|
1
|
Gong AJ, Bolsegui ML, Lee EE, Tan MR, Zeng Y, Ma J, Gowda PC, Garg T, Weiss CR. Quantifying the burden of hereditary hemorrhagic telangiectasia on quality of life and psychological health: a cross-sectional study. Orphanet J Rare Dis 2025; 20:109. [PMID: 40055726 PMCID: PMC11889918 DOI: 10.1186/s13023-025-03620-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 02/18/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND Despite the considerable burden that hereditary hemorrhagic telangiectasia (HHT) imposes, few studies have investigated its effect on health-related quality of life (HRQoL). We aimed to assess the impact of HHT on psychosocial QoL and identify demographic and clinical factors associated with lower QoL. METHODS We conducted an international, cross-sectional study of 1042 adults with HHT within the Cure HHT network, between 2022 and 2023. We used an online survey that included 5 standardized instruments to evaluate patients' perceptions of the impact of HHT on their QoL: Epistaxis Severity Score (ESS); Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE-HHT); Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue - Short Form 8a - Fatigue interfere scale (PROMIS-Fatigue 8a); Hospital Anxiety and Depression Scale (HADS-A and HADS-D); and Short Form Health Survey (SF-36). Statistical analyses included Spearman's correlations, univariate analyses, Tukey's honestly significant difference, and Kruskal-Wallis tests. RESULTS 565/1042 (54%) participants completed the survey. The most common symptoms were epistaxis 521/565 (92%) and fatigue 446/565 (79%). There were strong positive correlations between HADS-A and ESS (2.6 [95% CI 1.7-3.6]) and NOSE-HHT (4 [3.2-5]); HADS-D and ESS (1.4 [1.3-1.5]) and NOSE-HHT (4.4 [3.4-5.7]); PROMIS Fatigue 8a and ESS (8.2 [6.3-10]) and NOSE-HHT (5.9 [5.2-6.6]); and SF-36 scores and ESS (- 26.4 [- 33 to - 19.9]) and NOSE-HHT (- 33.1 [- 39.7 to - 28.6]). Liver failure and seizures indicated a higher likelihood of depression (3.1 [1-5.2]), anxiety (3 [0.6-5.4]), and fatigue (9.6 [4.7-14.5]). Seizures were associated with depression (2.9 [1.8-3.9]), anxiety (2.9 [1.7-4.1]), and fatigue (5 [2.34-7.7]). Participants expressed a substantial effect on their physical (143/560 [25%]), role (140/556 [25%]), emotional (124/554 [22%]), social (104/556 [18%]), and cognitive (64/550 [11%]) functioning. However, more participants considered extremely important to improve their physical (289/560 [51%]), cognitive (266/550 [47%]), role (253/556 [43%]), emotional (243/554 [45%]), and social (233/556 [41%]) functioning affected by HHT. CONCLUSIONS Severe epistaxis is associated with higher rates of depression, anxiety, and fatigue. Participants expressed desire for improvement in a broad range of functional domains disturbed by HHT. This suggests a need for increased awareness, resources, and more effective interventions to improve the QOL of patients with HHT.
Collapse
Affiliation(s)
- Anna J Gong
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA
| | - Marisabel Linares Bolsegui
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA
| | - Emerson E Lee
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA
| | - Matthew R Tan
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA
| | - Yong Zeng
- Biostatistics, Epidemiology, and Data Management (BEAD) Core, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jianqiao Ma
- Biostatistics, Epidemiology, and Data Management (BEAD) Core, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Prateek C Gowda
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA
| | - Tushar Garg
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA
| | - Clifford R Weiss
- Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, 7203 Sheikh Zayed Tower, Suite 7, 1800 Orleans Street, Baltimore, MD, 21287, USA.
| |
Collapse
|
|
2
|
Tarulli CM, Ma X, Chokar K, Vozoris NT, Clancy MS, Faughnan ME. Health outcomes following COVID-19 infection and vaccination in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2025; 20:94. [PMID: 40025608 PMCID: PMC11871591 DOI: 10.1186/s13023-025-03561-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/17/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND There has been concern that individuals living with Hereditary Hemorrhagic Telangiectasia (HHT) could be at higher risk for poor outcomes if infected with SARS-CoV2, the virus that causes COVID-19 disease. As literature is lacking on outcomes on COVID-19 infection and vaccination in HHT, the objectives of this study were to determine and assess outcomes in HHT, as well as quantify vaccination rates and vaccination side effects in a large cohort of individuals with HHT. METHOD Individuals previously recruited to OUR HHT Registry at St. Michael's Hospital, Toronto were contacted for participation in this study. Data were collected during annual assessment through a series of questionnaires asking specifically about HHT complications, treatments, and symptom management, along with COVID infection and vaccination data. RESULTS We attempted to contact all 262 subjects recruited to the registry. Of these, 215 (82.1%) responded at least once regarding COVID-19 related inquiries between April 2020 and August 2022, and these individuals formed our study sample. Forty-nine COVID-19 infections were reported in 47/215 (21.9%) individuals. Among 47 patients with recorded COVID-19 infection, 2/47 (4.3%) required urgent care and 7/47 (14.9%) were hospitalized following infection. Of the 7 individuals who were hospitalized, 3 (42.9%) required new supplemental oxygen. Zero deaths were reported due to COVID-19 infection. COVID vaccination history was available in 147/215 (68.4%). Of these, 135/147 (91.8%) of individuals reported vaccination and side effects were mild. DISCUSSION While our sample population is much like the general HHT population with regards to gender, HHT symptoms, and genetics, study limitations including survivor bias, lack of vaccine effectiveness assessment, and participant reported data should be acknowledged. CONCLUSION Our results suggest that HHT patients are not at higher risk of severe infection with COVID-19 compared to the general population. Vaccination rates are high with only mild side effects being observed.
