Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management—Part II

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 November 2023) | Viewed by 6788

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Guest Editor
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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Special Issue Information

Dear Colleagues,

Due to the impact of the Special Issue on Diagnosis and Management on Hereditary Hemorrhagic Telangiectasia, JCM decided to start a second Special Issue.

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 one of the most prevalent RDs and its diagnosis is based on the Curaçao criteria. HHT disease presents subtypes, depending on the mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway, or other locations to be determined. If no diagnosis or a wrong diagnosis happens, 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 (again) to highlight not only the current knowledge regarding the diagnosis and management of HHT but also the newest sequencing strategies and/or mutation hot spots. It also encourages to the presentation of international collaborative works in the diagnosis and management of the disease or related circumstances such as the pandemic year we have suffered.

All this knowledge will dramatically contribute to a better quality of life by shorting the diagnosis and 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 (7 papers)

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20 pages, 2590 KiB  
Article
Pathogenic Variant Frequencies in Hereditary Haemorrhagic Telangiectasia Support Clinical Evidence of Protection from Myocardial Infarction
by Kinshuk Jain, Sarah C. McCarley, Ghazel Mukhtar, Anna Ferlin, Andrew Fleming, Deborah J. Morris-Rosendahl and Claire L. Shovlin
J. Clin. Med. 2024, 13(1), 250; https://doi.org/10.3390/jcm13010250 - 31 Dec 2023
Cited by 1 | Viewed by 783
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, due to a single heterozygous loss-of-function variant, usually in ACVRL1 (encoding activin receptor-like kinase 1 [ALK1]), ENG (encoding endoglin [CD105]), or SMAD4. In a consecutive single-centre series of [...] Read more.
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, due to a single heterozygous loss-of-function variant, usually in ACVRL1 (encoding activin receptor-like kinase 1 [ALK1]), ENG (encoding endoglin [CD105]), or SMAD4. In a consecutive single-centre series of 37 positive clinical genetic tests performed in 2021–2023, a skewed distribution pattern was noted, with 30 of 32 variants reported only once, but ACVRL1 c.1231C>T (p.Arg411Trp) identified as the disease-causal gene in five different HHT families. In the same centre’s non-overlapping 1992–2020 series where 110/134 (82.1%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was identified in nine further families. In a 14-country, four-continent HHT Mutation Database where 181/250 (72.4%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was reported by 12 different laboratories, the adjacent ACVRL1 c.1232G>A (p.Arg411Gln) by 14, and ACVRL1 c.1120C>T (p.Arg374Trp) by 18. Unlike the majority of HHT-causal ACVRL1 variants, these encode ALK1 protein that reaches the endothelial cell surface but fails to signal. Six variants of this type were present in the three series and were reported 6.8–25.5 (mean 8.9) times more frequently than the other ACVRL1 missense variants (all p-values < 0.0039). Noting lower rates of myocardial infarction reported in HHT, we explore potential mechanisms, including a selective paradigm relevant to ALK1′s role in the initiating event of atherosclerosis, where a plausible dominant negative effect of these specific variants can be proposed. In conclusion, there is an ~9-fold excess of kinase-inactive, cell surface-expressed ACVRL1/ALK1 pathogenic missense variants in HHT. The findings support further examination of differential clinical and cellular phenotypes by HHT causal gene molecular subtypes. Full article
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0 pages, 4389 KiB  
Article
Pharmacogenomic Considerations for Anticoagulant Prescription in Patients with Hereditary Haemorrhagic Telangiectasia
by Sarah C. McCarley, Daniel A. Murphy, Jack Thompson and Claire L. Shovlin
J. Clin. Med. 2023, 12(24), 7710; https://doi.org/10.3390/jcm12247710 - 15 Dec 2023
Cited by 1 | Viewed by 1237
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia that commonly results in bleeding but with frequent indications for therapeutic anticoagulation. Our aims were to advance the understanding of drug-specific intolerance and evaluate if there was an indication for pharmacogenomic testing. Genes encoding proteins [...] Read more.
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia that commonly results in bleeding but with frequent indications for therapeutic anticoagulation. Our aims were to advance the understanding of drug-specific intolerance and evaluate if there was an indication for pharmacogenomic testing. Genes encoding proteins involved in the absorption, distribution, metabolism, and excretion of warfarin, heparin, and direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran were identified and examined. Linkage disequilibrium with HHT genes was excluded, before variants within these genes were examined following whole genome sequencing of general and HHT populations. The 44 genes identified included 5/17 actionable pharmacogenes with guidelines. The 76,156 participants in the Genome Aggregation Database v3.1.2 had 28,446 variants, including 9668 missense substitutions and 1076 predicted loss-of-function (frameshift, nonsense, and consensus splice site) variants, i.e., approximately 1 in 7.9 individuals had a missense substitution, and 1 in 71 had a loss-of-function variant. Focusing on the 17 genes relevant to usually preferred DOACs, similar variant profiles were identified in HHT patients. With HHT patients at particular risk of haemorrhage when undergoing anticoagulant treatment, we explore how pre-emptive pharmacogenomic testing, alongside HHT gene testing, may prove beneficial in reducing the risk of bleeding and conclude that HHT patients are well placed to be at the vanguard of personalised prescribing. Full article
