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Kaufman CS, Nguyen MA, Bezold A, Chesnutt MS. Pediatric Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia: Screening, Diagnosis, and Management. J Clin Med 2025; 14:3739. [PMID: 40507503 PMCID: PMC12155779 DOI: 10.3390/jcm14113739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/18/2025] [Accepted: 05/21/2025] [Indexed: 06/16/2025] Open
Abstract
Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between a pulmonary artery and pulmonary vein that bypass the capillary bed, resulting in right-to-left shunting. The majority of PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease. Asymptomatic children with either a confirmed diagnosis of HHT or who are at risk of HHT from positive family history, as well as those with signs or symptoms concerning for HHT and/or PAVMs, should undergo screening for PAVMs at the time of clinical presentation or diagnosis. Screening in children can use a conservative approach (pulse oximetry, exercise intolerance testing, and chest radiograph) or transthoracic contrast echocardiography with agitated saline (TTCE). Pediatric patients with large or physiologically significant PAVMs should be treated with transcatheter embolization. Close follow-up is required after treatment to evaluate for interval growth of other PAVMs or reperfusion of the treated PAVMs.
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Affiliation(s)
- Claire S. Kaufman
- Pacific Northwest HHT Center of Excellence, Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, OR 97239, USA;
| | - Minh Anh Nguyen
- School of Medicine, Oregon Health and Sciences University, Portland, OR 97239, USA;
| | - Amy Bezold
- Dotter Department of Interventional Radiology, Oregon Health and Sciences University, Portland, OR 97239, USA;
| | - Mark S. Chesnutt
- Pacific Northwest HHT Center of Excellence, Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, OR 97239, USA;
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Iacobas I, Hammill AM. Hereditary hemorrhagic telangiectasia - pediatric review. Curr Opin Pediatr 2024; 36:592-598. [PMID: 39254659 DOI: 10.1097/mop.0000000000001398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
PURPOSE OF REVIEW Hereditary hemorrhagic telangiectasia (HHT) diagnostic and management approach for pediatrics underwent significant advances over the last couple of years. RECENT FINDINGS In 2020, new guidelines for HHT were published that included a pediatric section thus attracting special focus into the childhood presentation. SUMMARY Curacao criteria are specific, but not sensitive enough in children. Genetic testing is encouraged for all family members even if asymptomatic. Standardized scoring for epistaxis is strongly encouraged, as it allows monitoring and can stratify therapeutic approaches. Early screening for pulmonary and brain visceral arteriovenous malformations (AVMs) in pediatric patients with confirmed genetic alterations of HHT should be instituted. Graded trans-esophageal echocardiogram with agitated saline contrast can be used as screening method for pulmonary AVMs. As pulmonary AVMs can develop throughout lifetime, guidelines recommend repeated screening even in asymptomatic patients at least every 5 years. Signs of stroke in childhood are more subtle than in adults. Cerebral imaging in early childhood can identify brain AVMs that may benefit from early intervention. Embolization of high-risk pulmonary and cerebral AVMs should be performed at specialized centers even at pediatric age. One or two classic HHT telangiectasia can be considered diagnostic in children. Antibiotic prophylaxis with dental procedures continues to be recommended.
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Affiliation(s)
- Ionela Iacobas
- Pediatric Hematology-Oncology, TCH Vascular Anomalies Center, TCH HHT Center of Excellence, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas
| | - Adrienne M Hammill
- Pediatrics Cancer and Blood Diseases Institute, Division of Hematology, HHT Center of Excellence, Sturge-Weber Center of Excellence Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Kelly C, Buscarini E, Manfredi G, Gregory S, Heneghan MA. Hepatic manifestations of hereditary haemorrhagic telangiectasia. Liver Int 2024; 44:2220-2234. [PMID: 38847503 DOI: 10.1111/liv.16008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 05/01/2024] [Accepted: 05/25/2024] [Indexed: 08/30/2024]
Abstract
Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor β/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored.
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Affiliation(s)
- Claire Kelly
- Institute of Liver Studies, Kings College Hospital, London, UK
| | | | - Guido Manfredi
- VASCERN HHT Reference Centre, ASST Maggiore Hospital, Crema, Italy
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Fish A, Wang D, Knight E, Pollak J, Schlachter T. Recurrence of Pulmonary Arteriovenous Malformation after Embolization in Patients with Pulmonary Hypertension. J Vasc Interv Radiol 2024; 35:1148-1153. [PMID: 38692392 DOI: 10.1016/j.jvir.2024.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024] Open
Abstract
PURPOSE To evaluate the correlation between pulmonary hypertension (PH) and recurrence of pulmonary arteriovenous malformation (PAVM) after embolization. MATERIALS AND METHODS With institutional review board (IRB) approval, the records of 377 patients with PAVMs evaluated at a single hereditary hemorrhagic telangiectasia (HHT) center of excellence between January 1, 2013, and September 10, 2023, were retrospectively reviewed. PAVMs embolized during this time period were evaluated for recurrence. Patients and PAVMs not treated during this time period were excluded. Growth of previously untreated PAVMs was not considered recurrence. Patients without chest computed tomography (CT) follow-up were excluded. General demographics, HHT status as defined by genetic testing or Curacao criteria, presence of PH, history of smoking, anemia, and hepatic arteriovenous malformations (AVMs) were documented. Odds ratio (OR) was calculated and stratified analysis was performed to assay the correlation between PAVM recurrence, PH, and possible confounders. RESULTS A total of 151 patients with PAVMs were treated during the study period, including 438 PAVMs, for which follow-up was available. This included 106 patients with definite, 31 with doubtful, and 14 with possible HHT. The presence of PH was significantly associated with PAVM recurrence both by patient (OR, 8.13; 95% CI, 3.50-19.67) and by lesion (OR, 4.07; 95% CI, 2.14-7.91). Multivariate analysis demonstrated that this correlation was independent of several variables including HHT status, smoking history, presence of hepatic AVMs, and anemia. CONCLUSIONS There is a high correlation between PH and PAVM recurrence, suspected to be due to high pulmonary artery pressures causing recanalization. PH may suggest the need for shorter surveillance intervals.
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Affiliation(s)
- Adam Fish
- Department of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut.
| | - Daniel Wang
- Department of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Elizabeth Knight
- Department of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Jeffrey Pollak
- Department of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Todd Schlachter
- Department of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
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DeMille D, McDonald J, Bernabeu C, Racher H, Olivieri C, Cantarini C, Sbalchiero A, Thompson BA, Jovine L, Shovlin CL, Dupuis-Girod S, Lesca G, Tusseau M, Ganguly A, Kasthuri RS, Jessen J, Massink MPG, Ichikawa S, Bayrak-Toydemir P. Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes- ENG and ACVRL1. Hum Mutat 2024; 2024:3043736. [PMID: 40225928 PMCID: PMC11919242 DOI: 10.1155/2024/3043736] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/15/2024] [Accepted: 04/24/2024] [Indexed: 04/15/2025]
Abstract
The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.
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Affiliation(s)
- Desiree DeMille
- Genomics Analysis, ARUP Laboratories, Salt Lake City, UT 84108, USA
| | - Jamie McDonald
- Department of Pathology, University of Utah, Salt Lake City, UT 84108, USA
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain
| | - Hilary Racher
- Impact Genetics/Dynacare, Brampton, Canada L6T 5M3
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada M5S 1A8
| | - Carla Olivieri
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
| | - Claudia Cantarini
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
| | - Anna Sbalchiero
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
| | - Bryony A. Thompson
- Department of Pathology, Royal Melbourne Hospital, Melbourne 3050, Australia
| | - Luca Jovine
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 141 83, Sweden
| | - Claire L. Shovlin
- National Heart and Lung Institute, Imperial College, London W12 0HN, UK
| | - Sophie Dupuis-Girod
- Hospices Civils de Lyon, National HHT Reference Center and Department of Medical Genetics, Femme Mère Enfants Hospital, 69500 Bron, France
| | - Gaetan Lesca
- Hospices Civils de Lyon, National HHT Reference Center and Department of Medical Genetics, Femme Mère Enfants Hospital, 69500 Bron, France
| | - Maud Tusseau
- Hospices Civils de Lyon, National HHT Reference Center and Department of Medical Genetics, Femme Mère Enfants Hospital, 69500 Bron, France
| | - Arupa Ganguly
- Department of Genetics, PSOM, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Raj S. Kasthuri
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jaime Jessen
- Impact Genetics/Dynacare, Brampton, Canada L6T 5M3
| | - Maarten P. G. Massink
- Department of Genetics, University Medical Center Utrecht, Utrecht 3584CX, Netherlands
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Kofoed MS, Tørring PM, Christensen AA, Lange B, Kjeldsen AD, Nielsen TH. High risk of ischaemic stroke amongst patients with hereditary haemorrhagic telangiectasia. Eur J Neurol 2024; 31:e16128. [PMID: 37955551 PMCID: PMC11235815 DOI: 10.1111/ene.16128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/19/2023] [Accepted: 10/19/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND AND PURPOSE Hereditary haemorrhagic telangiectasia (HHT) is a genetic disease with fragile blood vessels and vascular malformations, potentially causing neurological manifestations, including stroke and cerebral abscesses. The study aimed to investigate neurological manifestations in the Danish HHT database, focusing on pulmonary arteriovenous malformations (PAVMs) as a risk factor for cerebral events. METHODS Retrospective analysis of the Danish HHT database was conducted, cross-referencing neurological outcomes with the Danish Apoplexy Register for accuracy. Patients were stratified by HHT type. Primary outcomes included ischaemic stroke, transient ischaemic attack and cerebral haemorrhage. Secondary outcomes comprised age, age at HHT diagnosis, age at cerebral ischaemic event, and PAVM and cerebral arteriovenous malformation status. RESULTS Six hundred and sixty-four HHT patients were included. PAVM was diagnosed in 54% of patients, with higher prevalence in HHT type 1 (70%) compared to HHT type 2 (34%) and juvenile polyposis HHT (66%). Ischaemic stroke or transient ischaemic attack occurred in 12.5%, with a higher risk associated with macroscopic PAVM. Logistic regression showed a nearly 10 times increased risk of ischaemic stroke with macroscopic PAVM. Cerebral abscesses occurred in 3.2% of patients, all with macroscopic PAVM. Incomplete PAVM closure increased cerebral abscess risk. CONCLUSION This study provides valuable insights into the prevalence of neurological manifestations and vascular events in HHT patients. The presence of PAVM was associated with an increased risk of ischaemic stroke, highlighting the importance of early screening and intervention. The findings emphasize the need for comprehensive management strategies targeting both vascular and neurological complications in HHT patients, especially regarding secondary stroke prevention.