Collapse
Affiliation(s)
- Christopher M Tarulli
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital and Li Ka Shing Knowledge Institute, University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada
| | - Xiayi Ma
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital and Li Ka Shing Knowledge Institute, University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada
| | - Kamalprit Chokar
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital and Li Ka Shing Knowledge Institute, University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada
| | - Nicholas T Vozoris
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital and Li Ka Shing Knowledge Institute, University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada
| | | | - Marie E Faughnan
- Toronto HHT Centre, Division of Respirology, Department of Medicine, St. Michael's Hospital and Li Ka Shing Knowledge Institute, University of Toronto, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.
| |
Collapse
|
|
3
|
Gariballa N, Badawi S, Ali BR. Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele. Traffic 2024; 25:e12928. [PMID: 38272447 DOI: 10.1111/tra.12928] [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: 06/30/2023] [Revised: 11/24/2023] [Accepted: 12/13/2023] [Indexed: 01/27/2024]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting 1 in 5000-8000 individuals. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is the most common HHT and manifests as diverse vascular malformations ranging from mild symptoms such as epistaxis and mucosal and cutaneous telangiectases to severe arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is caused by heterozygous mutations in the ENG gene, which encodes endoglin, the TGFβ homodimeric co-receptor. It was previously shown that some endoglin HHT1-causing variants failed to traffic to the plasma membrane due to their retention in the endoplasmic reticulum (ER) and consequent degradation by ER-associated degradation (ERAD). Endoglin is a homodimer formed in the ER, and we therefore hypothesized that mixed heterodimers might form between ER-retained variants and WT protein, thus hampering its maturation and trafficking to the plasma membrane causing dominant negative effects. Indeed, HA-tagged ER-retained mutants formed heterodimers with Myc-tagged WT endoglin. Moreover, variants L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking of WT endoglin by reducing its maturation and plasma membrane localization. These results strongly suggest dominant negative effects exerted by these ER-retained variants aggravating endoglin loss of function in patients expressing them in the heterozygous state with the WT allele. Moreover, this study may help explain some of the variability observed among HHT1 patients due to the additional loss of function exerted by the dominant negative effects in addition to that due to haploinsufficiency. These findings might also have implications for some of the many conditions impacted by ERAD.
Collapse
Affiliation(s)
- Nesrin Gariballa
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Sally Badawi
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Bassam R Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| |
Collapse
|
|
4
|
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
|
|
5
|
Szmygin M, Szmygin P, Drelich K, Pustelniak O, Pech M, Jargiełło T. The role of interventional radiology in treatment of patients with hereditary hemorrhagic telangiectasia. Eur J Radiol 2023; 162:110769. [PMID: 36933496 DOI: 10.1016/j.ejrad.2023.110769] [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: 10/19/2022] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu disease is a rare autosomal dominant, multi-organ disorder that leads to formation of abnormal vascular connections resulting in devastating and life-threatening complications. Due to its multisystem character, wide range of clinical manifestations and variable expressivity, HHT remains a diagnostic challenge and requires close cooperation of specialists from various medical fields. Interventional radiology plays a key role in the management of this disease, helping maintain the health of HHT patients and minimize the risk of fatal complications. The aim of this article is to review clinical manifestations, diagnostic guidelines and criteria of HHT as well as to present the means of endovascular therapy in the management of HHT patients.
Collapse
Affiliation(s)
- Maciej Szmygin
- Medical University of Lublin, Department of Interventional Radiology and Neuroradiology, Lublin, Poland.
