telangiectasia (HHT), a vascular disorder characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). The aims of this study are to investigate the in vivo role of TMEM100 at various developmental and adult stages and to determine the extent to which TMEM100 contributed to the development of AVMs as a key downstream effector of ALK1., Methods and Results: Blood vasculature in Tmem100-null embryos and inducible Tmem100-null neonatal and adult mice was examined. We found that TMEM100 deficiency resulted in cardiovascular defects at embryonic stage; dilated vessels, hyperbranching, and increased number of filopodia in the retinal vasculature at neonatal stage; and various vascular abnormalities, including internal haemorrhage, arteriovenous shunts, and weakening of vasculature with abnormal elastin layers at adult stage. However, arteriovenous shunts in adult mutant mice appeared to be underdeveloped without typical tortuosity of vessels associated with AVMs. We uncovered that the expression of genes encoding cell adhesion and extracellular matrix proteins was significantly affected in lungs of adult mutant mice. Especially Mfap4, which is associated with elastin fibre formation, was mostly down-regulated., Conclusion: These results demonstrate that TMEM100 has essential functions for the maintenance of vascular integrity as well as the formation of blood vessels. Our results also indicate that down-regulation of Tmem100 is not the central mechanism of HHT pathogenesis, but it may contribute to the development of vascular pathology of HHT by weakening vascular integrity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inheritable vascular dysplasia caused by mutations in genes encoding either endoglin or activin receptor-like kinase-1 (ALK1). Functional significance of endoglin missense mutations remains largely unknown leading to a difficult discrimination between polymorphisms and pathogenic mutations. In order to study the functional significance of endoglin mutations and to help HHT1 diagnosis, we developed a cellular assay based on the ability of endoglin to enhance ALK1 response to bone morphogenetic protein 9 (BMP9). We generated and characterized 31 distinct ENG mutants reproducing human HHT1 missense mutations identified in patients of the Molecular Genetics Department in Lyon. We found that 16 mutants behaved like wild-type (WT) endoglin, and thus corresponded to benign rare variants. The 15 other variants showed defects in BMP9 response and were identified as pathogenic mutations. Interestingly, two mutants (S278P and F282V) had lost their ability to bind BMP9, identifying two crucial amino acids for BMP9 binding to endoglin. For all the others, the functional defect was correlated with a defective trafficking to the cell surface associated with retention in the endoplasmic reticulum. Further, we demonstrated that some intracellular mutants dimerized with WT endoglin and impaired its cell-surface expression thus acting as dominant-negatives. Taken together, we show that endoglin loss-of-function can result from different mechanisms in HHT1 patients. We also provide a diagnostic tool helping geneticists in screening for novel or conflicting ENG mutations., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that is characterized by multiple arteriovenous malformations (AVMs) involving the skin, mucosal surfaces, and internal organs. HHT has an age-dependent penetrance and usually initially presents with recurrent epistaxis followed by the characteristic telangiectasias of the face, oropharynx, and hands over time. Patients often have vascular malformations that involve their lungs, brain, spinal cord, and gastrointestinal tract as well, which are the main causes of morbidity in patients with HHT. The sequelae of visceral organ involvement include ischemic stroke, cerebral bacterial abscesses, intracranial hemorrhage, chronic hypoxia, dyspnea with exertion, pulmonary hypertension, high output heart failure, gastrointestinal bleeds and liver failure., (© 2015 Elsevier B.V. All rights reserved.)

Hereditary Haemorrhagic Telangiectasia also known as Osler-Rendu-Weber disease is a rare autosomal dominant disorder affecting small vessels of skin and mucosa, usually misdiagnosed because of its non specific symptomatology. This disease usually presents as epistaxis, gastrointestinal bleeding and visceral arteriovenous malformations. Although the epistaxis and gastrointestinal blood loss can result in anaemia, patients with hereditary haemorrhagic telangiectasia rarely presents as severe anaemia. Herein, we report a case of a 60 year-old man with severe anaemia resulting in congestive cardiac failure who ultimately was diagnosed as hereditary haemorrhagic telangiectasia with recurrent epistaxis as a cause of his severe anaemia.

Juvenile polyposis syndrome is an autosomal dominant polyposis syndrome. It is characterized by predisposition to multiple juvenile polyps in the gastrointestinal tract and is associated with an increased risk of colorectal and ventricular cancer. Patients and at risk family members should be offered surveillance. This article discusses clinical features and surveillance based on the current literature.

Objective: Hereditary hemorrhagic telangiectasia is a genetic disorder characterized by visceral and mucocutaneous arteriovenous malformations (AVMs). Clinically indistinguishable hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 are caused by mutations in ENG and ALK1, respectively. In this study, we have compared the development of visceral and mucocutaneous AVMs in adult stages between Eng- and Alk1-inducible knockout (iKO) models., Approach and Results: Eng or Alk1 were deleted from either vascular endothelial cells (ECs) or smooth muscle cells in adult stages using Scl-CreER and Myh11-CreER lines, respectively. Latex perfusion and intravital spectral imaging in a dorsal skinfold window chamber system were used to visualize remodeling vasculature during AVM formation. Global Eng deletion resulted in lethality with visceral AVMs and wound-induced skin AVMs. Deletion of Alk1 or Eng in ECs, but not in smooth muscle cells, resulted in wound-induced skin AVMs. Visceral AVMs were observed in EC-specific Alk1-iKO but not in Eng-iKO. Intravital spectral imaging revealed that Eng-iKO model exhibited more dynamic processes for AVM development when compared with Alk1-iKO model., Conclusions: Both Alk1- and Eng-deficient models require a secondary insult, such as wounding, and ECs are the primary cell type responsible for the pathogenesis. However, Alk1 but not Eng deletion in ECs results in visceral AVMs., (© 2014 American Heart Association, Inc.)