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Affiliation(s)
- Mikkel Seremet Kofoed
- Department of Neurosurgery, Odense University Hospital, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark
- BRIDGE (Brain Research—Inter Disciplinary Guided Excellence)University of Southern DenmarkOdenseDenmark
- Department of Ear, Nose and Throat Surgery, Odense University Hospital, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark
- University of Southern Denmark (SDU)OdenseDenmark
- OPENRegion of Southern DenmarkOdenseDenmark
| | - Pernille M. Tørring
- Department of Clinical GeneticsOdense University HospitalOdenseDenmark
- VASCERN HHT Reference CenterOdense Universitetshospital, Syddansk UniversitetOdenseDenmark
| | - Alex Alban Christensen
- Department of Neurology, Odense University Hospital, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark
| | - Bibi Lange
- Department of Ear, Nose and Throat Surgery, Odense University Hospital, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark
| | - Anette Drøhse Kjeldsen
- Department of Ear, Nose and Throat Surgery, Odense University Hospital, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark
- University of Southern Denmark (SDU)OdenseDenmark
- OPENRegion of Southern DenmarkOdenseDenmark
- VASCERN HHT Reference CenterOdense Universitetshospital, Syddansk UniversitetOdenseDenmark
| | - Troels Halfeld Nielsen
- Department of Neurosurgery, Odense University Hospital, Clinical InstituteUniversity of Southern DenmarkOdenseDenmark
- BRIDGE (Brain Research—Inter Disciplinary Guided Excellence)University of Southern DenmarkOdenseDenmark
- University of Southern Denmark (SDU)OdenseDenmark
- OPENRegion of Southern DenmarkOdenseDenmark
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Luhar AP, Pollak JS. Pulmonary Angiography: Arteriovenous Malformation and Pseudoaneurysm. IR PLAYBOOK 2024:311-324. [DOI: 10.1007/978-3-031-52546-9_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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Yusuf HM, Rasheed A, Hetts S, Kim H, Loftus P, Conrad M. Exploring effects of atmospheric conditions in hereditary hemorrhagic telangiectasia. Int Forum Allergy Rhinol 2023; 13:2172-2179. [PMID: 37189284 DOI: 10.1002/alr.23183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/08/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by recurrent epistaxis, telangiectasias, and visceral arteriovenous malformations. Individuals with HHT often identify low humidity and temperature as detrimental to epistaxis severity. We set out to assess the relationship between humidity and temperature on epistaxis severity in patients with HHT. METHODS Retrospective cross-sectional study at an academic hospital with an HHT center between July 1, 2014 and January 1, 2022. The primary outcome of this study was ESS. Pearson correlation analyses and multiple linear regression analyses were performed to test the association between weather variables and epistaxis severity scre (ESS). Results were reported as coefficient and 95% confidence interval (CI). RESULTS Four hundred twenty-nine patients were included in the analysis. Through a Pearson correlation analysis, neither humidity (regression coefficient = -0.01; 95% CI, -0.006 to 0.003; p = 0.50), daily low temperature (regression coefficient = 0.01; 95% CI, -0.011 to 0.016; p = 0.72), or daily high temperature (regression coefficient = 0.01; 95% CI, -0.004 to 0.013; p = 0.32) were significantly correlated with ESS. In a multiple linear regression analysis, adjusting for both daily low temperature and humidity, medications taken, demographics, and genotype, neither daily low temperature (regression coefficient = -0.02; 95% CI, -0.04 to 0.01; p = 0.14) nor humidity (regression coefficient = 0.01; 95% CI, -0.01 to 0.01; p = 0.64) were significantly associated with ESS. CONCLUSION We have shown in a large clinical sample that neither humidity nor temperature were strongly correlated with HHT patient epistaxis severity.
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Affiliation(s)
- Hamzah M Yusuf
- School of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Amna Rasheed
- Touro College of Medicine, Vallejo, California, USA
| | - Steven Hetts
- Neurointerventional Radiology, University of California, San Francisco, California, USA
| | - Helen Kim
- Center for Cerebrovascular Research, University of California, San Francisco, California, USA
| | - Patricia Loftus
- Otolaryngology, University of California, San Francisco, California, USA
| | - Miles Conrad
- Radiology, School of Medicine, University of California San Francisco, San Francisco, California, USA
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Wu JL, Zhao ZZ, Chen J, Zhang HW, Luan Z, Li CY, Zhao YM, Jing YJ, Wang SF, Sun G. Hereditary hemorrhagic telangiectasia involving portal venous system: A case report and review of the literature. World J Gastrointest Surg 2023; 15:2367-2375. [PMID: 37969701 PMCID: PMC10642469 DOI: 10.4240/wjgs.v15.i10.2367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/02/2023] [Accepted: 08/15/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 5000 in the general population. It is characterized by vasodilation, which affects specific organs, such as the skin, mucous membranes, brain, lungs, gastrointestinal tract, liver, and others. However, HHT rarely involves the portal venous system to cause serious clinical complications. CASE SUMMARY A 68-year-old woman was admitted to the emergency department due to four consecutive days of abdominal pain and bloody stool and was subsequently diagnosed with HHT. Computed tomography angiography confirmed the presence of an arteriovenous fistula (AVFs). Considering this specific manifestation, whole exome sequencing was performed. After a comprehensive evaluation, a selective superior mesenteric artery embolization was prioritized to avoid intestinal ischemia. The postoperative symptoms of the patient were quickly relieved. Unfortunately, two months post-procedure the patient died from intestinal necrosis and abdominal infection related to remaining AVFs. CONCLUSION For patients with diffuse superior mesenteric AVFs, selective mesenteric arterial embolization may lead to positive short-term outcomes.
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Affiliation(s)
- Jun-Ling Wu
- Medical School of Chinese PLA, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhi-Zhuang Zhao
- Department of Geriatrics, Hainan Hospital of PLA General Hospital, Sanya 572013, Hainan Province, China
| | - Jun Chen
- Medical School of Chinese PLA, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Han-Wen Zhang
- Medical School of Chinese PLA, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhe Luan
- Medical School of Chinese PLA, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Cong-Yong Li
- Department of Sixth Health Care, Second Medical Center of PLA General Hospital, Beijing 100853, China
| | - Yi-Ming Zhao
- Department of Gastroenterology and Hepatology, Hainan Hospital of PLA General Hospital, Sanya 572013, Hainan Province, China
| | - Yu-Jia Jing
- Medical School of Chinese PLA, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Shu-Fang Wang
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
| | - Gang Sun
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
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10
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Zhou X, Pucel JC, Nomura-Kitabayashi A, Chandakkar P, Guidroz AP, Jhangiani NL, Bao D, Fan J, Arthur HM, Ullmer C, Klein C, Marambaud P, Meadows SM. ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia. Arterioscler Thromb Vasc Biol 2023; 43:1384-1403. [PMID: 37288572 PMCID: PMC10524982 DOI: 10.1161/atvbaha.123.319385] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/16/2023] [Indexed: 06/09/2023]
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT. METHODS Cerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods. RESULTS Comparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes. CONCLUSIONS Elevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT.
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Affiliation(s)
- Xingyan Zhou
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA, USA
| | - Jenna C. Pucel
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA, USA
| | - Aya Nomura-Kitabayashi
- Litwin-Zucker Alzheimer’s Research Center, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Pallavi Chandakkar
- Litwin-Zucker Alzheimer’s Research Center, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Adella P. Guidroz
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA, USA
| | - Nikita L. Jhangiani
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA, USA
| | - Duran Bao
- Biochemistry and Molecular Biology Department, Tulane University School of Medicine, New Orleans, LA, USA
| | - Jia Fan
- Biochemistry and Molecular Biology Department, Tulane University School of Medicine, New Orleans, LA, USA
| | - Helen M. Arthur
- Biosciences Institute, Center for Life, Newcastle University, Newcastle NE1 3BZ, UK
| | | | | | - Philippe Marambaud
- Litwin-Zucker Alzheimer’s Research Center, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Stryder M. Meadows
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA, USA
- Tulane Brain Institute, Tulane University, New Orleans, LA, USA
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11
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Genetics of brain arteriovenous malformations and cerebral cavernous malformations. J Hum Genet 2023; 68:157-167. [PMID: 35831630 DOI: 10.1038/s10038-022-01063-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/13/2022] [Accepted: 06/26/2022] [Indexed: 11/08/2022]
Abstract
Cerebrovascular malformations comprise abnormal development of cerebral vasculature. They can result in hemorrhagic stroke due to rupture of lesions as well as seizures and neurological defects. The most common forms of cerebrovascular malformations are brain arteriovenous malformations (bAVMs) and cerebral cavernous malformations (CCMs). They occur in both sporadic and inherited forms. Rapidly evolving molecular genetic methodologies have helped to identify causative or associated genes involved in genesis of bAVMs and CCMs. In this review, we highlight the current knowledge regarding the genetic basis of these malformations.
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12
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Kahle KT, Duran D, Smith ER. Increasing precision in the management of pediatric neurosurgical cerebrovascular diseases with molecular genetics. J Neurosurg Pediatr 2023; 31:228-237. [PMID: 36609371 DOI: 10.3171/2022.12.peds22332] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 01/09/2023]
Abstract
Recent next-generation DNA and RNA sequencing studies of congenital and pediatric cerebrovascular anomalies such as moyamoya disease, arteriovenous malformations, vein of Galen malformations, and cavernous malformations have shed new insight into the genetic regulation of human cerebrovascular development by implicating multiple novel disease genes and signaling pathways in the pathogenesis of these disorders. These diseases are now beginning to be categorized by molecular disruptions in canonical signaling pathways that impact the differentiation and proliferation of specific venous, capillary, or arterial cells during the hierarchical development of the cerebrovascular system. Here, the authors discuss how the continued study of these and other congenital cerebrovascular conditions has the potential to replace the current antiquated, anatomically based disease classification systems with a molecular taxonomy that has the potential to increase precision in genetic counseling, prognostication, and neurosurgical and endovascular treatment stratification. Importantly, the authors also discuss how molecular genetic data are already informing clinical trials and catalyzing the development of targeted therapies for these conditions historically considered as exclusively neurosurgical lesions.
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Affiliation(s)
- Kristopher T Kahle
- 1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston
- 2Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston
- 3Division of Genetics and Genomics, Boston Children's Hospital, Boston
- 4Broad Institute of MIT and Harvard, Cambridge, Massachusetts; and
| | - Daniel Duran
- 5Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Edward R Smith
- 2Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston
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13
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Drapé E, Anquetil T, Larrivée B, Dubrac A. Brain arteriovenous malformation in hereditary hemorrhagic telangiectasia: Recent advances in cellular and molecular mechanisms. Front Hum Neurosci 2022; 16:1006115. [PMID: 36504622 PMCID: PMC9729275 DOI: 10.3389/fnhum.2022.1006115] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/27/2022] [Indexed: 11/25/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by vessel dilatation, such as telangiectasia in skin and mucosa and arteriovenous malformations (AVM) in internal organs such as the gastrointestinal tract, lungs, and brain. AVMs are fragile and tortuous vascular anomalies that directly connect arteries and veins, bypassing healthy capillaries. Mutations in transforming growth factor β (TGFβ) signaling pathway components, such as ENG (ENDOGLIN), ACVRL1 (ALK1), and SMAD4 (SMAD4) genes, account for most of HHT cases. 10-20% of HHT patients develop brain AVMs (bAVMs), which can lead to vessel wall rupture and intracranial hemorrhages. Though the main mutations are known, mechanisms leading to AVM formation are unclear, partially due to lack of animal models. Recent mouse models allowed significant advances in our understanding of AVMs. Endothelial-specific deletion of either Acvrl1, Eng or Smad4 is sufficient to induce AVMs, identifying endothelial cells (ECs) as primary targets of BMP signaling to promote vascular integrity. Loss of ALK1/ENG/SMAD4 signaling is associated with NOTCH signaling defects and abnormal arteriovenous EC differentiation. Moreover, cumulative evidence suggests that AVMs originate from venous ECs with defective flow-migration coupling and excessive proliferation. Mutant ECs show an increase of PI3K/AKT signaling and inhibitors of this signaling pathway rescue AVMs in HHT mouse models, revealing new therapeutic avenues. In this review, we will summarize recent advances and current knowledge of mechanisms controlling the pathogenesis of bAVMs, and discuss unresolved questions.