| | - Paweł Szmygin
- Medical University of Lublin, Department of Neurosurgery, Lublin, Poland
| | - Katarzyna Drelich
- Medical University of Lublin, Students' Scientific Society at the Department of Interventional Radiology and Neuroradiology, Lublin, Poland
| | - Olga Pustelniak
- Medical University of Lublin, Students' Scientific Society at the Department of Interventional Radiology and Neuroradiology, Lublin, Poland
| | - Maciej Pech
- Medical University of Magdeburg, Department of Radiology and Nuclear Medicine, Magdeburg, Germany
| | - Tomasz Jargiełło
- Medical University of Lublin, Department of Interventional Radiology and Neuroradiology, Lublin, Poland
| |
Collapse
|
|
6
|
Neuraxial Techniques in Obstetric Patients with Intracranial Lesions. CURRENT OBSTETRICS AND GYNECOLOGY REPORTS 2023. [DOI: 10.1007/s13669-023-00345-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
|
|
7
|
Brain AVMs-Related microRNAs: Machine Learning Algorithm for Expression Profiles of Target Genes. Brain Sci 2022; 12:brainsci12121628. [PMID: 36552089 PMCID: PMC9775264 DOI: 10.3390/brainsci12121628] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/20/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
INTRODUCTION microRNAs (miRNAs) are a class of non-coding RNAs playing a myriad of important roles in regulating gene expression. Of note, recent work demonstrated a critical role of miRNAs in the genesis and progression of brain arteriovenous malformations (bAVMs). Accordingly, here we examine miRNA signatures related to bAVMs and associated gene expression. In so doing we expound on the potential prognostic, diagnostic, and therapeutic significance of miRNAs in the clinical management of bAVMs. METHODS A PRISMA-based literature review was performed using PubMed/Medline database with the following search terms: "brain arteriovenous malformations", "cerebral arteriovenous malformations", "microRNA", and "miRNA". All preclinical and clinical studies written in English, regardless of date, were selected. For our bioinformatic analyses, miRWalk and miRTarBase machine learning algorithms were employed; the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was quired for associated pathways/functions. RESULTS four studies were ultimately included in the final analyses. Sequencing data consistently revealed the decreased expression of miR-18a in bAVM-endothelial cells, resulting in increased levels of vascular endodermal growth factor (VEGF), Id-1, matrix metalloproteinase, and growth signals. Our analyses also suggest that the downregulation of miR-137 and miR-195* within vascular smooth muscle cells (VSMCs) may foster the activation of inflammation, aberrant angiogenesis, and phenotypic switching. In the peripheral blood, the overexpression of miR-7-5p, miR-629-5p, miR-199a-5p, miR-200b-3p, and let-7b-5p may contribute to endothelial proliferation and nidus development. The machine learning algorithms employed confirmed associations between miRNA-related target networks, vascular rearrangement, and bAVM progression. CONCLUSION miRNAs expression appears to be critical in managing bAVMs' post-transcriptional signals. Targets of microRNAs regulate canonical vascular proliferation and reshaping. Although additional scientific evidence is needed, the identification of bAVM miRNA signatures may facilitate the development of novel prognostic/diagnostic tools and molecular therapies for bAVMs.
Collapse
|
|
8
|
Naruse G, Watanabe T, Okura H. Infective endocarditis with Osler’s nodule in a patient with Osler’s disease: a case report and review of the literature. J Med Case Rep 2022; 16:211. [PMID: 35643752 PMCID: PMC9148510 DOI: 10.1186/s13256-022-03427-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/25/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hereditary hemorrhagic telangiectasia, also known as Osler–Weber–Rendu disease, induces arteriovenous malformations in visceral organs. Arteriovenous malformations increase the risk of severe infections and are a common complication associated with hemorrhagic telangiectasia. However, cases of endocarditis associated with hemorrhagic telangiectasia are rarely reported. Although hemorrhagic telangiectasia causes erythematous macules on the extremities, these macules are usually painless. We encountered a rare case of infective endocarditis in a patient with Osler–Weber–Rendu disease.
Case presentation
A 52-year-old Japanese woman who was diagnosed with hemorrhagic telangiectasia 5 years prior presented to our hospital with fever and muscular pain. She had erythematous nodules and tenderness on the finger, heel, and toe, suggestive of Osler’s nodes. A physical examination revealed tachycardia with a 3/6 pansystolic murmur. A transesophageal echocardiogram showed vegetations along the atrial side of the mitral valve and mild mitral regurgitation because of prolapse of the anterior commissure. Methicillin-sensitive Staphylococcus aureus was identified in the blood cultures. Detection of distinctive skin lesions, so-called Osler’s nodes, was the symptomatic key to early diagnosis, and the patient was treated without surgery. She was discharged with negative blood cultures after a 6-week intravenous antibiotic administration.
Conclusions
Our report highlights the importance of considering the risk of extracerebral infections including endocarditis in hemorrhagic telangiectasia. This rare case effectively demonstrates the importance of proper diagnosis of skin lesions.
Collapse
|
|
9
|
Morton A. Pregnancy complicated by neurological and neurosurgical conditions - The evidence regarding mode of delivery. Obstet Med 2022; 15:11-18. [PMID: 35444727 PMCID: PMC9014549 DOI: 10.1177/1753495x211000176] [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: 09/21/2020] [Revised: 09/21/2020] [Accepted: 02/10/2021] [Indexed: 11/15/2022] Open
Abstract
Neurological and neurosurgical conditions complicating pregnancy may precipitate considerable concern regarding the risk of complications, and uncertainty regarding the preferred mode of delivery and anaesthesia. Caesarean section is known to be associated with significantly increased risk of adverse maternal outcomes compared with vaginal delivery in healthy pregnancy. Nevertheless, a common perception exists among the general population and some health professionals that caesarean section is safer for the mother and baby in high-risk pregnancies. This manuscript examines the literature regarding the risks and outcomes related to mode of delivery in pregnancy complicated by disorders of the central nervous system. With the exception of women with raised intracranial pressure, and some women with Von Hippel-Lindau syndrome, the available evidence suggests that the mode of delivery should be based upon obstetric indications.
