|
1
|
Ricciardelli AR, Genet G, Genet N, McClugage ST, Kan PT, Hirschi KK, Fish JE, Wythe JD. From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations. Angiogenesis 2025; 28:15. [PMID: 39899215 PMCID: PMC11790818 DOI: 10.1007/s10456-024-09953-5] [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: 08/15/2024] [Accepted: 11/06/2024] [Indexed: 02/04/2025]
Abstract
Brain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in the RAS-MAPK signaling pathway. Leveraging these genetic discoveries, preclinical mouse models have been developed to uncover the mechanisms underlying abnormal vessel formation, and thus revealing potential therapeutic targets. Impressively, initial preclinical studies suggest that pharmacological treatments disrupting these aberrant pathways may ameliorate the abnormal pathologic vessel remodeling and inflammatory and hemorrhagic nature of these high-flow vascular anomalies. Intriguingly, these studies also suggest uncontrolled angiogenic signaling may be a major driver in bAVM pathogenesis. This comprehensive review describes the genetics underlying both inherited and sporadic bAVM and details the state of the field regarding murine models of bAVM, highlighting emerging therapeutic targets that may transform our approach to treating these devastating lesions.
Collapse
Affiliation(s)
| | - Gael Genet
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Nafiisha Genet
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Samuel T McClugage
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA
- Division of Pediatric Neurosurgery, Texas Children's Hospital, Houston, TX, USA
| | - Peter T Kan
- Department of Neurosurgery, University of Texas Medical Branch, Galveston, TX, 77598, USA
| | - Karen K Hirschi
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Developmental Genomics Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Jason E Fish
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Joshua D Wythe
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
- Developmental Genomics Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, USA.
- Brain, Immunology, and Glia Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
| |
Collapse
|
|
2
|
Hermann R, Shovlin CL, Kasthuri RS, Serra M, Eker OF, Bailly S, Buscarini E, Dupuis-Girod S. Hereditary haemorrhagic telangiectasia. Nat Rev Dis Primers 2025; 11:1. [PMID: 39788978 DOI: 10.1038/s41572-024-00585-z] [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] [Accepted: 11/29/2024] [Indexed: 01/12/2025]
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway. Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT. In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases. Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess) and left-to-right through systemic AVMs (causing high cardiac output). Children usually experience isolated epistaxis; in rare cases, childhood complications occur from large AVMs in the lungs or central nervous system. Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members. Novel therapeutics, such as systemic antiangiogenic therapies, are actively being investigated. Although HHT is associated with increased morbidity, the appropriate screening and treatment of visceral AVMs, and the effective management of bleeding and anaemia, improves quality of life and overall survival.
Collapse
Affiliation(s)
- Ruben Hermann
- ENT department, Hôpital E Herriot, Hospices Civils de Lyon, Lyon, France
- European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HHT Rare Disease Working Group, Paris, France
| | - Claire L Shovlin
- National Heart and Lung Institute, Imperial College London, London, UK
- Respiratory Medicine, Imperial College Healthcare NHS Trust, London, UK
| | - Raj S Kasthuri
- Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Marcelo Serra
- Internal Medicine department, HHT Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Omer F Eker
- Department of Neuroradiology, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Sabine Bailly
- Biosanté Unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France
| | - Elisabetta Buscarini
- European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HHT Rare Disease Working Group, Paris, France
- Gastroenterology Department, ASST Ospedale Maggiore, Crema, Italy
| | - Sophie Dupuis-Girod
- European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HHT Rare Disease Working Group, Paris, France.
- Biosanté Unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France.
- HHT National Reference Center and Genetic Department, Hôpital Femme-Mère-Enfants, Hospices Civils de Lyon, Bron, France.
| |
Collapse
|
|
3
|
Ortman C, Ortolani E. Hereditary hemorrhagic telangiectasia: A pediatric-focused review. Semin Pediatr Neurol 2024; 52:101167. [PMID: 39622607 DOI: 10.1016/j.spen.2024.101167] [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: 10/14/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 12/07/2024]
Abstract
Clinical manifestations of hereditary hemorrhagic telangiectasia (HHT) include vascular malformations of the skin, nasal mucosa, gastrointestinal tract, lungs, liver and central nervous system. These malformations range from punctate telangiectasias to larger arteriovenous malformations within visceral organs and the central nervous system. Vascular malformations increase risk for acute and chronic bleeding, anemia, as well secondary complications related to arterial-venous shunting. Diagnosis can be made with the Curaçao criteria, which includes the presence of epistaxis, telangiectasias, arteriovenous malformations, and first-degree family member with HHT. Nearly all patients with HHT will have a pathogenic variant in the ENG or ACVRL1 genes, while a smaller number will have a variant in SMAD4 or no clear genetic etiology. While there is no cure for HHT, medical management of vascular complications may include oral tranexamic acid and IV bevacizumab. Endovascular and surgical treatments are clinically indicated when the benefits outweigh the risks of the interventions.
Collapse
Affiliation(s)
- Chelsey Ortman
- Department of Pediatric Neurosciences, Ascension Dell Children's Medical Center, University of Texas at Austin, United States
| | - Elissa Ortolani
- Department of Pediatrics, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, United States.
| |
Collapse
|
|
4
|
Yuan J, Wu X, Zhao J, Ding Q, Dai J, Wang X, Lu Y, Li J. Molecular mechanisms and clinical manifestations of hereditary hemorrhagic telangiectasia. Thromb Res 2024; 241:109117. [PMID: 39151291 DOI: 10.1016/j.thromres.2024.109117] [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: 05/14/2024] [Revised: 07/17/2024] [Accepted: 08/09/2024] [Indexed: 08/19/2024]
Abstract
INTRODUCTION Hereditary Hemorrhagic Telangiectasia (HHT) is charactered by telangiectasia and arteriovenous malformations (AVMs). Recurrent visceral and mucocutaneous bleeding is frequently reported among HHT patients, while data on the prevalence of thrombosis remains limited. This study aims to describe the clinical manifestations and molecular biological characteristics of HHT patients. METHODS We conducted a retrospective study at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. A total of 24 HHT patients, observed between January 2019 and December 2023, were included. We recorded the biological, clinical, and therapeutic events, with particular attention to bleeding and thrombotic events. Gene mutation analysis and blood constituent measurements were performed. RESULTS The prevalence of bleeding among all HHT patients was 100 %, while thrombotic events were noted in 41.70 % of cases. Hepatic arteriovenous malformations (HAVMs) were identified in six patients, pulmonary arteriovenous malformations (PAVMs) in five patients, and cerebral arteriovenous malformations (CAVMs) in one patient. For patients with thrombosis, the discontinuation rates were 23.08 % for antiplatelet therapy and 33.33 % for anticoagulant therapy due to the increased risk of bleeding. Genetic mutations related to HHT were present in 16 patients, with ACVRL1 (activin A receptor-like type 1) mutations being the most frequent at 41.67 %, followed by ENG (endoglin) mutations at 20.83 %, and GDF2 (growth differentiation factor 2) mutations at 4.17 %. The incidence of PAVMs was 75.00 % in HHT1 patients with ENG mutations and 20 % in HHT2 patients with ACVRL1 mutations, while HAVMs occurred in 0 % and 40.00 % of these groups, respectively. Patients were divided into non-AVMs and AVMs groups. Compared to normal controls, von Willebrand factor (vWF) activity was significantly increased in all HHT patients (149.10 % vs. 90.65 %, P < 0.001). In the non-AVMs group, the median level of stromal cell-derived factor-1 (SDF-1) was significantly elevated (124.31 pg/mL vs. 2413.57 pg/mL, P < 0.05), while vWF antigen levels were markedly higher in the AVMs group (165.30 % vs. 130.60 %, P = 0.021). Further grouping of HHT patients based on bleeding and thrombosis phenotypes revealed that those with thrombosis had significantly higher median percentages of schistocytes (3.50 % vs. 0 %, P = 0.002), ferritin concentrations (318.50 μg/L vs. 115.50 μg/L, P = 0.001), and lactate dehydrogenase (LDH) levels (437 U/L vs. 105 U/L, P < 0.001). There were no significant differences in the activity of vWF, protein C (PC), protein S (PS), and factor VIII (FVIII) between the two groups. CONCLUSION This study highlighted the complex relationship between arteriovenous malformations and genetic mutations in HHT patients. A comprehensive assessment of bleeding and thrombosis risks should be conducted for each HHT patient, additionally, further clinical studies are needed to explore the risk factors for thrombosis and anticoagulant-related bleeding in HHT.