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Affiliation(s)
- Elise Drapé
- Centre de Recherche, CHU St. Justine, Montréal, QC, Canada,Département de Pharmacologie et de Physiologie, Université de Montréal, Montréal, QC, Canada
| | - Typhaine Anquetil
- Centre de Recherche, CHU St. Justine, Montréal, QC, Canada,Département De Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, Canada
| | - Bruno Larrivée
- Département d’Ophtalmologie, Université de Montréal, Montréal, QC, Canada,Centre De Recherche, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada,*Correspondence: Bruno Larrivée,
| | - Alexandre Dubrac
- Centre de Recherche, CHU St. Justine, Montréal, QC, Canada,Département De Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, Canada,Département d’Ophtalmologie, Université de Montréal, Montréal, QC, Canada,Alexandre Dubrac,
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14
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Arthur HM, Roman BL. An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms. Front Med (Lausanne) 2022; 9:973964. [PMID: 36250069 PMCID: PMC9556665 DOI: 10.3389/fmed.2022.973964] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Endoglin (ENG) is expressed on the surface of endothelial cells (ECs) where it efficiently binds circulating BMP9 and BMP10 ligands to initiate activin A receptor like type 1 (ALK1) protein signalling to protect the vascular architecture. Patients heterozygous for ENG or ALK1 mutations develop the vascular disorder known as hereditary haemorrhagic telangiectasia (HHT). Many patients with this disorder suffer from anaemia, and are also at increased risk of stroke and high output heart failure. Recent work using animal models of HHT has revealed new insights into cellular and molecular mechanisms causing this disease. Loss of the ENG (HHT1) or ALK1 (HHT2) gene in ECs leads to aberrant arteriovenous connections or malformations (AVMs) in developing blood vessels. Similar phenotypes develop following combined EC specific loss of SMAD1 and 5, or EC loss of SMAD4. Taken together these data point to the essential role of the BMP9/10-ENG-ALK1-SMAD1/5-SMAD4 pathway in protecting the vasculature from AVMs. Altered directional migration of ECs in response to shear stress and increased EC proliferation are now recognised as critical factors driving AVM formation. Disruption of the ENG/ALK1 signalling pathway also affects EC responses to vascular endothelial growth factor (VEGF) and crosstalk between ECs and vascular smooth muscle cells. It is striking that the vascular lesions in HHT are both localised and tissue specific. Increasing evidence points to the importance of a second genetic hit to generate biallelic mutations, and the sporadic nature of such somatic mutations would explain the localised formation of vascular lesions. In addition, different pro-angiogenic drivers of AVM formation are likely to be at play during the patient’s life course. For example, inflammation is a key driver of vessel remodelling in postnatal life, and may turn out to be an important driver of HHT disease. The current wealth of preclinical models of HHT has led to increased understanding of AVM development and revealed new therapeutic approaches to treat AVMs, and form the topic of this review.
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Affiliation(s)
- Helen M. Arthur
- Biosciences Institute, Centre for Life, University of Newcastle, Newcastle, United Kingdom
- *Correspondence: Helen M. Arthur,
| | - Beth L. Roman
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States
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15
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Errasti Díaz S, Peñalva M, Recio-Poveda L, Vilches S, Casado-Vela J, Pérez Pérez J, Botella LM, Albiñana V, Cuesta AM. A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2. J Clin Med 2022; 11:3053. [PMID: 35683441 PMCID: PMC9181680 DOI: 10.3390/jcm11113053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 02/01/2023] Open
Abstract
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations in multiple organs. Different deletions or nonsense mutations have been described in the ENG (HHT1) or ACVRL1/ALK1 (HHT2) genes, all affecting endothelial homeostasis. A novel mutation in ACVRL1/ALK1 has been identified in a Peruvian family with a clinical history compatible to HHT. Subsequently, 23 DNA samples from oral exchanges (buccal swaps) of the immediate family members were analyzed together with their clinical histories. A routine cDNA PCR followed by comparative DNA sequencing between the founder and another healthy family member showed the presence of the aforementioned specific mutation. The single mutation detected (c.525 + 1G > T) affects the consensus splice junction immediately after exon 4, provokes anomalous splicing and leads to the inclusion of intron IV between exons 4 and 5 in the ACVRL1/ALK1 mRNA and, therefore, to ALK1 haploinsufficiency. Complete sequencing determined that 10 of the 25 family members analyzed were affected by the same mutation. Notably, the approach described in this report could be used as a diagnostic technique, easily incorporated in clinical practice in developing countries and easily extrapolated to other patients carrying such a mutation.
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Affiliation(s)
- Suriel Errasti Díaz
- Departamento Hematología, Instituto Nacional de Enfermedades Neoplásicas, Lima 15038, Peru;
| | - Mercedes Peñalva
- Departamento Biomedicina Molecular, Centro de Investigaciones Biológicas Margarita Salas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), 280406 Madrid, Spain; (M.P.); (L.R.-P.); (L.M.B.)
| | - Lucía Recio-Poveda
- Departamento Biomedicina Molecular, Centro de Investigaciones Biológicas Margarita Salas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), 280406 Madrid, Spain; (M.P.); (L.R.-P.); (L.M.B.)
- CIBERER, Unidad 707, Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Susana Vilches
- Laboratorio Diagnóstico Genético Secugen SL, CIB, CSIC, 28040 Madrid, Spain; (S.V.); (J.P.P.)
| | - Juan Casado-Vela
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Pozuelo, 28223 Madrid, Spain;
- Departamento Bioingeniería, Escuela Politécnica Superior, Universidad Carlos III de Madrid, 28911 Madrid, Spain
| | - Julián Pérez Pérez
- Laboratorio Diagnóstico Genético Secugen SL, CIB, CSIC, 28040 Madrid, Spain; (S.V.); (J.P.P.)
| | - Luisa María Botella
- Departamento Biomedicina Molecular, Centro de Investigaciones Biológicas Margarita Salas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), 280406 Madrid, Spain; (M.P.); (L.R.-P.); (L.M.B.)
- CIBERER, Unidad 707, Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Virginia Albiñana
- Departamento Biomedicina Molecular, Centro de Investigaciones Biológicas Margarita Salas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), 280406 Madrid, Spain; (M.P.); (L.R.-P.); (L.M.B.)
- CIBERER, Unidad 707, Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Angel M. Cuesta
- CIBERER, Unidad 707, Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
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16
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Neurovascular Manifestations in Pediatric Patients With Hereditary Haemorrhagic Telangiectasia. Pediatr Neurol 2022; 129:24-30. [PMID: 35176532 DOI: 10.1016/j.pediatrneurol.2021.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is a multiorgan vascular dysplasia with limited data regarding its neurovascular manifestations and genotype-phenotype correlation in children. The objective of this study was to describe the neurovascular findings in a large cohort of children with HHT and correlate between phenotype and genotype. METHODS This retrospective study was conducted on 221 children (<18 years) with a definite or possible diagnosis of HHT based on Curacao criteria, or with positive genetics for the mutated genes of ENG, ACVRL-1, and SMAD-4, who also underwent brain MRI and/or conventional angiography. Demographic and clinical information, imaging findings, and follow up information were gathered. RESULTS Two hundred twenty-one children with HHT (70.6% genetically confirmed, and 99.5% positive family history) were included, with a median age of 7 years (interquartile range: 3 to 11 years) and 58.8% male predominance. Neurovascular lesions were found in 64 of 221 (28.9%), with 3.1% prevalence of intracranial hemorrhage. The most commonly observed vascular malformations were developmental venous anomalies (48.5%) and brain arteriovenous malformations (AVMs) (31.2%), followed by capillary malformations (14.1%). Multiple AVMs were seen in 10.0% of the cohort. We found no instances of de novo AVM (1281.8 patient-years).A significantly higher proportion of patients with ENG mutations (19.7%) had brain AVM than those with ACVRL-1 (4.9%) and SMAD-4 (0%) mutations (P < 0.01). There was no significant difference in the hemorrhagic risk of shunting lesions associated with ENG (35.3%) or ACVRL-1 (33.3%) positivity (P = 0.9). CONCLUSIONS We describe the neurovascular imaging and genetic findings from a large pediatric cohort of HHT, to enhance clinical awareness and guide management of patients with HHT.
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17
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Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction. Int J Mol Sci 2022; 23:ijms23031225. [PMID: 35163148 PMCID: PMC8835690 DOI: 10.3390/ijms23031225] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/16/2022] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.
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18
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Genetics and Vascular Biology of Brain Vascular Malformations. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00012-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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19
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Tessier S, Lipton BA, Ido F, Longo S, Nanda S. Pathogenesis and therapy of arteriovenous malformations: A case report and narrative review. Int J Crit Illn Inj Sci 2021; 11:167-176. [PMID: 34760664 PMCID: PMC8547675 DOI: 10.4103/ijciis.ijciis_127_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/24/2020] [Accepted: 01/05/2021] [Indexed: 12/03/2022] Open
Abstract
Arteriovenous malformations (AVMs) are abnormal communications between arteries and veins that lack intervening capillary beds. They have been described in almost every organ in the body, emerging sporadically or as part of well-described syndromes. Hereditary hemorrhagic telangiectasia (HHT) is a rare, progressive, and lifelong disease characterized by AVMs and recurrent hemorrhaging. In the last 2 decades, significant advances have been made in understanding the pathogenesis of this condition. The accumulation of knowledge has led to a natural evolution of therapy, from open surgery to endovascular procedures, and now to a role for medications in certain AVMs. Here, we review a case of HHT and describe the most up-to-date clinical practice, including diagnosis of HHT, subtypes of HHT, and medical therapy.
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Affiliation(s)
- Steven Tessier
- Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Brooke A Lipton
- Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Firas Ido
- Department of Pulmonary and Critical Care, St. Luke's University Health Network, Bethlehem, PA, USA
| | - Santo Longo
- Department of Pathology, St. Luke's University Health Network, Bethlehem, PA, USA
| | - Sudip Nanda
- Department of Cardiology, St. Luke's University Health Network, Bethlehem, PA, USA
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20
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Incidence of Spontaneous Pulmonary AVM Rupture in HHT Patients. J Clin Med 2021; 10:jcm10204714. [PMID: 34682838 PMCID: PMC8540859 DOI: 10.3390/jcm10204714] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 11/18/2022] Open
Abstract
The spontaneous rupture of pulmonary AVMs, resulting in pulmonary hemorrhage and hydrothorax, is a life-threatening complication. While this phenomenon has been previously reported, the true incidence is not yet known. This study retrospectively reviewed records of 801 HHT patients with pulmonary AVMs to identify a single lifetime episode of hemothorax or pulmonary hemorrhage secondary to pulmonary AVM rupture. The lifetime prevalence and incidence of pulmonary AVM rupture in HHT patients was 2.7% and 0.16% respectively. In these patients, AVM rupture represented the initial presentation of HHT in nine (40.9%) cases and was life-threatening in nine (40.9%) cases. All cases occurred in virgin lesions, and subsequent embolization was curative. While a feared complication, pulmonary AVM rupture is rare and is likely effectively prevented by existing embolization techniques and indications.