Collapse
Affiliation(s)
- Adam Morton
- Obstetric Medicine Department, Mater Hospital, South Brisbane,
Australia
- Faculty of Medicine, University of Queensland, St Lucia,
Australia
| |
Collapse
|
|
10
|
Umscheid J, Albright J, Chazhoor J, Vasudeva R. Prolonged Asthma Exacerbation as an Initial Presentation in Hereditary Hemorrhagic Telangiectasia. Kans J Med 2021; 14:305-307. [PMID: 34888003 PMCID: PMC8647986 DOI: 10.17161/kjm.vol14.15752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/21/2021] [Indexed: 11/17/2022] Open
Affiliation(s)
- Jacob Umscheid
- University of Kansas School of Medicine-Wichita, Wichita, KS.,Department of Pediatrics
| | - Joshua Albright
- University of Kansas School of Medicine-Wichita, Wichita, KS.,Department of Pediatrics
| | - John Chazhoor
- University of Kansas School of Medicine-Wichita, Wichita, KS
| | - Rhythm Vasudeva
- University of Kansas School of Medicine-Wichita, Wichita, KS.,Internal Medicine/Pediatrics Residency Program
| |
Collapse
|
|
11
|
Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension. Cells 2021; 10:cells10113178. [PMID: 34831401 PMCID: PMC8624726 DOI: 10.3390/cells10113178] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 01/29/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.
Collapse
|
|
12
|
Li H, Nam Y, Huo R, Fu W, Jiang B, Zhou Q, Song D, Yang Y, Jiao Y, Weng J, Yan Z, Di L, Li J, Wang J, Xu H, Wang S, Zhao J, Wen Z, Wang J, Cao Y. De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation. Circ Res 2021; 129:825-839. [PMID: 34530633 DOI: 10.1161/circresaha.121.319004] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
[Figure: see text].
Collapse
Affiliation(s)
- Hao Li
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Yoonhee Nam
- Division of Life Science, State Key Laboratory of Molecular Neuroscience (Y.N., Q.Z., D.S., Z.W., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Ran Huo
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Weilun Fu
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Biaobin Jiang
- Chemical and Biological Engineering (B.J., Y.Y., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China.,the Hong Kong University of Science and Technology (B.J.,Y.Y.), Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Qiuxia Zhou
- Division of Life Science, State Key Laboratory of Molecular Neuroscience (Y.N., Q.Z., D.S., Z.W., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Dong Song
- Division of Life Science, State Key Laboratory of Molecular Neuroscience (Y.N., Q.Z., D.S., Z.W., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Yingxi Yang
- Chemical and Biological Engineering (B.J., Y.Y., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China.,the Hong Kong University of Science and Technology (B.J.,Y.Y.), Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Yuming Jiao
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Jiancong Weng
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Zihan Yan
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Lin Di
- Beijing Advanced Innovation Center for Genomics, Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences (L.D.), Peking University, Beijing, China.,School of Life Sciences (L.D.), Peking University, Beijing, China
| | - Jie Li
- School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China (J.L.)
| | - Jie Wang
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Hongyuan Xu
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Shuo Wang
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Jizong Zhao
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| | - Zilong Wen
- Division of Life Science, State Key Laboratory of Molecular Neuroscience (Y.N., Q.Z., D.S., Z.W., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China.,Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, China (Z.W.)
| | - Jiguang Wang
- Division of Life Science, State Key Laboratory of Molecular Neuroscience (Y.N., Q.Z., D.S., Z.W., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China.,Chemical and Biological Engineering (B.J., Y.Y., Jiguang Wang), Clear Water Bay, Kowloon, Hong Kong SAR, China.,Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong SAR, China (Jiguang Wang)
| | - Yong Cao
- Neurosurgery, Beijing Tiantan Hospital (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.), Capital Medical University, China.,Beijing Neurosurgical Institute (Y.C.), Capital Medical University, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China (H.L., R.H., W.F., Y.J., Jiancong Weng, Z.Y., Jie Wang, H.X., S.W., J.Z., Y.C.)
| |
Collapse
|
|
13
|
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
|
|
14
|
Fazal S, Bisserier M, Hadri L. Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension. Cells 2021; 10:638. [PMID: 33805595 PMCID: PMC7999465 DOI: 10.3390/cells10030638] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular "pressure overload", which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.