Collapse
Affiliation(s)
- Junwei Yuan
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialu Zhao
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiulan Ding
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Dai
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuefeng Wang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yeling Lu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jiaming Li
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Transfusion Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
5
|
Pearson M, McGowan R, Greene P, Lam W, Miedzybrodzka Z, Berg J. Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort. Eur J Hum Genet 2024; 32:731-735. [PMID: 38627541 PMCID: PMC11153582 DOI: 10.1038/s41431-024-01607-w] [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: 01/15/2024] [Revised: 03/20/2024] [Accepted: 03/28/2024] [Indexed: 06/07/2024] Open
Abstract
Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.
Collapse
Affiliation(s)
| | - Ruth McGowan
- West of Scotland Centre for Genomic Medicine, Glasgow, Scotland, UK
| | - Philip Greene
- South East of Scotland Clinical Genetics Service, Edinburgh, UK
| | - Wayne Lam
- South East of Scotland Clinical Genetics Service, Edinburgh, UK
| | - Zofia Miedzybrodzka
- School of Medicine, Medical Sciences, Nutrition and Dentistry, University of Aberdeen, Aberdeen, UK
| | - Jonathan Berg
- School of Medicine, University of Dundee, Dundee, Scotland, UK.
| |
Collapse
|
|
6
|
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]
|
|
7
|
Jain K, McCarley SC, Mukhtar G, Ferlin A, Fleming A, Morris-Rosendahl DJ, Shovlin CL. Pathogenic Variant Frequencies in Hereditary Haemorrhagic Telangiectasia Support Clinical Evidence of Protection from Myocardial Infarction. J Clin Med 2023; 13:250. [PMID: 38202257 PMCID: PMC10779873 DOI: 10.3390/jcm13010250] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/20/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
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 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.
Collapse
Affiliation(s)
- Kinshuk Jain
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (K.J.); (S.C.M.); (G.M.); (D.J.M.-R.)
| | - Sarah C. McCarley
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (K.J.); (S.C.M.); (G.M.); (D.J.M.-R.)
| | - Ghazel Mukhtar
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (K.J.); (S.C.M.); (G.M.); (D.J.M.-R.)
| | - Anna Ferlin
- Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, Guy’s and St Thomas’ NHS Trust, London SE1 7EH, UK; (A.F.); (A.F.)
| | - Andrew Fleming
- Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, Guy’s and St Thomas’ NHS Trust, London SE1 7EH, UK; (A.F.); (A.F.)
| | - Deborah J. Morris-Rosendahl
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (K.J.); (S.C.M.); (G.M.); (D.J.M.-R.)
- Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, Guy’s and St Thomas’ NHS Trust, London SE1 7EH, UK; (A.F.); (A.F.)
| | - Claire L. Shovlin
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (K.J.); (S.C.M.); (G.M.); (D.J.M.-R.)
- Specialist Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London W12 0HS, UK
- Social, Genetic and Environmental Determinants of Health, NIHR Imperial Biomedical Research Centre, London W2 1NY, UK
| |
Collapse
|
|
8
|
Manfredi G, Crinò SF, Alicante S, Romeo S, Berté R, Gandolfi S, Spinazzola A, Fiini M, Forner P, Buscarini E. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia: Long-term results of endoscopic treatment. Endosc Int Open 2023; 11:E1145-E1152. [PMID: 38108019 PMCID: PMC10723967 DOI: 10.1055/a-2190-9303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/04/2023] [Indexed: 12/19/2023] Open
Abstract
Background and study aims This longitudinal prospective study evaluated the long-term outcome of endoscopic treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectases (HHT), its safety and outcome predictors. Patients and methods Consecutive patients with HHT and either anemia disproportionate to epistaxis or overt gastrointestinal bleeding received endoscopic treatment of gastrointestinal telangiectases with argon plasma coagulation (APC). Hemoglobin levels and transfusion requirements were evaluated before and after treatment. Treatment effectiveness was classified as: 1) complete: hemoglobin level during the follow-up ≥9 g/dL; 2) complete with recurrence: hemoglobin ≥9 g/dL for at least 12 months with subsequent drop to <9 g/dL; or 3) absent: no improvement of hemoglobin level. Adverse events (AEs) were classified as mild, moderate, severe or fatal. Correlations were searched between treatment outcome and demographic/genetic characteristics, number, size and site of telangiectases, and hepatic arterio-venous malformations grade. Results Forty-seven patients with HHT were enrolled. At median follow-up of 134 months (range 20-243 months), 41 of 47 patients showed treatment response (complete or with recurrence) after one (14/47) or more (27/47) endoscopic treatments. Median hemoglobin levels were 7.0 g/dL and 11.9 g/dL at baseline and at the end of follow-up, respectively. Transfusion requirement decreased from 22.8 to 7.3 red cell unit/year. A higher baseline number of telangiectases was associated with a lower chance of response ( P =0.008). Only one severe AE (0.4%, jejunal perforation) was recorded. Conclusions Endoscopic treatment of gastrointestinal teleangiectases for gastrointestinal bleeding in patients with HHT is effective in the long term and safe.
Collapse
Affiliation(s)
- Guido Manfredi
- Gastroenterology and Endoscopy Department, Center of reference VASCERN HHT, Maggiore Hospital Crema, Crema, Italy
| | | | - Saverio Alicante
- Gastroenterology and Endoscopy Department, Center of reference VASCERN HHT, Maggiore Hospital Crema, Crema, Italy
| | - Samanta Romeo
- Gastroenterology and Endoscopy Department, Center of reference VASCERN HHT, Maggiore Hospital Crema, Crema, Italy
| | - Roberto Berté
- Gastroenterology and Endoscopy Department, Center of reference VASCERN HHT, Maggiore Hospital Crema, Crema, Italy
| | | | | | - Michela Fiini
- Cardiology Department, Maggiore Hospital Crema, Crema, Italy
| | | | - Elisabetta Buscarini
- Gastroenterology and Endoscopy Department, Center of reference VASCERN HHT, Maggiore Hospital Crema, Crema, Italy
| |
Collapse
|
|
9
|
Wits M, Becher C, de Man F, Sanchez-Duffhues G, Goumans MJ. Sex-biased TGFβ signalling in pulmonary arterial hypertension. Cardiovasc Res 2023; 119:2262-2277. [PMID: 37595264 PMCID: PMC10597641 DOI: 10.1093/cvr/cvad129] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/21/2023] [Accepted: 07/04/2023] [Indexed: 08/20/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.
Collapse
Affiliation(s)
- Marius Wits
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
| | - Clarissa Becher
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
| | - Frances de Man
- Department of Pulmonary Medicine, Amsterdam University Medical Center (UMC) (Vrije Universiteit), 1081 HV Amsterdam, The Netherlands
| | - Gonzalo Sanchez-Duffhues
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), 33011 Oviedo, Spain
| | - Marie-José Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands
| |
Collapse
|
|
10
|
Mukhtar G, Shovlin CL. Unsupervised machine learning algorithms identify expected haemorrhage relationships but define unexplained coagulation profiles mapping to thrombotic phenotypes in hereditary haemorrhagic telangiectasia. EJHAEM 2023; 4:602-611. [PMID: 37601877 PMCID: PMC10435691 DOI: 10.1002/jha2.746] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 08/22/2023]
Abstract
Hereditary haemorrhagic telangiectasia (HHT) can result in challenging anaemia and thrombosis phenotypes. Clinical presentations of HHT vary for relatives with identical casual mutations, suggesting other factors may modify severity. To examine objectively, we developed unsupervised machine learning algorithms to test whether haematological data at presentation could be categorised into sub-groupings and fitted to known biological factors. With ethical approval, we examined 10 complete blood count (CBC) variables, four iron index variables, four coagulation variables and eight iron/coagulation indices combined from 336 genotyped HHT patients (40% male, 60% female, 86.5% not using iron supplementation) at a single centre. T-SNE unsupervised, dimension reduction, machine learning algorithms assigned each high-dimensional datapoint to a location in a two-dimensional plane. k-Means clustering algorithms grouped into profiles, enabling visualisation and inter-profile comparisons of patients' clinical and genetic features. The unsupervised machine learning algorithms using t-SNE and k-Means identified two distinct CBC profiles, two iron profiles, four clotting profiles and three combined profiles. Validating the methodology, profiles for CBC or iron indices fitted expected patterns for haemorrhage. Distinct coagulation profiles displayed no association with age, sex, C-reactive protein, pulmonary arteriovenous malformations (AVMs), ENG/ACVRL1 genotype or epistaxis severity. The most distinct profiles were from t-SNE/k-Means analyses of combined iron-coagulation indices and mapped to three risk states - for venous thromboembolism in HHT; for ischaemic stroke attributed to paradoxical emboli through pulmonary AVMs in HHT; and for cerebral abscess attributed to odontogenic bacteremias in immunocompetent HHT patients with right-to-left shunting through pulmonary AVMs. In conclusion, unsupervised machine learning algorithms categorise HHT haematological indices into distinct, clinically relevant profiles which are independent of age, sex or HHT genotype. Further evaluation may inform prophylaxis and management for HHT patients' haemorrhagic and thrombotic phenotypes.