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21
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Farhan A, Yuan F, Partan E, Weiss CR. Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5. Am J Med Genet A 2021; 188:199-209. [PMID: 34611981 DOI: 10.1002/ajmg.a.62522] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 12/29/2022]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant fibrovascular dysplasia caused by mutations in ENG, ACVRL1, and SMAD4. Increasingly, there has been an appreciation for vascular conditions with phenotypic overlap to HHT but which have distinct clinical manifestations and arise from novel or uncharacterized gene variants. This study reported on a cohort of four unrelated probands who were diagnosed with a rare form of GDF2-related HHT5, for which only five prior cases have been described. Two patients harbored heterozygous missense variants not previously annotated as pathogenic (p.Val403Ile; p.Glu355Gln). Clinically, these patients had features resembling HHT1, including cerebrovascular involvement of their disease (first report documenting cerebral involvement of HHT5), but with earlier onset of epistaxis and a unique anatomic distribution of dermal capillary lesions that involved the upper forelimbs, trunk, and head. The other two patients harbored interstitial deletions larger than five megabases between 10q11.22 and 10q11.23 that included GDF2. To our knowledge, this is the first report detailing large genomic deletions leading to HHT5. These patients also demonstrated mucocutaneous capillary dysplasias, including intranasal vascular lesions complicated by childhood-onset epistasis, with a number of extravascular findings related to their 10q11.21q11.23 deletion. In conclusion, patients with GDF2-related HHT may present with a number of unique characteristics that differ from classically reported features of HHT.
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Affiliation(s)
- Ahmed Farhan
- Division of Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Frank Yuan
- Division of Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elizabeth Partan
- McKusick-Nathans Institute of Genetic Medicine, Department of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Clifford R Weiss
- Division of Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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22
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Abstract
Brain arteriovenous malformation (bAVM) is the most common cause of intracranial hemorrhage (ICH), particularly in young patients. However, the exact cause of bAVM bleeding and rupture is not yet fully understood. In bAVMs, blood bypasses the entire capillary bed and directly flows from arteries to veins. The vessel walls in bAVMs have structural defects, which impair vascular integrity. Mural cells are essential structural and functional components of blood vessels and play a critical role in maintaining vascular integrity. Changes in mural cell number and coverage have been implicated in bAVMs. In this review, we discussed the roles of mural cells in bAVM pathogenesis. We focused on 1) the recent advances in human and animal studies of bAVMs; 2) the importance of mural cells in vascular integrity; 3) the regulatory signaling pathways that regulate mural cell function. More specifically, the platelet-derived growth factor-B (PDGF-B)/PDGF receptor-β (PDGFR-β), EphrinB2/EphB4, and angiopoietins/tie2 signaling pathways that regulate mural cell-recruitment during vascular remodeling were discussed in detail.
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23
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Thompson KP, Nelson J, Kim H, Weinsheimer SM, Marchuk DA, Lawton MT, Krings T, Faughnan ME. Utility of modified Rankin Scale for brain vascular malformations in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2021; 16:390. [PMID: 34538258 PMCID: PMC8451134 DOI: 10.1186/s13023-021-02012-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/24/2021] [Indexed: 11/10/2022] Open
Abstract
Background Approximately 10% of hereditary hemorrhagic telangiectasia (HHT) patients harbour brain vascular malformations (VMs). Intracranial hemorrhage (ICH) from brain VMs can lead to death or morbidity, while treatment options for brain VMs also have associated morbidity. The modified Rankin Scale (mRS) may provide an approach to identifying HHT-brain VM patients with poor outcomes, and their predictors. We aimed to measure the relationship between mRS score and brain VM, brain VM number, as well as other aspects of HHT, at enrollment and during prospective follow-up. Methods 1637 HHT patients (342 with brain VMs) were recruited from 14 HHT centres of the Brain Vascular Malformation Consortium since 2010 and followed prospectively (mean = 3.4 years). We tested whether the presence of brain VM, other HHT organ involvement, and HHT mutation genotype were associated with worse mRS scores at baseline and during follow-up, using linear mixed models, adjusting for age, sex, and year of visit. Results Presence of brain VMs was not associated with worse mRS score at baseline and there was no significant worsening of mRS with prospective follow-up in these patients; 92% had baseline mRS of 0–2. HHT-related gastrointestinal (GI) bleeding was associated with worse mRS scores at baseline (0.37, 95% CI 0.26–0.47, p < 0.001), as were history of anemia (0.35, 95% CI 0.27–0.43, p < 0.001) and liver VMs (0.19, 95% CI 0.09–0.30, p < 0.001). Presence of pulmonary arteriovenous malformations (AVMs) was not associated with worse mRS scores at baseline. mRS score was not associated with either HHT genotype (Endoglin vs ACVRL1). Only GI bleeding was associated with a significantly worsening mRS during prospective follow-up (0.64, 95% CI 0.21–1.08, p = 0.004). Conclusion Most HHT-brain VM patients had good functional capacity (mRS scores 0–2) at baseline that did not change significantly over 3.4 mean years of follow-up, suggesting that mRS may not be useful for predicting or measuring outcomes in these patients. However, HHT patients with GI bleeding, anemia history or liver VMs had worse mRS scores, suggesting significant impact of these manifestations on functional capacity. Our study demonstrates the insensitivity of the mRS as an outcomes measure in HHT brain VM patients and reinforces the continued need to develop outcomes measures, and their predictors, in this group.
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Affiliation(s)
- K P Thompson
- Toronto HHT Centre, St. Michael's Hospital and Li Ka Shing Knowledge Institute, Toronto, Canada.,Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada
| | - J Nelson
- Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA
| | - H Kim
- Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.,Institute for Human Genetics, University of California, San Francisco, CA, USA.,Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - S M Weinsheimer
- Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.,Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - D A Marchuk
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
| | - M T Lawton
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA
| | - T Krings
- Division of Neurosurgery, Department of Medical Imaging, Department of Surgery, University of Toronto, Toronto, Canada.,Division of Neuroradiology, Toronto Western Hospital, Univeristy Health Network, Toronto, Canada
| | - M E Faughnan
- Toronto HHT Centre, St. Michael's Hospital and Li Ka Shing Knowledge Institute, Toronto, Canada. .,Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada.
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Primikiris P, Hadjigeorgiou G, Tsamopoulou M, Biondi A, Iosif C. Review on the current treatment status of vein of Galen malformations and future directions in research and treatment. Expert Rev Med Devices 2021; 18:933-954. [PMID: 34424109 DOI: 10.1080/17434440.2021.1970527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Vein of Galen malformations (VOGMs) represent a rare pathologic entity with often catastrophic natural history. The advances in endovascular treatment in recent years have allowed for a paradigm shift in the treatment and outcome of these high-flow shunts, even though their pathogenetic mechanisms and evolution remain in part obscure. AREAS COVERED The overall management of VOGMs requires a tailored case-to-case approach, starting with in utero detection and reserving endovascular treatment for indicated cases. Lately, the advances in translational research with whole-genome sequencing and the coupling with cellular-level hemodynamics attempt to shed more light in the pathogenesis and evolution of these lesions. At the same time the advances in endovascular techniques allow for more safety and tailored technical strategy planning. Furthermore, the advances in MRI techniques allow a better understanding of their vascular anatomy. In view of these recent advances and by performing a PUBMED literature review of the last 15 years, we attempt a review of the evolutions in the imaging, management, endovascular treatment and understanding of underlying mechanisms for VOGMs. EXPERT OPINION The progress in the fields detailed in this review appears very promising in better understanding VOGMs and expanding the available therapeutic arsenal.
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Affiliation(s)
- Panagiotis Primikiris
- Department of Interventional Neuroradiology, Jean Minjoz University Hospital, Besancon, France
| | | | - Maria Tsamopoulou
- School of Medicine, National Kapodistrian University of Athens, Greece
| | - Alessandra Biondi
- Department of Interventional Neuroradiology, Jean Minjoz University Hospital, Besancon, France
| | - Christina Iosif
- School of Medicine, European University of Cyprus, Nicosia, Cyprus.,Department of Interventional Neuroradiology, Henry Dunant Hospital, Athens, Greece
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25
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Major T, Bereczky Z, Gindele R, Balogh G, Rácz B, Bora L, Kézsmárki Z, Brúgós B, Pfliegler G. Current Status of Clinical and Genetic Screening of Hereditary Hemorrhagic Telangiectasia Families in Hungary. J Clin Med 2021; 10:jcm10173774. [PMID: 34501220 PMCID: PMC8432115 DOI: 10.3390/jcm10173774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/15/2021] [Accepted: 08/20/2021] [Indexed: 12/30/2022] Open
Affiliation(s)
- Tamás Major
- Division of Otorhinolaryngology and Head & Neck Surgery, Kenézy Gyula Campus, University of Debrecen Medical Center, University of Debrecen, H-4031 Debrecen, Hungary;
- Correspondence: (T.M.); (Z.B.); Tel.: +36-52-511777 (ext. 1756) (T.M.); +36-52-431956 (Z.B.); Fax: +36-52-511755 (T.M.); +36-52-340011 (Z.B.)
| | - Zsuzsanna Bereczky
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
- Correspondence: (T.M.); (Z.B.); Tel.: +36-52-511777 (ext. 1756) (T.M.); +36-52-431956 (Z.B.); Fax: +36-52-511755 (T.M.); +36-52-340011 (Z.B.)
| | - Réka Gindele
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
| | - Gábor Balogh
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
| | - Benedek Rácz
- Division of Otorhinolaryngology and Head & Neck Surgery, Kenézy Gyula Campus, University of Debrecen Medical Center, University of Debrecen, H-4031 Debrecen, Hungary;
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
| | - László Bora
- Department of Radiology, Szent Lázár County Hospital, H-3100 Salgótarján, Hungary;
| | - Zsolt Kézsmárki
- Division of Radiology, Kenézy Gyula Campus, University of Debrecen Medical Center, University of Debrecen, H-4031 Debrecen, Hungary;
| | - Boglárka Brúgós
- Division of Rare Diseases, Department of Internal Medicine Block B, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (G.P.)
| | - György Pfliegler
- Division of Rare Diseases, Department of Internal Medicine Block B, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (B.B.); (G.P.)
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Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1. Int J Mol Sci 2021; 22:ijms22168948. [PMID: 34445652 PMCID: PMC8396348 DOI: 10.3390/ijms22168948] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022] Open
Abstract
Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.
