Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Vascular Medicine".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 22326

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Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: angiogenesis; endothelial cells; hypoxia inducible factor; β-adrenergic receptor antagonists; cancer research; von hippel-lindau; hereditary hemorrhagic telangiectasia; translational research
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Dear Colleagues,

Hereditary Hemorrhagic Telangiectasia (HHT), an autosomal dominant heritable disease, leads to vascular multi-organ system and ranges from mucocutaneous telangiectases to large arteriovenous malformations. HHT has a prevalence of 1 in 5,000, becoming as one of the most prevalent RDs and its diagnosis is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. If a lack or a wrong diagnose happen, the disease leads to a decreased life expectancy since HHT is associated with a decreased quality of life and severe complications.

This Special Issue aims to highlight not only the current knowledge regarding diagnosis and management of HHT, but also the newest sequencing strategies and/or mutation hot-spots. This knowledge will dramatically short the timing from onset of symptoms for an accurate diagnosis and a further medical assistance.

Dr. Angel M. Cuesta
Guest Editor

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Keywords

  • Hereditary hemorrhagic telangiectasia (HHT)
  • Activin receptor-like kinase 1 (ALK1/ACVRL1)
  • endoglin (ENG)
  • Transforming growth factor beta (TGF-β)
  • Bone morphogenetic protein (BMP)
  • SMAD4
  • Genotype–phenotype correlation
  • Transcription regulation
  • Biomarker

Published Papers (11 papers)

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Editorial

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0 pages, 186 KiB  
Editorial
Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management
by Angel M. Cuesta
J. Clin. Med. 2022, 11(16), 4698; https://doi.org/10.3390/jcm11164698 - 11 Aug 2022
Cited by 2 | Viewed by 1050
Abstract
Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominantly inheritable rare disease with a prevalence of 1:5000–10,000 inhabitants [...] Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)