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12 pages, 1075 KiB  
Article
Tacrolimus as a Promising Drug for Epistaxis and Gastrointestinal Bleeding in HHT
by Paloma Álvarez-Hernández, José Luis Patier, Sol Marcos, Vicente Gómez del Olmo, Laura Lorente-Herraiz, Lucía Recio-Poveda, Luisa María Botella, Adrián Viteri-Noël and Virginia Albiñana
J. Clin. Med. 2023, 12(23), 7410; https://doi.org/10.3390/jcm12237410 - 29 Nov 2023
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Abstract
Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular autosomically inherited rare disease. Epistaxis (nose bleeds) is the most common symptom in HHT, leading to anemia and affecting the patient’s quality of life. In addition to epistaxis, gastrointestinal bleeding (GI), more often at older [...] Read more.
Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular autosomically inherited rare disease. Epistaxis (nose bleeds) is the most common symptom in HHT, leading to anemia and affecting the patient’s quality of life. In addition to epistaxis, gastrointestinal bleeding (GI), more often at older ages, may lead to severe anemia and the need for blood transfusions. Thus, finding drugs to control both types of bleeding is a primary necessity in HHT. Methods: A cross-sectional observational study was conducted in a series of 11 HHT patients treated with low tacrolimus doses (0.5–2 mg/day) on an off-label prescription basis. Patients showed refractory bleeding to previous treatments. The epistaxis severity score (ESS) and hemoglobin levels were the parameters used to evaluate the impact of tacrolimus. The occurrence of side effects was also recorded. Results: Tacrolimus was well tolerated in all of the patients except 2 (who stopped the treatment). The remaining patients tolerated the treatment, with a general improvement in their health condition. Epistaxis was significantly reduced when comparing the ESS before and after the treatment. Hemoglobin levels significantly increased, overcoming the anemia, during the course of the treatment. Conclusion: Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT. Full article
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18 pages, 3168 KiB  
Article
Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia
by Toru Iwasa, Akihiro Urasaki, Yuki Kakihana, Nami Nagata-Akaho, Yukihiro Harada, Soichi Takeda, Teruhisa Kawamura, Isao Shiraishi, Kenichi Kurosaki, Hiroko Morisaki, Osamu Yamada and Osamu Nakagawa
J. Clin. Med. 2023, 12(15), 5002; https://doi.org/10.3390/jcm12155002 - 29 Jul 2023
Cited by 1 | Viewed by 899
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays. Four variants with amino acid replacement in the motifs essential for the intracellular kinase function lost SMAD-dependent signaling. Most of other variations in the kinase domain also caused marked downregulation of signaling; however, two variants behaved as the wild-type ACVRL1 did, while computational classifiers predicted their functional abnormalities. Three-dimensional structure prediction using the ColabFold program supported the significance of the L45 loop and NANDOR domain of ACVRL1 for its association with SMAD1 and BMPR2, respectively, and the variations in these motifs resulted in the reduction of SMAD signaling. On the other hand, two of the GS domain variants maintained high signal transduction capacity, which did not accord with their computational pathogenicity prediction. These results affirm the requirement of a combinatory approach using computational and experimental analyses to accurately predict the pathogenicity of ACVRL1 missense variants in the HHT patients. Full article
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11 pages, 278 KiB  
Article
Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT
by Alexandra Kilian, Giuseppe A. Latino, Andrew J. White, Felix Ratjen, Jamie McDonald, Kevin J. Whitehead, James R. Gossage, Timo Krings, Michael T. Lawton, Helen Kim, Marie E. Faughnan and The Brain Vascular Malformation Consortium HHT Investigator Group
J. Clin. Med. 2023, 12(7), 2704; https://doi.org/10.3390/jcm12072704 - 04 Apr 2023
Cited by 4 | Viewed by 1662
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterized by the development of vascular malformations (VMs) in organs such as the brain and lungs, as well as telangiectases on mucosal surfaces. Prophylactic treatment of organ VMs may prevent potential complications, such [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterized by the development of vascular malformations (VMs) in organs such as the brain and lungs, as well as telangiectases on mucosal surfaces. Prophylactic treatment of organ VMs may prevent potential complications, such as hemorrhage. However, brain VM treatment—surgical resection, embolization, and/or radiosurgery—is not recommended for all patients due to the associated risks. Given the scarcity of data regarding HHT-related brain VM presentation and treatment trends in pediatric patients, we aim to describe the clinical presentations and the patterns of treatment of HHT-related brain VMs in a pediatric cohort, and compare pediatric trends to those of adults. Demographic and clinical data were analyzed in 114 pediatric patients with HHT-related brain VMs and compared with a cohort of 253 adult patients enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. Our data demonstrated that a higher proportion of pediatric patients with HHT-related brain VMs were symptomatic at presentation (p = 0.004). Moreover, a higher proportion of pediatric patients presented with intracranial hemorrhage (p < 0.001) and seizure (p = 0.002) compared to adult patients. Surgical resection was the most common brain VM treatment modality in both children and adults. We conclude that pediatric patients may be more likely to present with symptoms and complications from brain VMs, supporting the case for screening for brain VMs in children with HHT. Full article