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Fu Y, Wang H, Dai H, Zhu Q, Cui CP, Sun X, Li Y, Deng Z, Zhou X, Ge Y, Peng Z, Yuan C, Wu B, Yang X, Li R, Liu CH, He F, Wei W, Zhang L. OTULIN allies with LUBAC to govern angiogenesis by editing ALK1 linear polyubiquitin. Mol Cell 2021; 81:3187-3204.e7. [PMID: 34157307 DOI: 10.1016/j.molcel.2021.05.031] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 04/04/2021] [Accepted: 05/27/2021] [Indexed: 12/25/2022]
Abstract
OTULIN coordinates with LUBAC to edit linear polyubiquitin chains in embryonic development, autoimmunity, and inflammatory diseases. However, the mechanism by which angiogenesis, especially that of endothelial cells (ECs), is regulated by linear ubiquitination remains unclear. Here, we reveal that constitutive or EC-specific deletion of Otulin resulted in arteriovenous malformations and embryonic lethality. LUBAC conjugates linear ubiquitin chains onto Activin receptor-like kinase 1 (ALK1), which is responsible for angiogenesis defects, inhibiting ALK1 enzyme activity and Smad1/5 activation. Conversely, OTULIN deubiquitinates ALK1 to promote Smad1/5 activation. Consistently, embryonic survival of Otulin-deficient mice was prolonged by BMP9 pretreatment or EC-specific ALK1Q200D (constitutively active) knockin. Moreover, mutant ALK1 from type 2 hereditary hemorrhagic telangiectasia (HHT2) patients exhibited excessive linear ubiquitination and increased HOIP binding. As such, a HOIP inhibitor restricted the excessive angiogenesis of ECs derived from ALK1G309S-expressing HHT2 patients. These results show that OTULIN and LUBAC govern ALK1 activity to balance EC angiogenesis.
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Affiliation(s)
- Yesheng Fu
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; School of Life Sciences, Peking University, Beijing 100871, China
| | - Hongtian Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Hongmiao Dai
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Qiong Zhu
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Chun-Ping Cui
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Xiaoxuan Sun
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
| | - Yanchang Li
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Zhikang Deng
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Xuemei Zhou
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Yingwei Ge
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Zhiqiang Peng
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Chao Yuan
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Bo Wu
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Xi Yang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Rongyu Li
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Cui Hua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology (Chinese Academy of Sciences), Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100101, China.
| | - Fuchu He
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; School of Life Sciences, Peking University, Beijing 100871, China.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China.
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Iriarte A, Ochoa-Callejero L, García-Sanmartín J, Cerdà P, Garrido P, Narro-Íñiguez J, Mora-Luján JM, Jucglà A, Sánchez-Corral MA, Cruellas F, Gamundi E, Ribas J, Castellote J, Viñals F, Martínez A, Riera-Mestre A. Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia. Eur J Intern Med 2021; 88:89-95. [PMID: 33888392 DOI: 10.1016/j.ejim.2021.03.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/28/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Adrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity. The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. METHODS Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. RESULTS Forty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1-80.6] pg/mL in the HHT group and 47.7 [43.2-53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. CONCLUSIONS We detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.
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Affiliation(s)
- A Iriarte
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Internal Medicine Department. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain
| | - L Ochoa-Callejero
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño Spain
| | - J García-Sanmartín
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño Spain
| | - P Cerdà
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Internal Medicine Department. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain
| | - P Garrido
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño Spain
| | - J Narro-Íñiguez
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño Spain
| | - J M Mora-Luján
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Internal Medicine Department. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain
| | - A Jucglà
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain; Dermatology Department. Hospital Universitari de Bellvitge, Barcelona Spain
| | - M A Sánchez-Corral
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain; Cardiology Department. Hospital Universitari de Bellvitge, Barcelona Spain
| | - F Cruellas
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain; Otorhinolaryngology Department. Hospital Universitari de Bellvitge, Barcelona Spain
| | - E Gamundi
- Hematology Department. Hospital Universitari de Bellvitge, Barcelona Spain
| | - J Ribas
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain; Pneumology Department. Hospital Universitari de Bellvitge, Barcelona Spain
| | - J Castellote
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain; Liver Transplant Unit, Gastroenterology Department. Hospital Universitari de Bellvitge, Barcelona Spain; Physiological Sciences Department. Faculty of Medicine and Health Sciences. Universitat de Barcelona, Barcelona, Spain
| | - F Viñals
- Physiological Sciences Department. Faculty of Medicine and Health Sciences. Universitat de Barcelona, Barcelona, Spain; Program Against Cancer Therapeutic Resistance, Institut Catala d'Oncologia, Hospital Duran i Reynals, Barcelona Spain; Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - A Martínez
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño Spain
| | - A Riera-Mestre
- HHT Unit. Hospital Universitari de Bellvitge, Barcelona Spain; Internal Medicine Department. Hospital Universitari de Bellvitge, Barcelona Spain; Bellvitge Biomedical Research Institute (IDIBELL), Barcelona Spain; Faculty of Medicine and Health Sciences. Universitat de Barcelona, Barcelona, Spain.
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Major T, Gindele R, Balogh G, Bárdossy P, Bereczky Z. Founder Effects in Hereditary Hemorrhagic Telangiectasia. J Clin Med 2021; 10:jcm10081682. [PMID: 33919892 PMCID: PMC8070971 DOI: 10.3390/jcm10081682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 12/26/2022] Open
Abstract
A founder effect can result from the establishment of a new population by individuals from a larger population or bottleneck events. Certain alleles may be found at much higher frequencies because of genetic drift immediately after the founder event. We provide a systematic literature review of the sporadically reported founder effects in hereditary hemorrhagic telangiectasia (HHT). All publications from the ACVRL1, ENG and SMAD4 Mutation Databases and publications searched for terms “hereditary hemorrhagic telangiectasia” and “founder” in PubMed and Scopus, respectively, were extracted. Following duplicate removal, 141 publications were searched for the terms “founder” and “founding” and the etymon “ancest”. Finally, 67 publications between 1992 and 2020 were reviewed. Founder effects were graded upon shared area of ancestry/residence, shared core haplotypes, genealogy and prevalence. Twenty-six ACVRL1 and 12 ENG variants with a potential founder effect were identified. The bigger the cluster of families with a founder mutation, the more remarkable is its influence to the populational ACVRL1/ENG ratio, affecting HHT phenotype. Being aware of founder effects might simplify the diagnosis of HHT by establishing local genetic algorithms. Families sharing a common core haplotype might serve as a basis to study potential second-hits in the etiology of HHT.
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Affiliation(s)
- Tamás Major
- Division of Otorhinolaryngology and Head & Neck Surgery, Kenézy Gyula Campus, University of Debrecen Medical Center, H-4031 Debrecen, Hungary
- Correspondence: (T.M.); (Z.B.); Tel.: +36-52-511777/1756 (T.M.); +36-52-431956 (Z.B.); Fax: +36-52-511755 (T.M.); +36-52-340011 (Z.B.)
| | - Réka Gindele
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
| | - Gábor Balogh
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
| | - Péter Bárdossy
- Hungarian Heraldry and Genealogical Society, H-1014 Budapest, Hungary;
| | - Zsuzsanna Bereczky
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (R.G.); (G.B.)
- Correspondence: (T.M.); (Z.B.); Tel.: +36-52-511777/1756 (T.M.); +36-52-431956 (Z.B.); Fax: +36-52-511755 (T.M.); +36-52-340011 (Z.B.)
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30
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Latif MA, Sobreira NLD, Guthrie KS, Motaghi M, Robinson GM, Shafaat O, Gong AJ, Weiss CR. Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia: Experience from an HHT Center of Excellence. Am J Med Genet A 2021; 185:1981-1990. [PMID: 33768677 DOI: 10.1002/ajmg.a.62193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/10/2020] [Accepted: 03/06/2021] [Indexed: 11/11/2022]
Abstract
In this retrospective single-center study, we evaluated whether/how pathogenic/likely pathogenic variants of three hereditary hemorrhagic telangiectasia (HHT)-associated genes (ENG, ACVRL1, and SMAD4) are associated with specific clinical presentations of HHT. We also characterized the morphological features of pulmonary arteriovenous malformations (AVMs) in patients with these variants. Pathogenic or likely pathogenic variants were detected in 64 patients. Using nonparametric statistical tests, we compared the type and prevalence of specific HHT diagnostic features associated with these three variants. Pathogenic variants in these genes resulted in gene-specific HHT clinical presentations. Epistaxis was present in 93%, 94%, and 100% of patients with ENG, ACVRL1, and SMAD4 variants, respectively (p = 0.79). Pulmonary AVMs were more common in patients with the ENG variant (p = 0.034) compared with other subgroups. ACVRL1 variant was associated with the lowest frequency of pulmonary AVMs (p = 0.034) but the highest frequency of hepatic AVMs (p = 0.015). Patients with the ACVRL1 variant did not have significantly more pancreatic AVMs compared with the other groups (p = 0.72). ENG, ACVRL1, and SMAD4 pathogenic or likely pathogenic variants are associated with gene-specific HHT presentations, which is consistent with results from other HHT centers.
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Affiliation(s)
- Muhammad A Latif
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Epidemiology and Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Nara Lygia D Sobreira
- Department of Genetic Medicine, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kelsey S Guthrie
- Department of Genetic Medicine, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mina Motaghi
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Epidemiology and Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Gina M Robinson
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Omid Shafaat
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Anna J Gong
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Clifford R Weiss
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood 2021; 136:1907-1918. [PMID: 32573726 DOI: 10.1182/blood.2019004560] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 05/17/2020] [Indexed: 12/13/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT.
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Snodgrass RO, Chico TJA, Arthur HM. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Genes (Basel) 2021; 12:174. [PMID: 33513792 PMCID: PMC7911152 DOI: 10.3390/genes12020174] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies.
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Affiliation(s)
- Ryan O. Snodgrass
- Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK; (R.O.S.); (T.J.A.C.)
| | - Timothy J. A. Chico
- Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield S10 2RX, UK; (R.O.S.); (T.J.A.C.)
| | - Helen M. Arthur
- Biosciences Institute, Centre for Life, Newcastle University, Newcastle NE1 3BZ, UK
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Alvarez H, Niazi MH, Loewenstein J, Quinsey CS. Neonatal bilateral cerebral high flow fistulae leading to detection of a HHT-family carrier. Interv Neuroradiol 2020; 27:547-552. [PMID: 33353465 DOI: 10.1177/1591019920981308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Cerebral and spinal cord high-flow arteriovenous fistulae (HFAVF) are part of the spectrum of lesions found in Hereditary Hemorrhagic Telangiectasia (HHT). HFAVF consist of communications between large arteries and veins without interposed nidi or capillary transitions. The association between HHT and cerebral or spinal HFAVF in children has been reported and suggested as a potential marker for HHT. We present a newborn with bilateral intracranial HFAVF tested positive for HHT1 and belonging to a family non known for carrying a HHT mutation. We also review reported cases of neonates and infants with cerebral and spinal HFAVF emphasizing their associations with genetic syndromes. Our aim is to add a new case to the pertinent literature and emphasize the need for molecular testing in children with spinal or brain HFAVF.