Research

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10 pages, 1959 KiB  
Article
A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2
by Suriel Errasti Díaz, Mercedes Peñalva, Lucía Recio-Poveda, Susana Vilches, Juan Casado-Vela, Julián Pérez Pérez, Luisa María Botella, Virginia Albiñana and Angel M. Cuesta
J. Clin. Med. 2022, 11(11), 3053; https://doi.org/10.3390/jcm11113053 - 28 May 2022
Cited by 3 | Viewed by 1883
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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8 pages, 907 KiB  
Article
Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia
by Eleonora Gaetani, Elisabetta Peppucci, Fabiana Agostini, Luigi Di Martino, Emanuela Lucci Cordisco, Carmelo L. Sturiale, Alfredo Puca, Angelo Porfidia, Andrea Alexandre, Alessandro Pedicelli and Roberto Pola
J. Clin. Med. 2022, 11(10), 2685; https://doi.org/10.3390/jcm11102685 - 10 May 2022
Cited by 3 | Viewed by 1595
Abstract
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptor-like type 1 (ACVRL1) gene. Several hundred variants have been identified in [...] Read more.
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptor-like type 1 (ACVRL1) gene. Several hundred variants have been identified in these HHT-causing genes, including deletions, missense and nonsense mutations, splice defects, duplications, and insertions. In this study, we have analyzed retrospectively collected images of magnetic resonance angiographies (MRA) of the brain of HHT patients, followed at the HHT Center of our University Hospital, and looked for the distribution of cerebrovascular phenotypes according to specific gene variants. We found that cerebrovascular malformations were heterogeneous among HHT patients, with phenotypes that ranged from classical arteriovenous malformations (AVM) to intracranial aneurysms (IA), developmental venous anomalies (DVA), and cavernous angiomas (CA). There was also wide heterogeneity among the variants of the ENG and ACVRL1 genes, which included known pathogenic variants, variants of unknown significance, variants pending classification, and variants which had not been previously reported. The percentage of patients with cerebrovascular malformations was significantly higher among subjects with ENG variants than ACVRL1 variants (25.0% vs. 13.1%, p < 0.05). The prevalence of neurovascular anomalies was different among subjects with different gene variants, with an incidence that ranged from 3.3% among subjects with the c.1231C > T, c.200G > A, or c.1120C > T missense mutations of the ACVRL1 gene, to 75.0% among subjects with the c.1435C > T missense mutation of the ACVRL1 gene. Further studies and larger sample sizes are required to confirm these findings. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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13 pages, 806 KiB  
Article
HHT-Related Epistaxis and Pregnancy—A Retrospective Survey and Recommendations for Management from an Otorhinolaryngology Perspective
by Kornelia E. C. Andorfer, Caroline T. Seebauer, Carolin Dienemann, Steven C. Marcrum, René Fischer, Christopher Bohr and Thomas S. Kühnel
J. Clin. Med. 2022, 11(8), 2178; https://doi.org/10.3390/jcm11082178 - 13 Apr 2022
Cited by 2 | Viewed by 1717
Abstract
Appropriate management of hereditary hemorrhagic telangiectasia (HHT) is of particular importance in females, as HHT-mediated modifications of the vascular bed and circulation are known to increase the risk of complications during pregnancy and delivery. This study was undertaken to evaluate female HHT patients’ [...] Read more.
Appropriate management of hereditary hemorrhagic telangiectasia (HHT) is of particular importance in females, as HHT-mediated modifications of the vascular bed and circulation are known to increase the risk of complications during pregnancy and delivery. This study was undertaken to evaluate female HHT patients’ awareness of and experience with HHT during pregnancy and delivery, with a focus on epistaxis. In this retrospective study, 46 females (median age: 60 years) with confirmed HHT completed a 17-item questionnaire assessing knowledge of HHT and its pregnancy-associated complications, the severity of epistaxis during past pregnancies and deliveries, and the desire for better education and counselling regarding HHT and pregnancy. Results revealed that 85% of participants were unaware of their disease status prior to the completion of all pregnancies. Further, 91% reported no knowledge of increased pregnancy-related risk due to HHT. In regard to epistaxis, 61% of respondents reported experiencing nosebleeds during pregnancy. Finally, approximately a third of respondents suggested that receiving counseling on the risks of HHT in pregnancy could have been helpful. Findings suggest that awareness of HHT and its potential for increasing pregnancy-related risk is poor. Best practices in HHT management should be followed to minimize negative effects of the disorder. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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11 pages, 5350 KiB  
Article
Hereditary Hemorrhagic Telangiectasia: Success of the Osler Calendar for Documentation of Treatment and Course of Disease
by Caroline T. Seebauer, Viola Freigang, Franziska E. Schwan, René Fischer, Christopher Bohr, Thomas S. Kühnel and Kornelia E. C. Andorfer
J. Clin. Med. 2021, 10(20), 4720; https://doi.org/10.3390/jcm10204720 - 14 Oct 2021
Cited by 5 | Viewed by 1657
Abstract