Collapse
Affiliation(s)
- Ghazel Mukhtar
- National Heart and Lung InstituteImperial College LondonLondonUK
- Imperial College School of MedicineLondonUK
| | - Claire L. Shovlin
- National Heart and Lung InstituteImperial College LondonLondonUK
- Specialist MedicineImperial College Healthcare NHS TrustLondonUK
- NIHR Imperial Biomedical Research CentreLondonUK
| |
Collapse
|
|
11
|
Weinstein RM, Gowda PC, Yuan F, Khalil A, Motaghi M, Garg T, Gong AJ, Lin DD, Weiss CR. Risk factors and clinical features associated with basal ganglia manganese deposition in patients with hereditary hemorrhagic telangiectasia. Clin Imaging 2023; 101:183-189. [PMID: 37390610 DOI: 10.1016/j.clinimag.2023.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 06/06/2023] [Accepted: 06/16/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND T1-hyperintensity of the basal ganglia (BG) due to manganese deposition is a known radiologic finding in patients with hereditary hemorrhagic telangiectasia (HHT), but risk factors and associated clinical manifestations are unclear. This study conducted a quantitative analysis of the association of T1-hyperintensity in HHT patients with specific risk factors, signs, and symptoms. METHODS Patients seen at our center between 2005 and 2020 with a definitive diagnosis of HHT who had an available non-contrast T1-weighted brain MRI were included. Hyperintensity was evaluated using oval regions of interest measurements. The BG: thalamus intensity ratio was used to quantitatively evaluate T1-hyperintensity. Patient laboratory values and clinical findings were collected from electronic medical records. Hyperintensity was analyzed for its association with laboratory values, and clinical findings. Variables were analyzed through regression analysis. RESULTS A total of 239 patients were included in this study. On 1.5 T scanners, values that were significant on multivariable regression analysis were age (p < .001), hepatic AVMs (p < .001), iron deficiency anemia (p = .0021), and cirrhosis (p = .016). On 3 T scanners, values that were significant on multivariable analysis were hepatic AVMs (p = .0024) and cirrhosis (p = .0056). On 3 T scanners, hyperintensity was significantly associated with tremor (OR = 1.17, p = .033), restless leg syndrome (OR = 1.22, p = .0086), and memory problems (OR = 1.17, p = .046). CONCLUSIONS BG hyperintensity due to manganese deposition is significantly associated with hepatic risk factors on 1.5 T and 3 T scanners and iron deficiency anemia on 1.5 T scanners. On 3 T scanners, T1-hyperintensity is associated with neuropsychiatric signs and symptoms, such as tremor, restless leg syndrome, and memory problems.
Collapse
Affiliation(s)
- Robert M Weinstein
- The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Prateek C Gowda
- The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Frank Yuan
- The Johns Hopkins University School of Medicine, Russell H. Morgan Department of Radiology and Radiologic Science, Division of Interventional Radiology, United States of America
| | - Adham Khalil
- The Johns Hopkins University School of Medicine, Russell H. Morgan Department of Radiology and Radiologic Science, Division of Interventional Radiology, United States of America
| | - Mina Motaghi
- Georgia Southern University, Jiann-Ping Hsu College of Public Health, Department of Biostatistics, Epidemiology and Environmental Health Sciences, United States of America
| | - Tushar Garg
- The Johns Hopkins University School of Medicine, Russell H. Morgan Department of Radiology and Radiologic Science, Division of Interventional Radiology, United States of America
| | - Anna J Gong
- The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Doris D Lin
- The Johns Hopkins University School of Medicine, Russell H. Morgan Department of Radiology and Radiologic Science, Division of Neuroradiology, United States of America
| | - Clifford R Weiss
- The Johns Hopkins University School of Medicine, Russell H. Morgan Department of Radiology and Radiologic Science, Division of Interventional Radiology, United States of America.
| |
Collapse
|
|
12
|
Ielasi L, Tonnini M, Piscaglia F, Serio I. Current guidelines for diagnosis and management of hepatic involvement in hereditary hemorrhagic teleangiectasia. World J Hepatol 2023; 15:675-687. [PMID: 37305373 PMCID: PMC10251273 DOI: 10.4254/wjh.v15.i5.675] [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: 02/07/2023] [Revised: 04/04/2023] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
Hereditary hemorrhagic teleangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is the most common cause of hepatic vascular malformations in adults. Different vascular shunts (arteriovenous, arterioportal or portovenous) lead to different clinical manifestations. Even though no hepatic-related symptoms are reported in the majority of cases, the severity of liver disease could lead to refractory medical conditions, in some cases requiring liver transplantation. The aim of this manuscript is to provide an updated overview of the current evidence regarding the diagnosis and treatment of HHT liver involvement and liver-related complications.
Collapse
Affiliation(s)
- Luca Ielasi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Department of Internal Medicine, Ospedale per gli Infermi di Faenza, Faenza 48018, Italy
| | - Matteo Tonnini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Ilaria Serio
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| |
Collapse
|
|
13
|
Tuff-Gordon E, Faughnan ME, Kim H, Lawton MT, Vozoris NT. An analysis of sex differences in pulmonary arteriovenous malformation presentation, complications and management in a large, multinational registry of patients with hereditary haemorrhagic telangiectasia. ERJ Open Res 2023; 9:00751-2022. [PMID: 37483279 PMCID: PMC10359038 DOI: 10.1183/23120541.00751-2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/22/2023] [Indexed: 04/08/2023] Open
Abstract
This large, multinational, sex-based analysis among individuals with HHT showed that pulmonary AVM frequency, physical characteristics, presentation, complications and management do not generally significantly differ between males and females https://bit.ly/3TNLA6v.
Collapse
Affiliation(s)
| | - Marie E. Faughnan
- Toronto HHT Centre, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Respirology, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Helen Kim
- Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA
| | | | - Nicholas T. Vozoris
- Toronto HHT Centre, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Respirology, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
- ICES, Toronto, ON, Canada
| | | |
Collapse
|
|
14
|
Kilian A, Latino GA, White AJ, Ratjen F, McDonald J, Whitehead KJ, Gossage JR, Krings T, Lawton MT, Kim H, Faughnan ME. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. J Clin Med 2023; 12:2704. [PMID: 37048789 PMCID: PMC10094792 DOI: 10.3390/jcm12072704] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/14/2023] Open
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 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.
Collapse
Affiliation(s)
- Alexandra Kilian
- Department of Paediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
- Toronto HHT Centre, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON M5B 1W8, Canada
| | - Giuseppe A. Latino
- Toronto HHT Centre, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON M5B 1W8, Canada
- Department of Pediatrics, North York General Hospital, University of Toronto, Toronto, ON M2K 1E1, Canada
| | - Andrew J. White
- Department of Pediatrics, St Louis University, St. Louis, MO 63103, USA
| | - Felix Ratjen
- Division of Respiratory Medicine and Translational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Jamie McDonald
- Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
| | - Kevin J. Whitehead
- Department of Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT 84132, USA
- Department of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, UT 84132, USA
| | - James R. Gossage
- Department of Medicine, Augusta University, Augusta, GA 30912, USA
| | - Timo Krings
- Division of Neuroradiology, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada
| | - Michael T. Lawton
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Helen Kim
- Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94110, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA
| | - Marie E. Faughnan
- Toronto HHT Centre, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON M5B 1W8, Canada
- Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada
| | | |
Collapse
|
|
15
|
Evolution of Pulmonary Arteriovenous Malformations: The Role of Contrast Echocardiography. Chest 2023; 163:669-677. [PMID: 36368615 DOI: 10.1016/j.chest.2022.11.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/28/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Pulmonary arteriovenous malformations (PAVMs) are direct connections between the pulmonary artery and the pulmonary vein, mostly associated with hereditary hemorrhagic telangiectasia (HHT). PAVMs can lead to severe neurologic complications such as stroke and brain abscess. The risk of complications decreases after embolization. Therefore, screening for PAVMs using transthoracic contrast echocardiography (TTCE) is recommended, including a rescreening interval of 5 years. RESEARCH QUESTION Is extension of the interval for rescreening patients without a pulmonary right-to-left shunt (RLS) of up to 10 years appropriate? STUDY DESIGN AND METHODS Adult patients with HHT with 5- or 10-year follow-up TTCE, or both, were included. Patients who underwent PAVM embolization in the past or at baseline were excluded. The RLS grades and presence of a treatable PAVM were compared with baseline. RESULTS In total, 387 patients (median age, 45 years [interquartile range, 33-54 years]; 56% women) involving 5- and 10-year follow-up data in 363 and 166 patients, respectively, were included. None of the patients (n = 148) without a pulmonary RLS at baseline demonstrated a treatable PAVM after 5 and 10 years. Of the patients with a pulmonary RLS at baseline, 20 patients (9%) and three patients (3%) demonstrated a treatable PAVM at the 5- and 10-year follow-up, respectively. In most patients, the RLS grade remained stable over time. INTERPRETATION On the basis of the results of this retrospective study, we believe that the rescreening interval for patients with HHT without a pulmonary RLS at initial screening may be extended to 10 years. Those with a pulmonary RLS should be rescreened every 5 years because treatable PAVMs can evolve.