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Affiliation(s)
- Hortensia Alvarez
- Division of Interventional Neuroradiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Muhammad H Niazi
- Division of Interventional Neuroradiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Joshua Loewenstein
- Department of Neurosurgery at the University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Carolyn S Quinsey
- Department of Neurosurgery at the University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Gómez-Acebo I, Prado SR, De La Mora Á, Puente RZ, de la Roza Varela B, Dierssen-Sotos T, Llorca J. Ocular lesions in hereditary hemorrhagic telangiectasia: genetics and clinical characteristics. Orphanet J Rare Dis 2020; 15:168. [PMID: 32600370 PMCID: PMC7322834 DOI: 10.1186/s13023-020-01433-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/04/2020] [Indexed: 11/17/2022] Open
Abstract
Background The aim of our study is to study the association between eye lesions in Hereditary Hemorrhagic Telangiectasia (HHT) and other signs of the disease, as well as to characterize its genetics. Methods A cross-sectional study was conducted of a cohort of 206 patients studied in the HHT Unit of Hospital de Sierrallana, a reference centre for Spanish patients with HHT. Odds ratios for several symptoms or characteristics of HHT and ocular lesions were estimated using logistic regression adjusting for age and sex. Results The ocular involvement was associated with being a carrier of a mutation for the ENG gene, that is, suffering from a type 1 HHT involvement (OR = 2.09; 95% CI [1.17–3.72]). p = 0.012). In contrast, patients with ocular lesions have less frequently mutated ACVRL1/ALK1 gene (OR = 0.52; 95% CI [0.30–3.88], p = 0.022). Conclusions In conclusion, half of the patients with HHT in our study have ocular involvement. These eye lesions are associated with mutations in the ENG gene and ACVRL1/ALK1 gene. Thus, the ENG gene increases the risk of ocular lesions, while being a carrier of the mutated ACVRL1/ALK1 gene decreases said risk.
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Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia. J Clin Med 2020; 9:jcm9113571. [PMID: 33167572 PMCID: PMC7694477 DOI: 10.3390/jcm9113571] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.
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Kim AS, Henderson KJ, Pawar S, Kim MJ, Punjani S, Pollak JS, Fahey JT, Garcia‐Tsao G, Sugeng L, Young LH. Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations. J Am Heart Assoc 2020; 9:e016197. [PMID: 33054561 PMCID: PMC7763373 DOI: 10.1161/jaha.120.016197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background Patients with hereditary hemorrhagic telangiectasia have liver vascular malformations that can cause high‐output cardiac failure (HOCF). Known sequelae include pulmonary hypertension, tricuspid regurgitation, and atrial fibrillation. Methods and Results The objectives of this study were to describe the clinical, echocardiographic, and hemodynamic characteristics and prognosis of hereditary hemorrhagic telangiectasia patients with HOCF who were found to have a subaortic membrane (SAoM). A retrospective observational analysis comparing patients with and without SAoM was performed. Among a cohort of patients with HOCF, 9 were found to have a SAoM in the left ventricular outflow tract by echocardiography (all female, mean age 64.8±4.0 years). The SAoM was discrete and located in the left ventricular outflow tract 1.1±0.1 cm below the aortic annular plane. It caused turbulent flow, mild obstruction (peak velocity 2.8±0.2 m/s, peak gradient 32±4 mm Hg), and no more than mild aortic insufficiency. Patients with SAoM (n=9) had higher cardiac output (12.1±1.3 versus 9.3±0.7 L/min, P=0.04) and mean pulmonary artery pressures (36±3 versus 28±2 mm Hg, P=0.03) compared with those without SAoM (n=19) during right heart catheterization. Genetic analysis revealed activin receptor‐like kinase 1 mutations in each of the 8 patients with SAoM who had available test results. The presence of a SAoM was associated with a trend towards higher 5‐year mortality during follow‐up. Conclusions SAoM with mild obstruction occurs in patients with hereditary hemorrhagic telangiectasia and HOCF. SAoM was associated with features of more advanced HOCF and poor outcomes.
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Affiliation(s)
- Agnes S. Kim
- Department of Internal Medicine Calhoun Cardiology Center University of Connecticut School of Medicine Farmington CT
| | - Katharine J. Henderson
- Section of Vascular and Interventional Radiology Department of Radiology and Biomedical Imaging Yale University School of Medicine New Haven CT
| | - Sumeet Pawar
- Section of Cardiovascular Medicine Department of Internal Medicine Yale University School of Medicine New Haven CT
| | - Min Jung Kim
- Department of Internal Medicine Calhoun Cardiology Center University of Connecticut School of Medicine Farmington CT
| | - Shahnaz Punjani
- Section of Cardiovascular Medicine Department of Internal Medicine Yale University School of Medicine New Haven CT
| | - Jeffrey S. Pollak
- Section of Vascular and Interventional Radiology Department of Radiology and Biomedical Imaging Yale University School of Medicine New Haven CT
| | - John T. Fahey
- Section of Cardiology Department of Pediatrics Yale University School of Medicine New Haven CT
| | - Guadalupe Garcia‐Tsao
- Section of Digestive Disease Department of Internal Medicine Yale University School of Medicine New Haven CT
| | - Lissa Sugeng
- Section of Cardiovascular Medicine Department of Internal Medicine Yale University School of Medicine New Haven CT
| | - Lawrence H. Young
- Section of Cardiovascular Medicine Department of Internal Medicine Yale University School of Medicine New Haven CT
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Giraud S, Bardel C, Dupuis-Girod S, Carette MF, Gilbert-Dussardier B, Riviere S, Saurin JC, Eyries M, Patri S, Decullier E, Calender A, Lesca G. Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2020; 15:254. [PMID: 32962750 PMCID: PMC7507685 DOI: 10.1186/s13023-020-01533-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/07/2020] [Indexed: 11/23/2022] Open
Abstract
Background Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs. Methods We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs. Results The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383). Conclusions In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.
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Affiliation(s)
- Sophie Giraud
- Hospices Civils de Lyon, Service de Génétique, Groupement Hospitalier Est, 69677, Bron, France
| | - Claire Bardel
- Service de Biostatistique-Bioinformatique, plateforme de séquençage à haut débit, Hospices Civils de Lyon, Lyon, France.,Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne, France.,CNRS UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biotatistique-Santé, F-69100, Villeurbanne, France
| | - Sophie Dupuis-Girod
- Hospices Civils de Lyon, Service de Génétique, Groupement Hospitalier Est, 69677, Bron, France.,Centre de Référence National pour la maladie de Rendu-Osler, Groupement Hospitalier Est, Bron, France
| | | | | | - Sophie Riviere
- CHU de Montpellier, Service de Médecine Interne, Hôpital St Eloi, Montpellier, France
| | - Jean-Christophe Saurin
- Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne, France.,Hospices Civils de Lyon, Service de Gastro-Entérologie, Hôpital E. Herriot, Lyon, France
| | - Mélanie Eyries
- Assistance Publique-Hôpitaux de Paris, Département de Génétique, GH Pitié-Salpêtrière, Paris, France
| | - Sylvie Patri
- CHU la Milétrie, Laboratoire de Génétique, Poitiers, France
| | - Evelyne Decullier
- Unité de recherche clinique du pole IMER of the Hospices Civils de Lyon, Lyon, France
| | - Alain Calender
- Hospices Civils de Lyon, Service de Génétique, Groupement Hospitalier Est, 69677, Bron, France.,Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne, France.,Equipe EA7426, Immunopathologie des voies respiratoires, Université Lyon 1, Lyon, France
| | - Gaëtan Lesca
- Hospices Civils de Lyon, Service de Génétique, Groupement Hospitalier Est, 69677, Bron, France. .,Université Claude Bernard Lyon 1, Université de Lyon, Villeurbanne, France.
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Cell-free DNA next-generation sequencing liquid biopsy as a new revolutionary approach for arteriovenous malformation. JVS Vasc Sci 2020; 1:176-180. [PMID: 34617046 PMCID: PMC8489236 DOI: 10.1016/j.jvssci.2020.08.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 08/04/2020] [Indexed: 01/04/2023] Open
Abstract
Objective Somatic mosaicism of KRAS gene is currently recognized as the only established molecular basis of arteriovenous malformations (AVM). However, given the limitations of the current technologies, KRAS somatic mutations are detected only in a limited proportion of AVMs and tissue biopsy remains an invasive high risky, sometimes life-threatening, diagnostic procedure. Next-generation sequencing liquid biopsy using cell-free DNA (cfDNA) has emerged as an innovative noninvasive approach for early detection and monitoring of cancer. This approach overcomes the space-time profile constraint of tissue biopsies opens a new scenario for vascular malformations owing to somatic mosaicism. Here, we propose a new approach as a fast noninvasive reliable tool in order to investigate the cfDNA coming from the AVMs. Methods A group of five patients suffering from AVM were selected. Blood samples from peripheral vein and efferent vein from vascular malformation were collected and cfDNA was extracted. The cfDNA libraries were performed using Oncomine Pan-Cancer Cell-Free Assay. We used Ion Proton for sequencing and Ion Reporter Software for analysis (Life Technologies, Carlsbad, Calif). Results In all cases, either G12D or G12V mutations in KRAS were identified. The mutational load was higher in the efferent vein than in peripheral blood, confirming the causative role of the identified mutation at a somatic level. Conclusions We demonstrate that cfDNA next-generation sequencing liquid biopsy is able to identify the KRAS mutation detected in affected tissues. Moreover, we have shown that blood sample withdrawal at the lesion site increases variant allele frequency with an order of magnitude above the limit of detection (usually 0.05%), decreasing the risk of a false negative. Finally, the noninvasiveness of the method avoids any risk of bleeding, being easily performed also in children. We propose this technique as the method of choice to better investigate AVMs and consequently to identify the therapy tailored to the genetic defect. Clinical Relevance This article highlights the importance of using liquid biopsy as a new method to investigate the molecular profile of AVMs. In view of the frequent inaccessibility of vascular tissues owing to the invasiveness of solid biopsy and the relative high incidence of biopsies with low diagnostic power, here we evaluated the efficacy of detecting cfDNA fragments released into the bloodstream from the affected tissue cells. Through a simple blood draw from the efferent vein at the vascular malformation site, the liquid biopsy allowed us to identify KRAS pathogenic mutations piloting a personalized therapeutic approach and opening a new scenario for new therapeutic strategies.
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Genotype-Phenotype Correlations in Children with HHT. J Clin Med 2020; 9:jcm9092714. [PMID: 32842615 PMCID: PMC7565052 DOI: 10.3390/jcm9092714] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/15/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype-phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype-phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0-18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype-defined as both pulmonary AVMs and brain VMs-was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype-phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype.