Collapse
Affiliation(s)
| | | | - Lahouaria Hadri
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA; (S.F.); (M.B.)
| |
Collapse
|
|
15
|
Kamimura Y, Nakanishi T, Boku Sato A, Kako E, Tanaka M, Sobue K. Anesthetic considerations for cesarean delivery in a parturient with hereditary hemorrhagic telangiectasia: a case report. JA Clin Rep 2021; 7:19. [PMID: 33650024 PMCID: PMC7921269 DOI: 10.1186/s40981-021-00420-4] [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: 01/08/2021] [Revised: 02/07/2021] [Accepted: 02/14/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant disorder characterized by mucocutaneous telangiectasia and arteriovenous malformations (AVMs). There are some anesthetic considerations for cesarean delivery in a parturient with HHT. CASE PRESENTATION A 27-year-old parturient with pulmonary hemorrhage was admitted to our tertiary perinatal center. She was first diagnosed with HHT and a cesarean delivery using spinal anesthesia at 37 weeks of gestation was initially planned. However, magnetic resonance imaging (MRI) at 32 weeks of gestation revealed spinal AVM ranging from the thoracic to the lumbar levels. Thus, elective cesarean delivery under general anesthesia was planned. The parturient had an uneventful perioperative course. CONCLUSIONS HHT should be considered as a differential diagnosis when parturients develop pulmonary hemorrhage. In a cesarean delivery of parturients with HHT, spinal MRI during pregnancy can help in deciding the anesthetic procedure to be used.
Collapse
Affiliation(s)
- Yuji Kamimura
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Toshiyuki Nakanishi
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Aiji Boku Sato
- Department of Anesthesiology, Aichi Gakuin University School of Dentistry, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651, Japan
| | - Eisuke Kako
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Motoshi Tanaka
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kazuya Sobue
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| |
Collapse
|
|
16
|
Cannavicci A, Zhang Q, Kutryk MJB. Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia. J Clin Med 2020; 9:jcm9103333. [PMID: 33080889 PMCID: PMC7603193 DOI: 10.3390/jcm9103333] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 02/08/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are functional ribonucleic acid (RNA) species that include microRNAs (miRs), a class of short non-coding RNAs (∼21–25 nucleotides), and long non-coding RNAs (lncRNAs) consisting of more than 200 nucleotides. They regulate gene expression post-transcriptionally and are involved in a wide range of pathophysiological processes. Hereditary hemorrhagic telangiectasia (HHT) is a rare disorder inherited in an autosomal dominant fashion characterized by vascular dysplasia. Patients can develop life-threatening vascular malformations and experience severe hemorrhaging. Effective pharmacological therapies are limited. The study of ncRNAs in HHT is an emerging field with great promise. This review will explore the current literature on the involvement of ncRNAs in HHT as diagnostic and pathogenic factors.
Collapse
Affiliation(s)
- Anthony Cannavicci
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada;
- Division of Cardiology, Keenan Research Center for Biomedical Sciences, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada;
| | - Qiuwang Zhang
- Division of Cardiology, Keenan Research Center for Biomedical Sciences, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada;
| | - Michael J. B. Kutryk
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada;
- Division of Cardiology, Keenan Research Center for Biomedical Sciences, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada;
- Correspondence: ; Tel.: +1-(416)-360-4000 (ext. 6155)
| |
Collapse
|
|
17
|
Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med 2020; 22:1201-1205. [PMID: 32300199 DOI: 10.1038/s41436-020-0775-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/19/2020] [Accepted: 02/28/2020] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Determine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curaçao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia. METHODS Review of HHT center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed. RESULTS A variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval [CI], 36.0-52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7-60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2-4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7-6.6%) family probands did not have a variant in one of these genes. CONCLUSION Previous reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75-85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curaçao criteria is highly predictive of a causative variant in either ENG or ACVRL1.
Collapse
|
|
18
|
Moudgil K, Rajpurohit N, Bharbey P, Jatin M. Hereditary hemorrhagic telangiectasia: An informative review. IRAQI JOURNAL OF HEMATOLOGY 2020. [DOI: 10.4103/ijh.ijh_24_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
19
|
Baysal M, Demir S, Ümit EG, Gürkan H, Baş V, Karaman Gülsaran S, Demirci U, Kırkızlar HO, Demir AM. Genetic Diagnosis of Hereditary Hemorrhagic Telangiectasia: Four Novel Pathogenic Variations in Turkish Patients. Balkan Med J 2019; 37:43-46. [PMID: 31594285 PMCID: PMC6934015 DOI: 10.4274/balkanmedj.galenos.2019.2019.7.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Aims: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by telangiectasia, epistaxis, and vascular malformations. Pathogenic mutations were found in ENG, AVCRL1, SMAD4, and GDF genes. In this study, we present our database of patients with hereditary hemorrhagic telangiectasia regarding the phenotype-genotype relations and discuss two novel ENG gene pathogenic variations in two unrelated families. Methods: Next Generation Sequencing analysis was performed on the peripheral blood of nine patients with hereditary hemorrhagic telangiectasia in four unrelated families. All patients were diagnosed with hereditary hemorrhagic telangiectasia according to the Curaçao criteria. Data on treatment and screenings of visceral involvement were recorded from files. Results: We have found a pathogenic variation in either the ENG or ACVRL1 gene in each family. Two novel pathogenic variations in the ENG gene, including NM_000118.3 (ENG): c.416delC (p.P139fs*24) and NM_000118.3(ENG): c.1139dupT (p.Leu380PhefsTer16), were found in the same family. The NM_000020.2(ACVRL1): c.1298C>T (p.Pro433Leu) pathogenic variation in the ACVRL1 gene in our first family and a novel heterozygous likely pathogenic NM_000020.2(ACVRL1): c.95T>C (p.Val32Ala) variation was found in our second family. Seven of the nine patients were treated with thalidomide for controlling bleeding episodes. All patients responded to thalidomide. In one patient, the response to thalidomide was lost and switched to bevacizumab. Conclusion: In hereditary hemorrhagic telangiectasia, certain types of mutations correlate with disease phenotypes and with next generation sequencing methods. New pathogenic variations can be revealed, which might help manage patients with hereditary hemorrhagic telangiectasia.