Collapse
|
|
16
|
Jelsig AM, Kjeldsen A, Christensen LL, Bertelsen B, Karstensen JG, Brusgaard K, Torring PM. Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants in SMAD4: a nationwide study. J Med Genet 2022; 60:464-468. [PMID: 36038259 DOI: 10.1136/jmg-2022-108766] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/22/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIMS Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%-5% of patients, HHT is caused by pathogenic germline variants (PVs) in SMAD4, and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum of SMAD4-associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs in SMAD4 and compare the findings with current literature. METHODS The study is a retrospective nationwide study with all known Danish patients with PVs in SMAD4. In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital. RESULTS Twenty-nine patients with PVs in SMAD4 (83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities. CONCLUSION We present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.
Collapse
Affiliation(s)
- Anne Marie Jelsig
- Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
| | - Anette Kjeldsen
- Department of Otorhinolaryngology HHT-Centre, Odense University Hospital, Odense, Denmark
| | | | - Birgitte Bertelsen
- Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark
| | - John Gásdal Karstensen
- Danish Polyposis Registry, Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Brusgaard
- Department of Clinical Genetics, Odense Universitetshospital, Odense, Denmark
| | - Pernille M Torring
- Department of Clinical Genetics, Odense Universitetshospital, Odense, Denmark
| |
Collapse
|
|
17
|
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.
Collapse
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
| |
Collapse
|
|
18
|
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.
Collapse
|
|
19
|
Jargielo A, Rycyk A, Kasztelan-Szczerbinska B, Cichoz-Lach H. A Rare Case of Upper Gastrointestinal Bleeding: Osler-Weber-Rendu Syndrome. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:333. [PMID: 35334510 PMCID: PMC8951266 DOI: 10.3390/medicina58030333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 11/30/2022]
Abstract
Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia (HHT), is a rare, autosomal dominant condition that affects approximately 1 in 5000 patients causing abnormal blood vessel formation. HHT patients have mucocutaneous telangiectasias and arteriovenous malformations in various organs. The most prominent symptom of HHT is epistaxis, which, together with gastrointestinal bleeding, may cause iron deficiency anemia. This study is a case report of a 62-year-old patient who was admitted to the Department of Gastroenterology due to acute upper gastrointestinal bleeding and a history of recurrent epistaxis and melena for 4 days, which was confirmed in digital rectal examination. Urgent upper gastrointestinal endoscopy revealed active bleeding from multiple angioectatic spots with bright-looking salmon-colored patches in the antrum and the body suggestive of HHT. The bleeding from two angioectatic spots was stopped by argon plasma coagulation, and four clips were placed to provide good hemostasis. The patient was treated with a proton pomp inhibitor infusion and iron infusion. She was discharged with no signs of GI bleeding, normalized iron levels and a diagnosis of HHT. She was referred to further genetic testing, including evaluation of first-degree relatives. She also had performed unenhanced thin-cut computed tomography (CT) with angiography to exclude the presence of pulmonary arteriovenous malformations (PAVMs). Due to the fact that the patient did not manifest any other HHT-related symptoms and that the instrumental screening discloses no silent AVMs in other organs, the "watch-and-wait strategy" was applied. Although, Osler-Weber-Rendu syndrome is widely described in the medical literature, effective treatment of gastrointestinal telangiectasias is not always available and still lacks standardization to date, which makes the management of gastroenterological involvement still a challenging issue.
Collapse
Affiliation(s)
- Anna Jargielo
- Banacha Campus, Medical University of Warsaw, Zwirki i Wigury 61 St., 02-091 Warsaw, Poland;
| | - Anna Rycyk
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8 St., 20-954 Lublin, Poland; (B.K.-S.); (H.C.-L.)
| | - Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8 St., 20-954 Lublin, Poland; (B.K.-S.); (H.C.-L.)
| | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8 St., 20-954 Lublin, Poland; (B.K.-S.); (H.C.-L.)
| |
Collapse
|
|
20
|
Abdolrahimzadeh S, Formisano M, Marani C, Rahimi S. An update on the ophthalmic features in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Int Ophthalmol 2022; 42:1987-1995. [PMID: 35034241 PMCID: PMC9156511 DOI: 10.1007/s10792-021-02197-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/18/2021] [Indexed: 11/29/2022]
Abstract
Hereditary haemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber syndrome is a rare autosomal dominant disease, characterised by systemic angiodysplasia. Dysfunction of the signalling pathway of β transforming growth factor is the main cause of HHT principally owing to mutations of the genes encoding for endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1). Clinical manifestations can range from mucocutaneous telangiectasia to organ arterio-venous malformations and recurrent epistaxis. The early clinical manifestations may sometimes be subtle, and diagnosis may be delayed. The main ophthalmic manifestations historically reported in HHT are haemorrhagic epiphora, and conjunctival telangiectasia present in 45-65% of cases, however, imaging with wide-field fluorescein angiography has recently shown peripheral retinal telangiectasia in 83% of patients. Optimal management of HHT requires both understanding of the clinical presentations and detection of early signs of disease. Advances in imaging methods in ophthalmology such as wide-field fluorescein angiography, spectral domain optical coherence tomography, and near infrared reflectance promise further insight into the ophthalmic signs of HHT towards improved diagnosis and early management of possible severe complications.
Collapse
Affiliation(s)
- Solmaz Abdolrahimzadeh
- Ophthalmology Unit, Neurosciences, Mental Health and Sense Organs (NESMOS) Department, University of Rome Sapienza, Rome, Italy. .,Faculty of Medicine and Psychology, St. Andrea Hospital, Via di Grottarossa 1035/1039, 00189, Rome, Italy.
| | - Martina Formisano
- Department of Sense Organs, Ophthalmology Unit, University of Rome Sapienza, Azienda Policlinico Umberto I, viale del Policlinico 155, 00161, Rome, Italy
| | - Carla Marani
- San Carlo Hospital, Via Aurelia 275, 00165, Rome, Italy
| | - Siavash Rahimi
- Istituto Dermopatico dell'Immacolata (IDI-IRCCS) Department of Histopathology, Via Monti di Creta 104, 00167, Rome, Italy
| |
Collapse
|
|
21
|
Hvelplund T, Lange B, Bird SD, Korsholm M, Kjeldsen AD. A retrospective cohort study on European Reference Network for Rare Vascular Diseases 5 outcome measures for Hereditary Haemorrhagic Telangiectasia in Denmark. Orphanet J Rare Dis 2022; 17:8. [PMID: 34991676 PMCID: PMC8734368 DOI: 10.1186/s13023-021-02160-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/19/2021] [Indexed: 11/20/2022] Open
Abstract
Background Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by several clinical symptoms including epistaxis, arteriovenous malformations (AVM), and telangiectasia. In 2018, European Reference Network for Rare Vascular Diseases (VASCERN) recommended five outcome measures for HHT-patients to guide health care providers, some with limited experience in treating HHT, and thereby maximizing the number of HHT-patients receiving good care. The outcome measures cover the following aspects: (1) 90% of the patients should receive a pulmonary AVM (PAVM) screening; (2) 90% of the patients should receive written advice on nosebleed; (3) 70% should be assessed for iron deficiency; (4) 100% of the patients should receive written advice on antibiotic (AB) prophylaxis prior to dental and surgical procedures, and (5) 100% of relevant patients should receive written advice on pregnancy. We have introduced the outcome measures as Benchmarks in our HHT-centre and wanted to evaluate the extend of implementation we have achieved. We constantly struggle to secure the best possible treatment of our HHT-patients. Methods The study was a non-interventional retrospective study. Data was collected manually from patient records and from the Danish HHT-database. Results A total of 180 HHT-patients were included, all diagnosed in the period from January 1st, 2016, to December 31st, 2020. All patients were screened for PAVM. We could confirm that 66% of patients who had epistaxis received thoroughly advice. Assessment for iron deficiency was performed in 80% of the adult patients. Thoroughly advice on AB prophylaxis was documented in 75%. Thoroughly advice on pregnancy was documented in 80% of female patients 15–45 years of age. There were no significant differences over time for any of the outcome measures. Conclusions The Danish HHT-centre reached the target threshold for outcome measures 1 and 3. It could not be documented that the target thresholds for outcome measures 2, 4, and 5 were achieved. As information and education are a very important part of HHT care, focus on and documentation that all patients receive the relevant advice must be a priority in order to ensure best care.