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Hwan Kim Y, Vu PN, Choe SW, Jeon CJ, Arthur HM, Vary CPH, Lee YJ, Oh SP. Overexpression of Activin Receptor-Like Kinase 1 in Endothelial Cells Suppresses Development of Arteriovenous Malformations in Mouse Models of Hereditary Hemorrhagic Telangiectasia. Circ Res 2020; 127:1122-1137. [PMID: 32762495 DOI: 10.1161/circresaha.119.316267] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
RATIONALE Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease caused by mutations in ENG, ALK1, or SMAD4. Since proteins from all 3 HHT genes are components of signal transduction of TGF-β (transforming growth factor β) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce. OBJECTIVE We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT. METHODS AND RESULTS We generated a novel mouse allele (ROSA26Alk1) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26Alk1 allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of Alk1- and Eng-inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in Eng-iKO as well as Alk1-iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in Alk1-iKO models. CONCLUSIONS These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.
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Affiliation(s)
- Yong Hwan Kim
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.).,Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ (Y.H.K., S.P.O.)
| | - Phuong-Nhung Vu
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (N.V.P., Y.J.L.)
| | - Se-Woon Choe
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.).,Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, Republic of Korea (S.-w.C.)
| | - Chang-Jin Jeon
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Korea (C.J.J.)
| | - Helen M Arthur
- Institute of Genetic Medicine, Newcastle University, United Kingdom (H.M.A.)
| | - Calvin P H Vary
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (C.P.V.)
| | - Young Jae Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea (N.V.P., Y.J.L.)
| | - S Paul Oh
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville (Y.H.K., S.-w.C., S.P.O.).,Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ (Y.H.K., S.P.O.)
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Beckman JD, Li Q, Hester ST, Leitner O, Smith KL, Kasthuri RS. Integration of clinical parameters, genotype and epistaxis severity score to guide treatment for hereditary hemorrhagic telangiectasia associated bleeding. Orphanet J Rare Dis 2020; 15:185. [PMID: 32660636 PMCID: PMC7359017 DOI: 10.1186/s13023-020-01453-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/29/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Hereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT. METHODOLOGY We conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS. RESULTS One hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p < 0.05). Neither ESS nor genotype was predictive of pulmonary or brain AVMs. Twenty-four HHT patients with ESS > 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months. CONCLUSIONS We demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.
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Affiliation(s)
- Joan D Beckman
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Quefeng Li
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Samuel T Hester
- Department of Internal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ofri Leitner
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Karen L Smith
- Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB#7035, 8206B Mary Ellen Jones Bldg, 116 Manning Drive, Chapel Hill, NC, 27599, USA
| | - Raj S Kasthuri
- Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, CB#7035, 8206B Mary Ellen Jones Bldg, 116 Manning Drive, Chapel Hill, NC, 27599, USA.
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Kang HC, Martins Pereira MA, Silva LNL, Oliveira LC, Márvila IS. Hereditary Hemorrhagic Telangiectasia in a Sickle Cell Trait Patient: A Report of a Rare Case with Use of Nuclear Medicine, and a Literature Review. AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e923355. [PMID: 32614805 PMCID: PMC7347035 DOI: 10.12659/ajcr.923355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Patient: Female, 49-year-old Final Diagnosis: Hereditary haemorrhagic telangiectasia Symptoms: Anemia • dyspnea • epistaxis • lipothymia • melena • weakness Medication:— Clinical Procedure: Electrofulguration Specialty: Gastroenterology and Hepatology • Genetics • Radiology
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Affiliation(s)
- Hye Chung Kang
- Department of Pathology, Fluminense Federal University, Niterói, RJ, Brazil
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Han Z, Shaligram S, Faughnan ME, Clark D, Sun Z, Su H. Reduction of endoglin receptor impairs mononuclear cell-migration. EXPLORATION OF MEDICINE 2020; 1:136-148. [PMID: 32954380 PMCID: PMC7500529 DOI: 10.37349/emed.2020.00010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Aim: To test if the impairment of mononuclear cell (MNC) migration in patients with hereditary hemorrhagic telangiectasia (HHT) is due to the reduction of the endoglin (ENG) receptor on the cell surface and oxidative stress. Methods: MNCs of HHT patients and normal controls were subjected to migration assay. Fractions of MNCs were pre-incubated with antibodies specific to HHT causative genes ENG [hereditary hemorrhagic telangiectasia type 1 (HHT1)] or activin receptor-like kinase 1 [ALK1, hereditary hemorrhagic telangiectasia type 2 (HHT2)], AMD3100 or Diprotin-A to block ENG, ALK1 C-X-C chemokine receptor 4 (CXCR4) or CD26 (increased in HHT1 MNCs) before migration assay. The MNCs were allowed to migrate toward stromal cell-derived factor-1α (SDF-1α) for 18 h. The expression of CXCR4, CD26, superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPX1) in MNCs and nitric oxide levels in the plasma were analyzed. Results: Compared to the controls, fewer HHT1 MNCs and similar number of HHT2 MNCs migrated toward SDF-1α. Diprotin-A pre-treatment improved HHT1 MNC-migration, but had no effect on normal and HHT2 MNCs. Pre-incubation with an anti-ENG antibody reduced the migration of normal MNCs. Diprotin-A did not improve the migration of ENG antibody pre-treated MNCs. Anti-ALK1 antibody had no effect on MNC-migration. AMD3100 treatment reduced normal and HHT MNC-migration. ENG mRNA level was reduced in HHT1 and HHT2 MNCs. ALK1 mRNA was reduced in HHT2 MNCs only. CD26 expression was higher in HHT1 MNCs. Pre-treatment of MNCs with anti-ENG or anti-ALK1 antibody had no effect on CD26 and CXCR4 expression. The expression of antioxidant enzymes, SOD1, was reduced in HHT1 MNCs, which was accompanied with an increase of ROS in HHT MNCs and nitric oxide in HHT1 plasma. Conclusions: Reduction of ENG receptor on MNC surface reduced monocyte migration toward SDF-1α independent of CD26 expression. Increased oxidative stress could alter HHT MNC migration behavior.
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Affiliation(s)
- Zhenying Han
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.,Center for Cerebrovascular Research, University of California, San Francisco, CA 94143, USA
| | - Sonali Shaligram
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.,Center for Cerebrovascular Research, University of California, San Francisco, CA 94143, USA
| | - Marie E Faughnan
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital, University of Toronto, Ontario M5B 1W8, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario M5B 1W8, Canada
| | - Dewi Clark
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital, University of Toronto, Ontario M5B 1W8, Canada
| | - Zhengda Sun
- Department of Radiology, University of California, San Francisco, CA 94143, USA
| | - Hua Su
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.,Center for Cerebrovascular Research, University of California, San Francisco, CA 94143, USA
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Sánchez-Martínez R, Iriarte A, Mora-Luján JM, Patier JL, López-Wolf D, Ojeda A, Torralba MA, Juyol MC, Gil R, Añón S, Salazar-Mendiguchía J, Riera-Mestre A. Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. Orphanet J Rare Dis 2020; 15:138. [PMID: 32503579 PMCID: PMC7275435 DOI: 10.1186/s13023-020-01422-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/27/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis. METHODS We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. RESULTS By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. CONCLUSIONS ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.
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Affiliation(s)
- Rosario Sánchez-Martínez
- Internal Medicine Department, Hospital General Universitario de Alicante - ISABIAL, Alicante, Spain.,Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain
| | - Adriana Iriarte
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Hereditary Hemorrhagic Telangiectasia Unit, Internal Medicine Department, Hospital Universitari de Bellvitge - IDIBELL, Feixa Llarga s/n. 08907 L'Hospitalet de Llobregat, Barcelona, Spain
| | - José María Mora-Luján
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Hereditary Hemorrhagic Telangiectasia Unit, Internal Medicine Department, Hospital Universitari de Bellvitge - IDIBELL, Feixa Llarga s/n. 08907 L'Hospitalet de Llobregat, Barcelona, Spain
| | - José Luis Patier
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Department of Internal Medicine, Systemic and Orphan Diseases Unit, University Hospital Ramón y Cajal, University of Alcalá, IRYCIS, Madrid, Spain
| | - Daniel López-Wolf
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Internal Medicine Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | - Ana Ojeda
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Internal Medicine Department, Hospital Insular Universitario de Gran Canaria, Gran Canaria, Spain
| | - Miguel Angel Torralba
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Internal Medicine Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - María Coloma Juyol
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Internal Medicine Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Ricardo Gil
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Internal Medicine Department, Hospital La Fe, Valencia, Spain
| | - Sol Añón
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain.,Internal Medicine Department, Hospital Arnau de Vilanova, Valencia, Spain
| | - Joel Salazar-Mendiguchía
- Health in Code, A Coruña, Spain.,Clinical Genetics Program, Hospital Universitari de Bellvitge - IDIBELL, Barcelona, Spain.,Genetics Department, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Antoni Riera-Mestre
- Rare Diseases Working Group, Spanish Society of Internal Medicine, Madrid, Spain. .,Hereditary Hemorrhagic Telangiectasia Unit, Internal Medicine Department, Hospital Universitari de Bellvitge - IDIBELL, Feixa Llarga s/n. 08907 L'Hospitalet de Llobregat, Barcelona, Spain. .,Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain.
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Mora-Luján JM, Iriarte A, Alba E, Sánchez-Corral MA, Cerdà P, Cruellas F, Ordi Q, Corbella X, Ribas J, Castellote J, Riera-Mestre A. Gender differences in hereditary hemorrhagic telangiectasia severity. Orphanet J Rare Dis 2020; 15:63. [PMID: 32122373 PMCID: PMC7053104 DOI: 10.1186/s13023-020-1337-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/25/2020] [Indexed: 12/13/2022] Open
Abstract
Background Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. Methods Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations -AVMs- embolization, liver transplantation or Young’s surgery) or the presence of adverse outcomes (severe anemia, emergency department -ED- or hospital admissions and mortality). Results One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. Conclusions HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.
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Affiliation(s)
- J M Mora-Luján
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Internal Medicine Department, Hospital Universitari Bellvitge, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - A Iriarte
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Internal Medicine Department, Hospital Universitari Bellvitge, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - E Alba
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Radiology Department, Hospital Universitari Bellvitge, Barcelona, Spain
| | - M A Sánchez-Corral
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Cardiology Department, Hospital Universitari Bellvitge, Barcelona, Spain
| | - P Cerdà
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Internal Medicine Department, Hospital Universitari Bellvitge, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - F Cruellas
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Otorhinolaryngology Department, Hospital Universitari Bellvitge, Barcelona, Spain
| | - Q Ordi
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Radiology Department, Hospital Universitari Bellvitge, Barcelona, Spain
| | - X Corbella
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Internal Medicine Department, Hospital Universitari Bellvitge, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain
| | - J Ribas
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Pneumology Department, Hospital Universitari Bellvitge, Barcelona, Spain
| | - J Castellote
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Liver Transplant Unit, Department of Digestive Diseases, Hospital Universitari Bellvitge, Barcelona, Spain.,Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - A Riera-Mestre
- HHT Unit, Hospital Universitari de Bellvitge, C/Feixa Llarga s/n. L'Hospitalet de Llobregat, 08907, Barcelona, Spain. .,Internal Medicine Department, Hospital Universitari Bellvitge, Barcelona, Spain. .,Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. .,Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain.