Collapse
Affiliation(s)
- Mehmet Baysal
- Department of Hematology, Trakya University School of Medicine, Edirne, Turkey
| | - Selma Demir
- Department of Medical Genetics, Trakya University School of Medicine, Edirne, Turkey
| | - Elif G. Ümit
- Department of Hematology, Trakya University School of Medicine, Edirne, Turkey
| | - Hakan Gürkan
- Department of Medical Genetics, Trakya University School of Medicine, Edirne, Turkey
| | - Volkan Baş
- Department of Hematology, Trakya University School of Medicine, Edirne, Turkey
| | | | - Ufuk Demirci
- Department of Medical Genetics, Trakya University School of Medicine, Edirne, Turkey
| | | | | |
Collapse
|
|
20
|
Zhao Y, Zhang Y, Wang X, Zhang L. Variant analysis in Chinese families with hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med 2019; 7:e893. [PMID: 31400083 PMCID: PMC6732279 DOI: 10.1002/mgg3.893] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 07/09/2019] [Accepted: 07/15/2019] [Indexed: 11/25/2022] Open
Abstract
Background Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia disorder characterized by epistaxis, mucocutaneous telangiectasias and arteriovenous malformations in internal organs. Recurrent epistaxis is the primary complaint in 90%‐96% of HHT patients and the other symptoms come with age. The aim of this study was to analyze HHT‐associated gene variant spectrum in Chinese HHT patients and to assess whether genetic testing could contribute to the early diagnosis. Methodology/Principal Thirty one HHT families including 62 individuals were recruited. Variants in the coding regions of four genes involved in HHT were amplified and analyzed using Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA). Results Twenty unique variants, including 8 novel variants were found in 24 of the 31 (77.4%) kindred. Diagnosis is confirmed for 7 possible individuals from 6 kindred. Thirteen ACVRL1 variants were detected from 17 isolated HHT families. Variants in ACVRL1 from 8/17 (47.1%) families were located in exon8. Seven ENG variants were found in 7 unrelated families throughout the coding region. Conclusion We conclude that ACVRL1 gene variant is 2.4 times more prevalent than that in ENG in Chinese individuals with HHT, and exon8 of the ACVRL1 gene may be a hotspot region. Genetic testing could contribute to early diagnosis for HHT.
Collapse
Affiliation(s)
- Yali Zhao
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
| | - Yuan Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
| | - Xiangdong Wang
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
| | - Luo Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.,Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
21
|
Bioengineering an Artificial Human Blood⁻Brain Barrier in Rodents. Bioengineering (Basel) 2019; 6:bioengineering6020038. [PMID: 31052208 PMCID: PMC6630638 DOI: 10.3390/bioengineering6020038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/18/2019] [Accepted: 04/23/2019] [Indexed: 12/15/2022] Open
Abstract
Our group has recently created a novel in-vivo human brain organoid vascularized with human iPSC-derived endothelial cells. In this review article, we discuss the challenges of creating a perfused human brain organoid model in an immunosuppressed rodent host and discuss potential applications for neurosurgical disease modeling.
Collapse
|
|
22
|
Ruiz-Llorente L, Chiapparino E, Plumitallo S, Danesino C, Bayrak-Toydemir P, Pagella F, Manfredi G, Bernabeu C, Jovine L, Olivieri C. Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia. Gene 2019; 696:33-39. [PMID: 30763665 DOI: 10.1016/j.gene.2019.02.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 02/06/2019] [Indexed: 10/27/2022]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding, skin and mucosa telangiectasias, and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes, which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1), respectively, both belonging to the TGF-β/BMP signaling pathway. In this work, we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family, all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact, transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression.
Collapse
Affiliation(s)
- Lidia Ruiz-Llorente
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Ramiro de Maeztu 9, 28040 Madrid, Spain.
| | - Elisa Chiapparino
- Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy.
| | - Sara Plumitallo
- Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy; IRCCS Fondazione Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.
| | - Cesare Danesino
- Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy; IRCCS Fondazione Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.
| | - Pinar Bayrak-Toydemir
- ARUP Institute for Clinical and Experimental Pathology, Department of Pathology, University of Utah, Salt Lake City, UT, USA.
| | - Fabio Pagella
- Head and Neck Department, ENT Unit, IRCCS Fondazione Policlinico "San Matteo", Piazzale Golgi 2, 27100 Pavia, Italy.
| | - Guido Manfredi
- UOC Gastroenterology and Endoscopy Unit, ASST, Ospedale Maggiore, 26013 Crema, CR, Italy.