Collapse
Affiliation(s)
- Troels Hvelplund
- Research Unit for ORL - Head and Neck Surgery and Audiology, Odense University Hospital, J.B. Winsløws Vej 4, 1st Floor, 5000, Odense C, Denmark.,University of Southern Denmark, Odense, Denmark.,Open Patient Data Explorative Network (OPEN), Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Bibi Lange
- Research Unit for ORL - Head and Neck Surgery and Audiology, Odense University Hospital, J.B. Winsløws Vej 4, 1st Floor, 5000, Odense C, Denmark
| | - Susanne Djernes Bird
- Research Unit for ORL - Head and Neck Surgery and Audiology, Odense University Hospital, J.B. Winsløws Vej 4, 1st Floor, 5000, Odense C, Denmark
| | - Malene Korsholm
- Research Unit for ORL - Head and Neck Surgery and Audiology, Odense University Hospital, J.B. Winsløws Vej 4, 1st Floor, 5000, Odense C, Denmark.,University of Southern Denmark, Odense, Denmark
| | - Anette Drøhse Kjeldsen
- Research Unit for ORL - Head and Neck Surgery and Audiology, Odense University Hospital, J.B. Winsløws Vej 4, 1st Floor, 5000, Odense C, Denmark. .,University of Southern Denmark, Odense, Denmark. .,Open Patient Data Explorative Network (OPEN), Department of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark.
| |
Collapse
|
|
22
|
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]
|
|
23
|
Kitayama K, Ishiguro T, Komiyama M, Morisaki T, Morisaki H, Minase G, Hamanaka K, Miyatake S, Matsumoto N, Kato M, Takahashi T, Yorifuji T. Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia. BMC Med Genomics 2021; 14:288. [PMID: 34872578 PMCID: PMC8647423 DOI: 10.1186/s12920-021-01139-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/29/2021] [Indexed: 12/28/2022] Open
Abstract
Background Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. Methods Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. Results In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. Conclusions In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-021-01139-y.
Collapse
Affiliation(s)
- Kana Kitayama
- Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-hondori, Miyakojima, Osaka, 534-0021, Japan
| | - Tomoya Ishiguro
- Department of Neuro-Intervention, Osaka City General Hospital, Osaka, Japan
| | - Masaki Komiyama
- Department of Neuro-Intervention, Osaka City General Hospital, Osaka, Japan
| | - Takayuki Morisaki
- Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Hiroko Morisaki
- Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan
| | - Gaku Minase
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Kohei Hamanaka
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Satoko Miyatake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Masaru Kato
- Department of Genetic Medicine, Osaka City General Hospital, Osaka, Japan
| | - Toru Takahashi
- Department of Genetic Medicine, Osaka City General Hospital, Osaka, Japan
| | - Tohru Yorifuji
- Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-hondori, Miyakojima, Osaka, 534-0021, Japan. .,Department of Genetic Medicine, Osaka City General Hospital, Osaka, Japan.
| |
Collapse
|
|
24
|
Yamamoto H, Itamoto C, Yamaguchi T, Koshyo T. Severe Hypoxemia Caused by High-Output Heart Failure and Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia. JACC Case Rep 2021; 3:1863-1868. [PMID: 34917969 PMCID: PMC8642735 DOI: 10.1016/j.jaccas.2021.10.008] [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: 08/11/2021] [Accepted: 10/05/2021] [Indexed: 11/28/2022]
Abstract
A man affected by hereditary hemorrhagic telangiectasia who had chronic severe hypoxemia is presented. This hypoxemia was synergistically caused by high-output heart failure due to severe hepatic shunts and multiple pulmonary arteriovenous shunts. The symptomatic combination is rare, and genetic testing showed a novel endoglin mutation. (Level of Difficulty: Advanced.)
Collapse
Affiliation(s)
- Hiroaki Yamamoto
- Department of Cardiology, Nagano Chuo Hospital, Nagano, Japan
- Address for correspondence: Dr Hiroaki Yamamoto. Department of Cardiology, Nagano Chuo Hospital, Nishitsuruga 1570, Nagano City, Nagano Prefecture, Japan.
| | - Chieko Itamoto
- Department of Cardiology, Nagano Chuo Hospital, Nagano, Japan
| | - Tomomi Yamaguchi
- Department of Genetic Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Center for Medical Genetics; and
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoki Koshyo
- Department of Genetic Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Center for Medical Genetics; and
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan
| |
Collapse
|
|
25
|
Kolarich AR, Solomon AJ, Bailey C, Latif MA, Rowan NR, Galiatsatos P, Weiss CR. Imaging Manifestations and Interventional Treatments for Hereditary Hemorrhagic Telangiectasia. Radiographics 2021; 41:2157-2175. [PMID: 34723698 DOI: 10.1148/rg.2021210100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Hemorrhagic hereditary telangiectasia (HHT) is a rare autosomal dominant disorder that causes multisystem vascular malformations including mucocutaneous telangiectasias and arteriovenous malformations (AVMs). Clinical and genetic screening of patients with signs, symptoms, or a family history suggestive of HHT is recommended to confirm the diagnosis on the basis of the Curaçao criteria and prevent associated complications. Patients with HHT frequently have epistaxis and gastrointestinal bleeding from telangiectasias. Pulmonary AVMs are common right-to-left shunts between pulmonary arteries and veins that can result in dyspnea and exercise intolerance, heart failure, migraine headaches, stroke or transient ischemic attacks, brain abscesses, or in rare cases, pulmonary hemorrhage. Primary neurologic complications from cerebral AVMs, which can take on many forms, are less common but particularly severe complications of HHT. Multimodality imaging, including transthoracic echocardiography, Doppler US, CT, and MRI, is used in the screening and initial characterization of vascular lesions in patients with HHT. Diagnostic angiography is an important tool in characterization of and interventional treatments for HHT, particularly those in the lungs and central nervous system. A multidisciplinary approach to early diagnosis, treatment, imaging, and surveillance at high-volume HHT Centers of Excellence is recommended. Although a variety of idiopathic, traumatic, or genetic conditions can result in similar clinical and imaging features, the Curaçao criteria are particularly useful for the proper diagnosis of HHT. Imaging and treatment options are reviewed, with a focus on screening, diagnosis, and posttreatment findings, with the use of updated international guidelines. Online supplemental material is available for this article. ©RSNA, 2021.
Collapse
Affiliation(s)
- Andrew R Kolarich
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| | - Alex J Solomon
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| | - Christopher Bailey
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| | - Muhammad Aamir Latif
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| | - Nicholas R Rowan
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| | - Panagis Galiatsatos
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| | - Clifford R Weiss
- From the Russell H. Morgan Department of Radiology and Radiological Science (A.R.K., A.J.S., C.B., M.A.L., C.R.W.), Department of Otolarygology-Head and Neck Surgery (N.R.R.), and Department of Medicine, Division of Pulmonology (P.G.), The Johns Hopkins University School of Medicine, 1800 Orleans St, Sheikh Zayed Tower, Baltimore, MD 21287
| |
Collapse
|
|
26
|
Green RJ, Swift AC. Hereditary haemorrhagic telangiectasia: an overview from an ear, nose and throat perspective. Br J Hosp Med (Lond) 2021; 82:1-9. [PMID: 34817255 DOI: 10.12968/hmed.2020.0560] [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: 11/11/2022]
Abstract
Patients with hereditary haemorrhagic telangiectasia can present with a multitude of symptoms caused by telangiectasia and arteriovenous malformations in the nose, brain, gastrointestinal tract, liver and spinal cord. Clinicians should be aware of the potential diagnosis of hereditary haemorrhagic telangiectasia and how to manage these patients both in the acute and chronic setting. Identifying these patients and optimising their management can help reverse the reduced life expectancy back to that of the normal population. The management of these patients is complex and often requires a multidisciplinary approach, with difficult discussions to be had around screening for arteriovenous malformations and genetic testing. The stepwise management ladder can be used in both the medical and surgical strategies; there are multiple pharmacological and surgical options available, all with their own side effects and risks. Patient education is key to help informed decision making. This article outlines the clinical characteristics of the disease and management options available.
Collapse
Affiliation(s)
- Richard J Green
- Department of Otolaryngology, Ninewells Hospital, Dundee, UK
| | - Andrew C Swift
- Liverpool Head and Neck Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| |
Collapse
|
|
27
|
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.
Collapse
|
|
28
|
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.
Collapse
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.
| | | |
Collapse
|
|
29
|
Wetzel-Strong SE, Weinsheimer S, Nelson J, Pawlikowska L, Clark D, Starr MD, Liu Y, Kim H, Faughnan ME, Nixon AB, Marchuk DA. Pilot investigation of circulating angiogenic and inflammatory biomarkers associated with vascular malformations. Orphanet J Rare Dis 2021; 16:372. [PMID: 34479577 PMCID: PMC8414780 DOI: 10.1186/s13023-021-02009-7] [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: 04/26/2021] [Accepted: 08/24/2021] [Indexed: 01/03/2023] Open
Abstract
Background Vascular malformations in the central nervous system are difficult to monitor and treat due to their inaccessible location. Angiogenic and inflammatory proteins are secreted into the bloodstream and may serve as useful biomarkers for identifying patients at risk for complications or with certain disease phenotypes.