Hereditary hemorrhagic telangiectasia (HHT; Rendu-Osler-Weber syndrome) affects the capillary and larger vessels, leading to arteriovenous shunts. Epistaxis is the main symptom impairing quality of life. The aim of the Osler Calendar is to offer information about the extent of the systemic disease and [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT; Rendu-Osler-Weber syndrome) affects the capillary and larger vessels, leading to arteriovenous shunts. Epistaxis is the main symptom impairing quality of life. The aim of the Osler Calendar is to offer information about the extent of the systemic disease and the current state of treatment. A care plan with information on the rare disease and self-treatment of epistaxis was created. Organ examinations and ongoing treatments were recorded. A questionnaire documents the treatment success, including patient satisfaction, frequency of hemorrhage and hemoglobin levels. The patients using the Osler Calendar for at least one year (n = 54) were surveyed. Eighty-five percent of patients (n = 46) used the calendar to gain information about HHT. Seventy-two percent (n = 39) used the Osler Calendar for instructions on the self-treatment of nosebleeds. The calendar increased patients’ understanding for the need for organ screenings from 48% (n = 26) to 81% (n = 44). Seventy-nine percent (n = 43) of patients confirmed that the Osler Calendar documented their therapeutic process either well or very well. Fifty-two percent (n = 28) saw an improvement in the therapeutic process due to the documentation. The Osler Calendar records the individual intensity of the disease and facilitates the communication between attending physicians. It is a tool for specialists to review treatment strategies. Furthermore, the calendar enhances patients’ comprehension of their condition. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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11 pages, 1947 KiB  
Article
Sclerotherapy on Demand with Polidocanol to Treat HHT Nosebleeds
by Sol Marcos, Luisa María Botella, Virginia Albiñana, Agustina Arbia and Anna María de Rosales
J. Clin. Med. 2021, 10(17), 3845; https://doi.org/10.3390/jcm10173845 - 27 Aug 2021
Cited by 6 | Viewed by 1957
Abstract
Epistaxis is the most prevalent clinical symptom in Hereditary Haemorrhagic Telangiectasia (HHT), causing anaemia and decreasing the quality of life (QOL). Since 2013, in Hospital Universitario Fundación Alcorcón, more than 150 HHT patients have been treated by nose sclerotherapy on demand. This study [...] Read more.
Epistaxis is the most prevalent clinical symptom in Hereditary Haemorrhagic Telangiectasia (HHT), causing anaemia and decreasing the quality of life (QOL). Since 2013, in Hospital Universitario Fundación Alcorcón, more than 150 HHT patients have been treated by nose sclerotherapy on demand. This study shows the results of 105 patients treated with sclerotherapy between 2017 and 2019. HHT-ESS (epistaxis severity score) was used to measure the severity and frequency of epistaxis. QOL was determined before and after treatment by EuroQol-5D (EQ-5D) and the visual analogue scale (VAS) on the health condition. According to HHT-ESS before treatment, 22 patients presented mild, 35 moderate, and 47 severe epistaxes. Sclerotherapy significantly decreased the frequency and severity of epistaxis, with a significant drop of HHT-ESS in 4.6 points, from 6.23 ± 2.3 to 1.64 ± 1.6. Furthermore, the QOL significantly improved, the EQ-5D scale raised from 0.7 ± 0.26 pre- to 0.92 ± 0.16 post-treatment (p < 0.05). Additionally, VAS mean value showed a significant increase from 4.38 ± 2.4 to 8.35 ± 1.2. The QOL improvement was correlated with the ESS decrease. In conclusion, this study shows that on-demand sclerotherapy at the office significantly reduces HHT epistaxis as well as improved the patients’ QOL. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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17 pages, 1936 KiB  
Article
Current Status of Clinical and Genetic Screening of Hereditary Hemorrhagic Telangiectasia Families in Hungary
by Tamás Major, Zsuzsanna Bereczky, Réka Gindele, Gábor Balogh, Benedek Rácz, László Bora, Zsolt Kézsmárki, Boglárka Brúgós and György Pfliegler
J. Clin. Med. 2021, 10(17), 3774; https://doi.org/10.3390/jcm10173774 - 24 Aug 2021
Cited by 4 | Viewed by 1642
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a rare germline vascular malformation syndrome with a prevalence of 1:5000–1:10,000 [...] Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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7 pages, 219 KiB  
Article
Beneficial Effects of Remote Medical Care for Patients with Hereditary Hemorrhagic Telangiectasia during the COVID-19 Pandemic
by Eleonora Gaetani, Fabiana Agostini, Luigi Di Martino, Denis Occhipinti, Giulio Cesare Passali, Mariaconsiglia Santantonio, Giuseppe Marano, Marianna Mazza, Roberto Pola and on behalf of the Multidisciplinary Gemelli Group for HHT
J. Clin. Med. 2021, 10(11), 2311; https://doi.org/10.3390/jcm10112311 - 25 May 2021
Cited by 2 | Viewed by 1891
Abstract
Background: Hereditary hemorrhagic telangiectasia (HHT) needs high-quality care and multidisciplinary management. During the COVID-19 pandemic, most non-urgent clinical activities for HHT outpatients were suspended. We conducted an analytical observational cohort study to evaluate whether medical and psychological support, provided through remote consultation during [...] Read more.