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Ramiro de Maeztu 9, 28040 Madrid, Spain.
| | - Luca Jovine
- Department of Biosciences and Nutrition and Center for Innovative Medicine, Karolinska Institutet, Medicinaren 25 Neo, SE-141 83 Huddinge, Sweden.
| | - Carla Olivieri
- Molecular Medicine Department, General Biology and Medical Genetics Unit, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy.
| |
Collapse
|
|
23
|
Wooderchak-Donahue WL, McDonald J, Farrell A, Akay G, Velinder M, Johnson P, VanSant-Webb C, Margraf R, Briggs E, Whitehead KJ, Thomson J, Lin AE, Pyeritz RE, Marth G, Bayrak-Toydemir P. Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. J Med Genet 2018; 55:824-830. [DOI: 10.1136/jmedgenet-2018-105561] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/14/2018] [Accepted: 08/23/2018] [Indexed: 01/09/2023]
Abstract
IntroductionHereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases.MethodsDNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants.ResultsEight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich ‘hotspot’ region of ACVRL1intron 9 that disrupted splicing.ConclusionsDespite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.
Collapse
|
|
24
|
Karlsson T, Cherif H. Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital. Ups J Med Sci 2018; 123:153-157. [PMID: 30251589 PMCID: PMC6198721 DOI: 10.1080/03009734.2018.1483452] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AIM The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT). METHODS The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess. RESULTS Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications. CONCLUSION Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.
Collapse
Affiliation(s)
- Torbjörn Karlsson
- Department of Haematology, Uppsala University Hospital, Uppsala, Sweden
- Center for Osler’s Disease, Uppsala University Hospital, Uppsala, Sweden
- Department of Medicine, Västmanlands Hospital, Västerås, Sweden
- CONTACT Torbjörn Karlsson Department of Haematology, Uppsala University Hospital, 751 85Uppsala, Sweden
| | - Honar Cherif
- Department of Haematology, Uppsala University Hospital, Uppsala, Sweden
- Center for Osler’s Disease, Uppsala University Hospital, Uppsala, Sweden
| |
Collapse
|
|
25
|
Thompson CF, Suh JD, McWilliams J, Duckwiler G, Wang MB. Initial experience of a hereditary hemorrhagic telangiectasia center of excellence. EAR, NOSE & THROAT JOURNAL 2018. [PMID: 28636740 DOI: 10.1177/014556131709600607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Our objectives in reviewing the initial experience of a hereditary hemorrhagic telangiectasia center of excellence (HHT COE) were to better understand the interventions being performed in the comprehensive care of these patients and to present the early data as a reference for other tertiary centers considering starting an HHT COE. We conducted a retrospective review of consecutive patients referred to our newly developed HHT COE for evaluation and treatment between May 2010 and June 2013. Clinical presentation, otolaryngologic treatments, and other operative interventions were analyzed. One hundred forty-four of the 198 patients (73%) evaluated at the HHT COE had definite HHT based on the Curaçao diagnostic criteria, with 20 additional patients possibly having HHT and undergoing further evaluation to confirm the diagnosis. Sixteen of the 31 patients (52%) referred to otolaryngology required intervention in the operating room for epistaxis. Seventy-two of the 164 (44%) patients with definite or possible HHT required other interventions for internal organ arteriovenous malformations (AVMs), with interventional radiology embolization of pulmonary AVMs being the most common procedure. An HHT COE is important in providing comprehensive care for patients with this rare disease, which has significant clinical sequelae. Having an HHT COE allows for early screening and subspecialty referral within a system of specialists experienced in preventing the morbidity and mortality associated with severe epistaxis and internal organ AVMs.
Collapse
Affiliation(s)
- Christopher F Thompson
- Department of Otolaryngology, Northwestern University, 675 N. St. Clair, Galter Pavilion 15th Floor, Room 200, Chicago, IL 60614.
| | | | | | | | | |
Collapse
|
|
26
|
Clinical presentation and treatment paradigms in patients with hereditary hemorrhagic telangiectasia and spinal vascular malformations. J Clin Neurosci 2018; 50:51-57. [PMID: 29398197 DOI: 10.1016/j.jocn.2018.01.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 01/05/2018] [Indexed: 11/23/2022]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that causes angiodysplasia and results in mucocutaneous telangiectasias and arteriovenous malformations of organs. Although central nervous system vascular malformations can occur anywhere along the neuraxis, spinal vascular malformations are rare. We present our experience with the presentation and management of spinal vascular malformations in patients with HHT. Of the more than 800 patients with the diagnosis of HHT screened at our institution from 1995 through 2017, four patients with spinal vascular malformations (age range 1 month-77 years; 2 male, 2 female) were identified, three of whom came to clinical attention after significant neurological deterioration from previously unknown malformations. A review of the literature including our patients demonstrated 29 total spinal arteriovenous fistulas (AVFs) in 28 HHT patients (69% male). The lesions were located predominantly in the thoracic spine (65.5%). Three lesions were not treated, 17 were treated with embolization, 6 were surgically resected, and 3 were treated with embolization and surgery. In 14 cases, the patients presented with hemorrhage of the AVF. Overall, 79% of patients achieved complete or near-complete occlusion, with 75% reporting improvement in neurological function. Discovery of spinal lesions often occurs after neurological decline because current screening protocols do not include evaluation of the patient for spinal lesions. Most patients benefit from intervention, which is tailored to the characteristics of the patient and their malformation. Given the often-severe neurological deficit encountered at presentation, we favor a protocol that screens HHT patients for spinal vascular malformations.