Methods A validated multiplex protein array consisting of 26 angiogenic and inflammatory biomarkers (Angiome) was assessed in plasma isolated from healthy controls and patients with either sporadic brain arteriovenous malformation (BAVM), familial cerebral cavernous malformation (CCM), or hereditary hemorrhagic telangiectasia (HHT). These samples were obtained from archives of ongoing research studies at the University of California San Francisco and through prospective collection at the Toronto HHT Centre at St. Michael’s Hospital. Results We compared circulating biomarker levels from each patient group to healthy controls and analyzed each pairwise combination of patient groups for differences in biomarker levels. Additionally, we analyzed the HHT samples to determine the association between biomarker levels and the following HHT-specific phenotypes, BAVM, pulmonary arteriovenous malformation (PAVM), liver vascular malformation (LVM), and gastrointestinal (GI) bleeding. Compared to controls, levels of SDF1 were significantly elevated in HHT patients (Proportional Increase [PI] = 1.87, p < 0.001, q = 0.011). Levels of sENG were significantly reduced in HHT patients compared to controls (PI = 0.56, p < 0.001, q < 0.001), reflecting the prevalence of HHT1 patients in this cohort. Levels of IL6 (PI = 3.22, p < 0.001, q < 0.001) and sTGFβR3 (PI = 0.70, p = 0.001, q < 0.029) differed significantly in CCM patients compared to controls. Compared to controls, ten of the biomarkers were significantly different in sporadic BAVM patients (q-values < 0.05). Among the pairwise combinations of patient groups, a significant elevation was observed in TGFβ1 in CCM patients compared to sporadic BAVM patients (PI = 2.30, p < 0.001, q = 0.034). When examining the association of circulating biomarker levels with HHT-specific phenotypes, four markers were significantly lower in HHT patients with BAVM (q-values < 0.05), and four markers were significantly higher in patients with LVM (q-values < 0.05). Conclusions This pilot study suggests that the profile of circulating angiogenic and inflammatory biomarkers may be unique to each type of vascular malformation. Furthermore, this study indicates that circulating biomarkers may be useful for assessing phenotypic traits of vascular malformations. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02009-7.
Collapse
Affiliation(s)
- Sarah E Wetzel-Strong
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, 265 CARL Bldg., Box #3175 DUMC, Durham, NC, 27710, USA
| | - Shantel Weinsheimer
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Jeffrey Nelson
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Ludmila Pawlikowska
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Dewi Clark
- Toronto HHT Centre, St. Michael's Hospital and the Li Ka Shing Knowledge Institute, Toronto, Canada
| | - Mark D Starr
- Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Yingmiao Liu
- Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Helen Kim
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Marie E Faughnan
- Toronto HHT Centre, St. Michael's Hospital and the Li Ka Shing Knowledge Institute, Toronto, Canada.,Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Andrew B Nixon
- Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Douglas A Marchuk
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, 265 CARL Bldg., Box #3175 DUMC, Durham, NC, 27710, USA.
| |
Collapse
|
|
30
|
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.)
| |
Collapse
|
|
31
|
Lam S, Guthrie KS, Latif MA, Weiss CR. Genetic counseling and testing for hereditary hemorrhagic telangiectasia. Clin Genet 2021; 101:275-284. [PMID: 34415050 DOI: 10.1111/cge.14050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/04/2021] [Accepted: 08/15/2021] [Indexed: 12/13/2022]
Abstract
Genetic counseling is an important means of identifying a patient's genetic risk of hereditary hemorrhagic telangiectasia (HHT) and assisting patients in making informed decisions about their health. With an increase in understanding of the genetic mechanisms underlying HHT over the last decade, genetic counseling is increasingly being incorporated into the care of patients affected by HHT. In addition to refining the diagnosis of symptomatic patients, genetic testing can help to distinguish asymptomatic, at-risk patients from those who are unaffected by HHT. The purpose of this review article is to summarize the current knowledge regarding the role of genetic counseling and genetic testing in identifying and managing HHT in at-risk populations. This article also reviews the guidelines, outcomes, risks, and challenges of genetic counseling and testing for HHT in various patient populations, and provides an algorithm for the use of genetic counseling in symptomatic and asymptomatic patients.
Collapse
Affiliation(s)
- Shravika Lam
- Russel H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Kelsey S Guthrie
- Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Muhammad A Latif
- Russel H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Clifford R Weiss
- Russel H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
32
|
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: 6] [Impact Index Per Article: 1.5] [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.
Collapse
|
|
33
|
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: 21] [Impact Index Per Article: 5.3] [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.
Collapse
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.
| |
Collapse
|
|
34
|
Mahendra Y, He M, Rouf MA, Tjakra M, Fan L, Wang Y, Wang G. Progress and prospects of mechanotransducers in shear stress-sensitive signaling pathways in association with arteriovenous malformation. Clin Biomech (Bristol, Avon) 2021; 88:105417. [PMID: 34246943 DOI: 10.1016/j.clinbiomech.2021.105417] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 06/21/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023]
Abstract
Arteriovenous malformations are congenital vascular lesions characterized by a direct and tangled connection between arteries and veins, which disrupts oxygen circulation and normal blood flow. Arteriovenous malformations often occur in the patient with hereditary hemorrhagic telangiectasia. The attempts to elucidate the causative factors and pathogenic mechanisms of arteriovenous malformations are now still in progress. Some studies reported that shear stress in blood flow is one of the factors involved in arteriovenous malformations manifestation. Through several mechanotransducers harboring the endothelial cells membrane, the signal from shear stress is transduced towards the responsible signaling pathways in endothelial cells to maintain cell homeostasis. Any disruption in this well-established communication will give rise to abnormal endothelial cells differentiation and specification, which will later promote arteriovenous malformations. In this review, we discuss the update of several mechanotransducers that have essential roles in shear stress-induced signaling pathways, such as activin receptor-like kinase 1, Endoglin, Notch, vascular endothelial growth factor receptor 2, Caveolin-1, Connexin37, and Connexin40. Any disruption of these signaling potentially causes arteriovenous malformations. We also present some recent insights into the fundamental analysis, which attempts to determine potential and alternative solutions to battle arteriovenous malformations, especially in a less invasive and risky way, such as gene treatments.
Collapse
Affiliation(s)
- Yoga Mahendra
- Key Laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing 400030, China
| | - Mei He
- Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing, China
| | - Muhammad Abdul Rouf
- Key Laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing 400030, China
| | - Marco Tjakra
- Key Laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing 400030, China
| | - Longling Fan
- Key Laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing 400030, China
| | - Yeqi Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing 400030, China.
| | - Guixue Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University, Chongqing 400030, China.
| |
Collapse
|
|
35
|
Zong Y, Liu W, Hou C, Zhang H, Jiang X, Sun X, Xie L, Xiao T, Zhang Y, Li Y. A novel endoglin mutation in a family with hereditary hemorrhagic telangiectasia: a case report. Transl Pediatr 2021; 10:2123-2130. [PMID: 34584883 PMCID: PMC8429878 DOI: 10.21037/tp-20-156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/29/2021] [Indexed: 11/25/2022] Open
Abstract
Hereditary hemorrhagic telangiectasis (HHT) is an autosomal dominant vascular disease, and approximately 80% of all HHT cases are caused by gene mutation. In this report, we analyzed the case of an 11-year-old girl who had intracranial bleeding when she was 7 years old. Her brain computed tomography (CT) scans and craniocerebral angiography results revealed that she had multiple cerebral arteriovenous malformations (CAVMs). Cardiac computed tomography angiography (CTA) revealed a pulmonary arteriovenous malformation (PAVM) located in a segment of the left lung. This patient's primary diagnosis was of CAVMs and PAVMs. Both cerebral vascular embolization therapy and interventional treatment for PAVMs were performed to treat these respective conditions. The operations were successful and the patient's prognosis was good. To confirm the patient's diagnosis and the cause of her conditions, peripheral blood was collected from her and her family for whole-exome sequencing (WES). Sanger sequencing was used to verify these results and STRUM software was used to predict the presence of mutant proteins. We found a new mutation of the endoglin (ENG) gene present in this family; this mutation is known as c.1466del (p.Gln489Argfs*2). The patient's mother was a carrier of this heterozygous mutation. STRUM software confirmed that the configuration of the ENG protein p.Gln489Argfs2 site changed with this mutation. We believe this c.1466del (p.Gln489Argfs*2) mutation affects ENG protein function, and the resultant ENG protein dysfunction leads to HHT. When a child has multiple vascular malformation, HHT should be considered as a primary diagnosis.