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2 pages, 174 KiB  
Reply
Reply to Eker et al. Comment on “Kilian et al. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. J. Clin. Med. 2023, 12, 2704”
by Alexandra Kilian, Giuseppe A. Latino, Andrew J. White, Felix Ratjen, Jamie McDonald, Kevin J. Whitehead, James R. Gossage, Timo Krings, Michael T. Lawton, Helen Kim, Marie E. Faughnan and The Brain Vascular Malformation Consortium HHT Investigator Group
J. Clin. Med. 2023, 12(23), 7462; https://doi.org/10.3390/jcm12237462 - 01 Dec 2023
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Abstract
We are grateful to Eker et al. for their thoughtful analysis and response to our publication titled Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT [...] Full article
3 pages, 181 KiB  
Comment
Comment on Kilian et al. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. J. Clin. Med. 2023, 12, 2704
by Omer F. Eker, Sophie Dupuis-Girod, Claire L. Shovlin and Edoardo Boccardi
J. Clin. Med. 2023, 12(22), 7179; https://doi.org/10.3390/jcm12227179 - 20 Nov 2023
Cited by 1 | Viewed by 413
Abstract
We read with interest the recent article by Killian et al. regarding the characteristics and treatment of brain vascular malformations (VMs) in children and adults with hereditary hemorrhagic telangiectasia (HHT) [...] Full article
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