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Crist AM, Zhou X, Garai J, Lee AR, Thoele J, Ullmer C, Klein C, Zabaleta J, Meadows SM. Angiopoietin-2 Inhibition Rescues Arteriovenous Malformation in a Smad4 Hereditary Hemorrhagic Telangiectasia Mouse Model. Circulation 2020; 139:2049-2063. [PMID: 30744395 DOI: 10.1161/circulationaha.118.036952] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFβ) pathway members, including the central transcriptional mediator of the TGFβ pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFβ downstream effectors responsible for hereditary hemorrhagic telangiectasia-associated AVM formation are currently unknown. METHODS To identify potential biological targets of the TGFβ pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation-sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4-iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development. RESULTS Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4-iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4-deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4. CONCLUSIONS Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFβ downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.
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Affiliation(s)
- Angela M Crist
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)
| | - Xingyan Zhou
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)
| | - Jone Garai
- Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans (J.G., J.Z.)
| | - Amanda R Lee
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)
| | - Janina Thoele
- Roche Innovation Center, Basel, Switzerland (J.T., C.U.)
| | | | | | - Jovanny Zabaleta
- Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans (J.G., J.Z.)
| | - Stryder M Meadows
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)
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Sellier J, Karam C, Beauchet A, Dallongeville A, Binsse S, Blivet S, Bourgault-Villada I, Charron P, Chinet T, Eyries M, Fagnou C, Lesniak J, Lesur G, Lucas J, Nicod-Tran A, Ozanne A, Palmyre A, Soubrier F, El Hajjam M, Lacombe P. Higher prevalence of splenic artery aneurysms in hereditary hemorrhagic telangiectasia: Vascular implications and risk factors. PLoS One 2020; 15:e0226681. [PMID: 31971937 PMCID: PMC6977744 DOI: 10.1371/journal.pone.0226681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 12/02/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Splenic artery aneurysm (SAA) is a rare but potentially fatal condition. Rupture results in 25% mortality up to 75% in pregnant women with 95% fetal mortality. Brief reports suggest an increased risk of developing SAA in patients with HHT. METHODS We analyzed enhanced multidetector CT data in 186 HHT patients matched (gender and ± 5 year old) with 186 controls. We screened for SAA and recorded diameter of splenic and hepatic arteries and hepatic, pancreatic and splenic parenchymal involvements. We determined by univariate and multivariate analysis, the relationship with age, sex, genetic status, cardiovascular risk factors (CVRF) and visceral involvement. RESULTS SAA concerned 24.7% of HHT patients and 5.4% of controls, p<0.001. Factors associated with increased risk of SAA in HHT were female gender (p = 0.04, OR = 2.12, IC 95% = 1.03-4.50), age (p = 0.0003, OR = 1.04, 95% CI = 1.02-1.06) and pancreatic parenchymal involvement (p = 0.04, OR = 2.13, 95% CI = 1.01-4.49), but not type of mutation, hepatic or splenic parenchymal involvements, splenic size or splenic artery diameter or CVRF. CONCLUSIONS We found a 4.57 higher rate of SAA in HHT patients without evidence of splenic high output related disease or increased CVRF. These results suggest the presence of a vascular intrinsic involvement. It should lead to screening all HHT patients for SAA. The vasculopathy hypothesis could require a change in management as screening of all systemic arteries and even the aorta and to further research in the field.
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Affiliation(s)
- Jacques Sellier
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Carma Karam
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
- * E-mail:
| | - Alain Beauchet
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Axel Dallongeville
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Stephen Binsse
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Sandra Blivet
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Isabelle Bourgault-Villada
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Philippe Charron
- Pitié-Salpêtrière Hospital, Department of Genetics, AP-HP, Paris, France
| | - Thierry Chinet
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Mélanie Eyries
- Pitié-Salpêtrière Hospital, Department of Genetics, AP-HP, Paris, France
| | - Carole Fagnou
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Jérome Lesniak
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Gilles Lesur
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Jérome Lucas
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Agnès Nicod-Tran
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Augustin Ozanne
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Aurélien Palmyre
- Pitié-Salpêtrière Hospital, Department of Genetics, AP-HP, Paris, France
| | - Florent Soubrier
- Pitié-Salpêtrière Hospital, Department of Genetics, AP-HP, Paris, France
| | - Mostafa El Hajjam
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
| | - Pascal Lacombe
- Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, University of Versailles-Saint Quentin en Yvelines, France
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Baysal M, Demir S, Ümit EG, Gürkan H, Baş V, Karaman Gülsaran S, Demirci U, Kırkızlar HO, Demir AM. Genetic Diagnosis of Hereditary Hemorrhagic Telangiectasia: Four Novel Pathogenic Variations in Turkish Patients. Balkan Med J 2019; 37:43-46. [PMID: 31594285 PMCID: PMC6934015 DOI: 10.4274/balkanmedj.galenos.2019.2019.7.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Aims: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by telangiectasia, epistaxis, and vascular malformations. Pathogenic mutations were found in ENG, AVCRL1, SMAD4, and GDF genes. In this study, we present our database of patients with hereditary hemorrhagic telangiectasia regarding the phenotype-genotype relations and discuss two novel ENG gene pathogenic variations in two unrelated families. Methods: Next Generation Sequencing analysis was performed on the peripheral blood of nine patients with hereditary hemorrhagic telangiectasia in four unrelated families. All patients were diagnosed with hereditary hemorrhagic telangiectasia according to the Curaçao criteria. Data on treatment and screenings of visceral involvement were recorded from files. Results: We have found a pathogenic variation in either the ENG or ACVRL1 gene in each family. Two novel pathogenic variations in the ENG gene, including NM_000118.3 (ENG): c.416delC (p.P139fs*24) and NM_000118.3(ENG): c.1139dupT (p.Leu380PhefsTer16), were found in the same family. The NM_000020.2(ACVRL1): c.1298C>T (p.Pro433Leu) pathogenic variation in the ACVRL1 gene in our first family and a novel heterozygous likely pathogenic NM_000020.2(ACVRL1): c.95T>C (p.Val32Ala) variation was found in our second family. Seven of the nine patients were treated with thalidomide for controlling bleeding episodes. All patients responded to thalidomide. In one patient, the response to thalidomide was lost and switched to bevacizumab. Conclusion: In hereditary hemorrhagic telangiectasia, certain types of mutations correlate with disease phenotypes and with next generation sequencing methods. New pathogenic variations can be revealed, which might help manage patients with hereditary hemorrhagic telangiectasia.
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Affiliation(s)
- Mehmet Baysal
- Department of Hematology, Trakya University School of Medicine, Edirne, Turkey
| | - Selma Demir
- Department of Medical Genetics, Trakya University School of Medicine, Edirne, Turkey
| | - Elif G. Ümit
- Department of Hematology, Trakya University School of Medicine, Edirne, Turkey
| | - Hakan Gürkan
- Department of Medical Genetics, Trakya University School of Medicine, Edirne, Turkey
| | - Volkan Baş
- Department of Hematology, Trakya University School of Medicine, Edirne, Turkey
| | | | - Ufuk Demirci
- Department of Medical Genetics, Trakya University School of Medicine, Edirne, Turkey
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Barbosa Do Prado L, Han C, Oh SP, Su H. Recent Advances in Basic Research for Brain Arteriovenous Malformation. Int J Mol Sci 2019; 20:ijms20215324. [PMID: 31731545 PMCID: PMC6862668 DOI: 10.3390/ijms20215324] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 10/11/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
Arteriovenous malformations (AVMs) are abnormal connections of vessels that shunt blood directly from arteries into veins. Rupture of brain AVMs (bAVMs) can cause life-threatening intracranial bleeding. Even though the majority of bAVM cases are sporadic without a family history, some cases are familial. Most of the familial cases of bAVMs are associated with a genetic disorder called hereditary hemorrhagic telangiectasia (HHT). The mechanism of bAVM formation is not fully understood. The most important advances in bAVM basic science research is the identification of somatic mutations of genes in RAS-MAPK pathways. However, the mechanisms by which mutations of these genes lead to AVM formation are largely unknown. In this review, we summarized the latest advance in bAVM studies and discussed some pathways that play important roles in bAVM pathogenesis. We also discussed the therapeutic implications of these pathways.
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Affiliation(s)
- Leandro Barbosa Do Prado
- Center for Cerebrovascular Research, Department of Anesthesia, University of California, San Francisco, CA 94143, USA;
| | - Chul Han
- Barrow Aneurysm & AVM Research Center, Barrow Neurological Institute/Dignity Health, Phoenix, AZ 85013, USA; (C.H.); (S.P.O.)
| | - S. Paul Oh
- Barrow Aneurysm & AVM Research Center, Barrow Neurological Institute/Dignity Health, Phoenix, AZ 85013, USA; (C.H.); (S.P.O.)
| | - Hua Su
- Center for Cerebrovascular Research, Department of Anesthesia, University of California, San Francisco, CA 94143, USA;
- Correspondence: ; Tel.: +01-415-206-3162
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Major T, Csobay-Novák C, Gindele R, Szabó Z, Bora L, Jóni N, Rácz T, Karosi T, Bereczky Z. Pitfalls of delaying the diagnosis of hereditary haemorrhagic telangiectasia. J Int Med Res 2019; 48:300060519860971. [PMID: 31510822 PMCID: PMC7607172 DOI: 10.1177/0300060519860971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT; Osler–Weber–Rendu disease) is an
autosomal dominant vascular disease characterized by nosebleeds, mucocutaneous
telangiectases, visceral arteriovenous malformations (AVM) and a first-degree
relative with HHT. Diagnosis is definite if three or four criteria are present.
This case report describes a 19-year-old male with incidentally detected
polycythaemia and an associated soft-tissue opacity over the left lower lobe on
his frontal chest radiogram. He had experienced dyspnoea on exertion since
infancy and clubbing at physical examination. Polycythaemia vera, chronic
obstructive pulmonary disease, sleep apnoea and cyanotic congenital heart
disease were excluded. Chest computed tomography (CT) was initially refused by
the patient, but 3 years later he presented with severe epistaxis. Considering
the unvarying soft tissue mass and erythrocytosis, an HHT-associated pulmonary
AVM (PAVM) was eventually confirmed by chest CT. A pathogenic family-specific
ENG c.817-2 A>C mutation was detected in the patient.
The large PAVM was successfully treated using AMPLATZER™ vascular plug
embolization. A combination of the multisystemic nature of his symptoms, the
age-related penetrance of HHT symptoms and insufficient patient compliance
delayed the diagnosis of HHT in this current case.
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Affiliation(s)
- Tamás Major
- Department of Otolaryngology and Head and Neck Surgery, Borsod-Abaúj-Zemplén County Central Hospital and University Teaching Hospital, Miskolc, Hungary
| | | | - Réka Gindele
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsuzsanna Szabó
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - László Bora
- Department of Radiology, Szent Lázár County Hospital, Salgótarján, Hungary
| | - Natália Jóni
- Department of Internal Medicine, Ferenc Markhot County Hospital, Eger, Hungary
| | - Tamás Rácz
- Department of Otorhinolaryngology, Ferenc Markhot County Hospital, Eger, Hungary
| | - Tamás Karosi
- Department of Otolaryngology and Head and Neck Surgery, Borsod-Abaúj-Zemplén County Central Hospital and University Teaching Hospital, Miskolc, Hungary
| | - Zsuzsanna Bereczky
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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