Collapse
Affiliation(s)
- Yanfang Zong
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Liu
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Cuilan Hou
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Han Zhang
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xunwei Jiang
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaomin Sun
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lijian Xie
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Tingting Xiao
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yongwei Zhang
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yun Li
- Department of Cardiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
36
|
Desroches-Castan A, Tillet E, Bouvard C, Bailly S. BMP9 and BMP10: two close vascular quiescence partners that stand out. Dev Dyn 2021; 251:178-197. [PMID: 34240497 DOI: 10.1002/dvdy.395] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 12/11/2022] Open
Abstract
Bone morphogenetic proteins (BMPs) are dimeric transforming growth factor ß (TGFß) family cytokines that were first described in bone and cartilage formation but have since been shown to be involved in many pleiotropic functions. In human, there are 15 BMP ligands, which initiate their cellular signaling by forming a complex with two copies of type I receptors and two copies of type II receptors, both of which are transmembrane receptors with an intracellular serine/threonine kinase domain. Within this receptor family, ALK1 (Activin receptor-Like Kinase 1), which is a type I receptor mainly expressed on endothelial cells, and BMPRII (BMP Receptor type II), a type II receptor also highly expressed on endothelial cells, have been directly linked to two rare vascular diseases: hereditary haemorrhagic telangiectasia (HHT), and pulmonary arterial hypertension (PAH), respectively. BMP9 (gene name GDF2) and BMP10, two close members of the BMP family, are the only known ligands for the ALK1 receptor. This specificity gives them a unique role in physiological and pathological angiogenesis and tissue homeostasis. The aim of this current review is to present an overview of what is known about BMP9 and BMP10 on vascular regulation with a particular emphasis on recent results and the many questions that remain unanswered regarding the roles and specificities between BMP9 and BMP10. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
| | - Emmanuelle Tillet
- Laboratory BioSanté, Univ. Grenoble Alpes, INSERM, CEA, Grenoble, France
| | - Claire Bouvard
- Laboratory BioSanté, Univ. Grenoble Alpes, INSERM, CEA, Grenoble, France
| | - Sabine Bailly
- Laboratory BioSanté, Univ. Grenoble Alpes, INSERM, CEA, Grenoble, France
| |
Collapse
|
|
37
|
Abston E, Hon S, Rodriguez-Lopez J, Moll M, Lanuti M, Farber HW, Wilson KC. Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia - A case series and systematic review. Pulm Pharmacol Ther 2021; 68:102033. [PMID: 33895318 DOI: 10.1016/j.pupt.2021.102033] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/22/2021] [Accepted: 04/12/2021] [Indexed: 11/19/2022]
Abstract
RATIONALE Pulmonary Arterial Hypertension (PAH), a rare complication of HHT is associated with poor outcome. There are no trials to date that have investigated whether pulmonary vasodilator therapy improves hemodynamics or survival in this disease. OBJECTIVE To determine whether pulmonary vasodilator therapy improves survival, exercise capacity, or hemodynamics in HHT patients with pre-capillary PH. METHODS We performed a before-and-after observational study on a multicenter cohort of subjects with HHT-PAH who received intravenous prostanoid therapy. We then conducted a systematic review, searching Medline and EMBASE through December 2019. Studies that enrolled HHT-PAH subjects and reported treatment outcomes were selected. PROSPERO #158179. RESULTS Twenty-one articles were selected. Studies were before-and-after observational studies, case reports, and case series. Among all subjects with HHT-PAH, both mPAP (65 ± 19 pre-treatment vs 51 ± 16 mmHg post-treatment p = 0.04) and PVR (12 ± 6 pre-treatment vs 8 ± 4 WU post-treatment p = 0.01) improved with treatment. The mPAP improved with either oral (57 ± 17 pre-treatment versus 44 ± 13 mmHg post-treatment, p = 0.03) or intravenous (80 ± 15 pre-treatment versus 64 ± 16 mmHg post-treatment, p = 0.017) therapy. PVR also improved with either oral (10 ± 4 pre-treatment versus 6 ± 3 WU post-treatment, p = 0.004) or intravenous (17 ± 5 pre-treatment versus 10 ± 4 WU post-treatment, p = 0.04) therapy. Survival among HHT-PAH patients who received oral or intravenous therapy was not different (p = 0.2). Unadjusted survival among HHT-PAH patients was longer than that of IPAH patients (p = 0.008). There was no difference in side effects among HHT-PAH patient who received oral or intravenous therapy (p = 0.1). CONCLUSION Pulmonary vasodilator therapy is effective in improving hemodynamics of subjects with HHT-PAH and was not associated with increased risk of side effects.
Collapse
Affiliation(s)
- Eric Abston
- Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Center for Thoracic Cancers, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
| | - Stephanie Hon
- Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Division of Pulmonary, Critical Care, And Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Josanna Rodriguez-Lopez
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Matt Moll
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Michael Lanuti
- Center for Thoracic Cancers, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Harrison W Farber
- Division of Pulmonary, Critical Care, And Sleep Medicine, Department of Medicine, Tufts Medical Center, Boston, MA, USA
| | - Kevin C Wilson
- Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| |
Collapse
|
|
38
|
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.
Collapse
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
| |
Collapse
|
|
39
|
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.
Collapse
|
|
40
|
Abstract
Systemic diseases often manifest with cutaneous findings. Many pediatric conditions with prominent skin findings also have significant pulmonary manifestations. These conditions include both inherited multisystem genetic disorders such as yellow-nail syndrome, neurofibromatosis type 1, tuberous sclerosis complex, hereditary hemorrhagic telangiectasia, Klippel-Trénaunay-Weber syndrome, cutis laxa, Ehlers-Danlos syndrome, dyskeratosis congenita, reactive processes such as mastocytosis, and aquagenic wrinkling of the palms. This overview discusses the pulmonary manifestations of skin disorders.
Collapse
Affiliation(s)
- Bernard A Cohen
- Division of Pediatric Dermatology, Johns Hopkins Medical Institutions, 200 N. Wolfe Street, Baltimore, MD 21287, USA.
| | | |
Collapse
|
|
41
|
Thompson KP, Nelson J, Kim H, Pawlikowska L, Marchuk DA, Lawton MT, Faughnan ME. Predictors of mortality in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2021; 16:12. [PMID: 33407668 PMCID: PMC7789194 DOI: 10.1186/s13023-020-01579-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 10/13/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Retrospective questionnaire and healthcare administrative data suggest reduced life expectancy in untreated hereditary hemorrhagic telangiectasia (HHT). Prospective data suggests similar mortality, to the general population, in Denmark's centre-treated HHT patients. However, clinical phenotypes vary widely in HHT, likely affecting mortality. We aimed to measure predictors of mortality among centre-treated HHT patients. HHT patients were recruited at 14 HHT centres of the Brain Vascular Malformation Consortium (BVMC) since 2010 and followed annually. Vital status, organ vascular malformations (VMs) and clinical symptoms data were collected at baseline and during follow-up (N = 1286). We tested whether organ VMs, HHT symptoms and HHT genes were associated with increased mortality using Cox regression analysis, adjusting for patient age, sex, and smoking status. RESULTS 59 deaths occurred over average follow-up time of 3.4 years (max 8.6 years). A history of anemia was associated with increased mortality (HR = 2.93, 95% CI 1.37-6.26, p = 0.006), as were gastro-intestinal (GI) bleeding (HR = 2.63, 95% CI 1.46-4.74, p = 0.001), and symptomatic liver VMs (HR = 2.10, 95% CI 1.15-3.84, p = 0.015). Brain VMs and pulmonary arteriovenous malformations (AVMs) were not associated with mortality (p > 0.05). Patients with SMAD4 mutation had significantly higher mortality (HR = 18.36, 95% CI 5.60-60.20, p < 0.001) compared to patients with ACVRL1 or ENG mutation, but this estimate is imprecise given the rarity of SMAD4 patients (n = 33, 4 deaths). CONCLUSIONS Chronic GI bleeding, anemia and symptomatic liver VMs are associated with increased mortality in HHT patients, independent of age, and in keeping with the limited treatment options for these aspects of HHT. Conversely, mortality does not appear to be associated with pulmonary AVMs or brain VMs, for which patients are routinely screened and treated preventatively at HHT Centres. This demonstrates the need for development of new therapies to treat chronic anemia, GI bleeding, and symptomatic liver VMs in order to reduce mortality among HHT patients.
Collapse
Affiliation(s)
- K P Thompson
- Toronto HHT Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond St, Toronto, ON, M5B-1W8, USA
- Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada
| | - J Nelson
- Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA
| | - H Kim
- Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, 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
| | - L Pawlikowska
- Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, 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
- Barrow Neurological Institute, Phoenix, AZ, USA
| | - Marie E Faughnan
- Toronto HHT Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond St, Toronto, ON, M5B-1W8, USA.
- Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada.
| |
Collapse
|
|
42
|
Northup PG, Garcia-Pagan JC, Garcia-Tsao G, Intagliata NM, Superina RA, Roberts LN, Lisman T, Valla DC. Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 73:366-413. [PMID: 33219529 DOI: 10.1002/hep.31646] [Citation(s) in RCA: 358] [Impact Index Per Article: 89.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Patrick G Northup
- Division of Gastroenterology and Hepatology, Center for the Study of Hemostasis in Liver Disease, University of Virginia, Charlottesville, VA
| | - Juan Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-Liver), Barcelona, Spain
| | - Guadalupe Garcia-Tsao
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT.,Veterans Administration Healthcare System, West Haven, CT
| | - Nicolas M Intagliata
- Division of Gastroenterology and Hepatology, Center for the Study of Hemostasis in Liver Disease, University of Virginia, Charlottesville, VA
| | - Riccardo A Superina
- Department of Transplant Surgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Lara N Roberts
- Department of Haematological Medicine, King's Thrombosis Centre, King's College Hospital National Health Service (NHS) Foundation Trust, London, United Kingdom
| | - Ton Lisman
- Section of Hepatobiliary Surgery and Liver Transplantation, Surgical Research Laboratory, Department of Surgery, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Dominique C Valla
- Hepatology Service, Hospital Beaujon, Clichy, France.,Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-Liver), Barcelona, Spain
| |
Collapse
|
|
43
|
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.
Collapse
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.
| |
Collapse
|
|
44
|
Ruiz S, Zhao H, Chandakkar P, Papoin J, Choi H, Nomura-Kitabayashi A, Patel R, Gillen M, Diao L, Chatterjee PK, He M, Al-Abed Y, Wang P, Metz CN, Oh SP, Blanc L, Campagne F, Marambaud P. Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models. J Clin Invest 2020; 130:942-957. [PMID: 31689244 DOI: 10.1172/jci127425] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 10/31/2019] [Indexed: 12/17/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.
Collapse
Affiliation(s)
- Santiago Ruiz
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | - Haitian Zhao
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | | | - Julien Papoin
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | - Hyunwoo Choi
- Barrow Aneurysm and AVM Research Center, Department of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA
| | | | - Radhika Patel
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | - Matthew Gillen
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and
| | - Li Diao
- Center for Immunology and Inflammation
| | | | - Mingzhu He
- Center for Molecular Innovation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Yousef Al-Abed
- Center for Molecular Innovation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Ping Wang
- Center for Immunology and Inflammation.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Christine N Metz
- Institute of Molecular Medicine, and.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - S Paul Oh
- Barrow Aneurysm and AVM Research Center, Department of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Lionel Blanc
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Fabien Campagne
- The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and.,Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, USA
| | - Philippe Marambaud
- Litwin-Zucker Center for Alzheimer's Disease and Memory Disorders and.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| |
Collapse
|
|
45
|
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: 13] [Impact Index Per Article: 2.6] [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.
Collapse
|
|
46
|
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.
Collapse
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.
| |
Collapse
|
|
47
|
Eker OF, Boccardi E, Sure U, Patel MC, Alicante S, Alsafi A, Coote N, Droege F, Dupuis O, Fialla AD, Jones B, Kariholu U, Kjeldsen AD, Lefroy D, Lenato GM, Mager HJ, Manfredi G, Nielsen TH, Pagella F, Post MC, Rennie C, Sabbà C, Suppressa P, Toerring PM, Ugolini S, Buscarini E, Dupuis-Girod S, Shovlin CL. European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT). Orphanet J Rare Dis 2020; 15:165. [PMID: 32600364 PMCID: PMC7322871 DOI: 10.1186/s13023-020-01386-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/22/2020] [Indexed: 12/13/2022] Open
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial. Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an “AVM” bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening: 1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion. 2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients. 3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider. 4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly. We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.
Collapse
Affiliation(s)
- Omer F Eker
- VASCERN HHT Reference Centre, Hospices Civils de Lyon, Lyon, France.
| | - Edoardo Boccardi
- Niguarda Hospital, Milan, Italy and VASCERN HHT Reference Centre, Crema, Italy
| | - Ulrich Sure
- VASCERN HHT Reference Centre, Essen University Hospital, Essen, Germany
| | - Maneesh C Patel
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Saverio Alicante
- VASCERN HHT Reference Centre, ASST Maggiore Hospital, Crema, Italy
| | - Ali Alsafi
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Nicola Coote
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Freya Droege
- VASCERN HHT Reference Centre, Essen University Hospital, Essen, Germany
| | - Olivier Dupuis
- VASCERN HHT Reference Centre, Hospices Civils de Lyon, Lyon, France
| | - Annette Dam Fialla
- VASCERN HHT Reference Centre, Odense Universitetshospital, Syddansk Universitet, Odense, Denmark
| | - Bryony Jones
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Ujwal Kariholu
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Anette D Kjeldsen
- VASCERN HHT Reference Centre, Odense Universitetshospital, Syddansk Universitet, Odense, Denmark
| | - David Lefroy
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Gennaro M Lenato
- VASCERN HHT Reference Centre, "Frugoni" Internal Medicine Unit, University of Bari "A. Moro", Policlinico, Bari, Italy
| | - Hans Jurgen Mager
- VASCERN HHT Reference Centre, St Antonius Ziekenhuis, Nieuwegein, Netherlands
| | - Guido Manfredi
- VASCERN HHT Reference Centre, ASST Maggiore Hospital, Crema, Italy
| | - Troels H Nielsen
- VASCERN HHT Reference Centre, Odense Universitetshospital, Syddansk Universitet, Odense, Denmark
| | - Fabio Pagella
- VASCERN HHT Reference Centre, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | - Marco C Post
- VASCERN HHT Reference Centre, St Antonius Ziekenhuis, Nieuwegein, Netherlands
| | - Catherine Rennie
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK
| | - Carlo Sabbà
- VASCERN HHT Reference Centre, "Frugoni" Internal Medicine Unit, University of Bari "A. Moro", Policlinico, Bari, Italy.
| | - Patrizia Suppressa
- VASCERN HHT Reference Centre, "Frugoni" Internal Medicine Unit, University of Bari "A. Moro", Policlinico, Bari, Italy
| | - Pernille M Toerring
- VASCERN HHT Reference Centre, Odense Universitetshospital, Syddansk Universitet, Odense, Denmark
| | - Sara Ugolini
- VASCERN HHT Reference Centre, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
| | | | | | - Claire L Shovlin
- VASCERN HHT Reference Centre, Imperial College Healthcare National Health Service Trust, London, UK and Imperial College London, London, UK.
| |
Collapse
|
|
48
|
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.
Collapse
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
| |
Collapse
|
|
49
|
Sidhwani P, Leerberg DM, Boezio GLM, Capasso TL, Yang H, Chi NC, Roman BL, Stainier DYR, Yelon D. Cardiac function modulates endocardial cell dynamics to shape the cardiac outflow tract. Development 2020; 147:dev185900. [PMID: 32439760 PMCID: PMC7328156 DOI: 10.1242/dev.185900] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 04/27/2020] [Indexed: 01/06/2023]
Abstract
Physical forces are important participants in the cellular dynamics that shape developing organs. During heart formation, for example, contractility and blood flow generate biomechanical cues that influence patterns of cell behavior. Here, we address the interplay between function and form during the assembly of the cardiac outflow tract (OFT), a crucial connection between the heart and vasculature that develops while circulation is under way. In zebrafish, we find that the OFT expands via accrual of both endocardial and myocardial cells. However, when cardiac function is disrupted, OFT endocardial growth ceases, accompanied by reduced proliferation and reduced addition of cells from adjacent vessels. The flow-responsive TGFβ receptor Acvrl1 is required for addition of endocardial cells, but not for their proliferation, indicating distinct modes of function-dependent regulation for each of these essential cell behaviors. Together, our results indicate that cardiac function modulates OFT morphogenesis by triggering endocardial cell accumulation that induces OFT lumen expansion and shapes OFT dimensions. Moreover, these morphogenetic mechanisms provide new perspectives regarding the potential causes of cardiac birth defects.
Collapse
Affiliation(s)
- Pragya Sidhwani
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Dena M Leerberg
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Giulia L M Boezio
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, 61231 Bad Nauheim, Germany
| | - Teresa L Capasso
- Department of Human Genetics, Graduate School of Public Health, and Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Hongbo Yang
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Neil C Chi
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Beth L Roman
- Department of Human Genetics, Graduate School of Public Health, and Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Didier Y R Stainier
- Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, 61231 Bad Nauheim, Germany
| | - Deborah Yelon
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| |
Collapse
|
|
50
|
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.
Collapse
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.
| | | |
Collapse
|