Background: Hereditary hemorrhagic telangiectasia (HHT) needs high-quality care and multidisciplinary management. During the COVID-19 pandemic, most non-urgent clinical activities for HHT outpatients were suspended. We conducted an analytical observational cohort study to evaluate whether medical and psychological support, provided through remote consultation during the COVID-19 pandemic, could reduce the complications of HHT. Methods: A structured regimen of remote consultations, conducted by either video-calls, telephone calls, or e-mails, was provided by a multidisciplinary group of physicians to a set of patients of our HHT center. The outcomes considered were: number of emergency room visits/hospitalizations, need of blood transfusions, need of iron supplementation, worsening of epistaxis, and psychological status. Results: The study included 45 patients who received remote assistance for a total of eight months. During this period, 9 patients required emergency room visits, 6 needed blood transfusions, and 24 needed iron supplementation. This was not different from what was registered among the same 45 patients in the same period of the previous year. Remote care also resulted in better management of epistaxis and improved quality of life, with the mean epistaxis severity score and the Euro-Quality of Life-Visual Analogue Scale that were significantly better at the end than at the beginning of the study. Discussion: Remote medical care might be a valid support for HHT subjects during periods of suspended outpatient surveillance, like the COVID-19 pandemic. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
9 pages, 3689 KiB  
Article
Restless Leg Syndrome Is Underdiagnosed in Hereditary Hemorrhagic Telangiectasia—Results of an Online Survey
by Freya Droege, Andreas Stang, Kruthika Thangavelu, Carolin Lueb, Stephan Lang, Michael Xydakis and Urban Geisthoff
J. Clin. Med. 2021, 10(9), 1993; https://doi.org/10.3390/jcm10091993 - 6 May 2021
Cited by 1 | Viewed by 2508
Abstract
Background: Recurrent bleeding in patients with hereditary hemorrhagic telangiectasia (HHT) can lead to chronic iron deficiency anemia (CIDA). Existing research points to CIDA as a contributing factor in restless leg syndrome (RLS). The association between HHT-related symptoms and the prevalence of RLS was [...] Read more.
Background: Recurrent bleeding in patients with hereditary hemorrhagic telangiectasia (HHT) can lead to chronic iron deficiency anemia (CIDA). Existing research points to CIDA as a contributing factor in restless leg syndrome (RLS). The association between HHT-related symptoms and the prevalence of RLS was analyzed. Methods: An online survey was conducted whereby the standardized RLS-Diagnostic Index questionnaire (RLS-DI) was supplemented with 82 additional questions relating to HHT. Results: A total of 474 persons responded to the survey and completed responses for questions pertaining to RLS (mean age: 56 years, 68% females). Per RLS-DI criteria, 48 patients (48/322, 15%; 95% confidence interval (CI): 11–19%) self-identified as having RLS. An analysis of physician-diagnosed RLS and the RLS-DI revealed a relative frequency of RLS in HHT patients of 22% (95% CI: 18–27%). In fact, 8% (25/322; 95% CI: 5–11%) of the HHT patients had RLS which had not been diagnosed before. This equals 35% of the total amount of patients diagnosed with RLS (25/72; 95% CI: 25–46%). HHT patients with a history of gastrointestinal bleeding (prevalence ratio (PR) = 2.70, 95% CI: 1.53–4.77), blood transfusions (PR = 1.90, 95% CI: 1.27–2.86), or iron intake (PR = 2.05, 95% CI: 0.99–4.26) had an increased prevalence of RLS. Conclusions: Our data suggest that RLS is underdiagnosed in HHT. In addition, physicians should assess CIDA parameters for possible iron supplementation. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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13 pages, 1539 KiB  
Article
SARS-CoV-2 Infection in Hereditary Hemorrhagic Telangiectasia Patients Suggests Less Clinical Impact Than in the General Population
by Sol Marcos, Virginia Albiñana, Lucia Recio-Poveda, Belisa Tarazona, María Patrocinio Verde-González, Luisa Ojeda-Fernández and Luisa-María Botella
J. Clin. Med. 2021, 10(9), 1884; https://doi.org/10.3390/jcm10091884 - 27 Apr 2021
Cited by 7 | Viewed by 3067
Abstract
At the moment of writing this communication, the health crisis derived from the COVID-19 pandemic has affected more than 120 million cases, with 40 million corresponding to Europe. In total, the number of deaths is almost 3 million, but continuously rising. Although COVID-19 [...] Read more.
At the moment of writing this communication, the health crisis derived from the COVID-19 pandemic has affected more than 120 million cases, with 40 million corresponding to Europe. In total, the number of deaths is almost 3 million, but continuously rising. Although COVID-19 is primarily a respiratory disease, SARS-CoV-2 infects also endothelial cells in the pulmonary capillaries. This affects the integrity of the endothelium and increases vascular permeability. In addition, there are serious indirect consequences, like disruption of endothelial cells’ junctions leading to micro-bleeds and uncontrolled blood clotting. The impact of COVID-19 in people with rare chronic cardiovascular diseases is unknown so far, and interesting to assess, because the virus may cause additional complications in these patients. The aim of the present work was to study the COVID-19 infection among the patients with Hereditary Hemorrhagic Telangiectasia (HHT). A retrospective study was carried out in a 138 HHT patients’ sample attending an Ear Nose and Throat (ENT) reference consult. The evaluation of the COVID-19 infection in them reveals milder symptoms; among the 25 HHT patients who were infected, only 3 cases were hospitalized, and none of them required ICU or ventilation assistance. The results are discussed in the light of macrophage immune response. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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Review

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20 pages, 1289 KiB  
Review
Founder Effects in Hereditary Hemorrhagic Telangiectasia
by Tamás Major, Réka Gindele, Gábor Balogh, Péter Bárdossy and Zsuzsanna Bereczky
J. Clin. Med. 2021, 10(8), 1682; https://doi.org/10.3390/jcm10081682 - 14 Apr 2021
Cited by 4 | Viewed by 2312
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management)
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