Collapse
|
|
27
|
Hsu CC, Kwan GNC, Evans‐Barns H, van Driel ML, Cochrane Cystic Fibrosis and Genetic Disorders Group. Embolisation for pulmonary arteriovenous malformation. Cochrane Database Syst Rev 2018; 1:CD008017. [PMID: 29298459 PMCID: PMC6491094 DOI: 10.1002/14651858.cd008017.pub5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Pulmonary arteriovenous malformations are abnormal direct connections between the pulmonary artery and pulmonary vein which result in a right-to-left shunt. They are associated with substantial morbidity and mortality mainly from the effects of paradoxical emboli. Potential complications include stroke, cerebral abscess, pulmonary haemorrhage and hypoxaemia. Embolisation is an endovascular intervention based on the occlusion of the feeding arteries the pulmonary arteriovenous malformations thus eliminating the abnormal right-to-left-shunting. This is an update of a previously published review. OBJECTIVES To determine the efficacy and safety of embolisation in patients with pulmonary arteriovenous malformations including a comparison with surgical resection and different embolisation devices. SEARCH METHODS We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register; date of last search: 10 April 2017.We also searched the following databases: the Australian New Zealand Clinical Trials Registry; ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Register; International Clinical Trials Registry Platform Search Portal (last searched 27 August 2017). to be updatedWe checked cross-references and searched references from review articles. SELECTION CRITERIA Trials in which individuals with pulmonary arteriovenous malformations were randomly allocated to embolisation compared to no treatment, surgical resection or embolisation using a different embolisation device. DATA COLLECTION AND ANALYSIS Studies identified for potential inclusion were independently assessed for eligibility by two authors, with excluded studies further checked by a third author. No trials were identified for inclusion in the review and hence no analysis was performed. MAIN RESULTS There were no randomised controlled trials included in the review; one ongoing trial has been identified which may be eligible for inclusion in the future. AUTHORS' CONCLUSIONS There is no evidence from randomised controlled trials for embolisation of pulmonary arteriovenous malformations. However, randomised controlled trials are not always feasible on ethical grounds. Accumulated data from observational studies suggest that embolisation is a safe procedure which reduces morbidity and mortality. A standardised approach to reporting with long-term follow-up through registry studies can help to strengthen the evidence for embolisation in the absence of randomised controlled trials.
Collapse
Affiliation(s)
- Charlie C‐T Hsu
- University of TorontoDepartment of Medical Imaging4th Floor, 263 McCaul StreetTorontoOntarioCanadaM5T 1W7
| | - Gigi NC Kwan
- Princess Alexandra HospitalDepartment of Medical Imaging199 Ipswich RoadBrisbaneQueenslandAustralia4102
| | - Hannah Evans‐Barns
- University of MelbourneFaculty of Medicine, Dentistry and Health SciencesGrattan Street, ParkvilleMelbourneVictoriaAustralia3010
| | - Mieke L van Driel
- The University of QueenslandPrimary Care Clinical Unit, Faculty of MedicineBrisbaneQueenslandAustralia4029
- Bond UniversityCentre for Research in Evidence‐Based Practice (CREBP)Gold CoastQueenslandAustralia4229
- Ghent UniversityDepartment of Family Medicine and Primary Health Care1K3, De Pintelaan 185GhentBelgium9000
| | | |
Collapse
|
|
28
|
Characterization of pulmonary arteriovenous malformations in ACVRL1 versus ENG mutation carriers in hereditary hemorrhagic telangiectasia. Genet Med 2017; 20:639-644. [DOI: 10.1038/gim.2017.160] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 08/11/2017] [Indexed: 11/08/2022] Open
|
|
29
|
Gamboa NT, Taussky P, Park MS, Couldwell WT, Mahan MA, Kalani MYS. Neurovascular patterning cues and implications for central and peripheral neurological disease. Surg Neurol Int 2017; 8:208. [PMID: 28966815 PMCID: PMC5609400 DOI: 10.4103/sni.sni_475_16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 06/28/2017] [Indexed: 12/20/2022] Open
Abstract
The highly branched nervous and vascular systems run along parallel trajectories throughout the human body. This stereotyped pattern of branching shared by the nervous and vascular systems stems from a common reliance on specific cues critical to both neurogenesis and angiogenesis. Continually emerging evidence supports the notion of later-evolving vascular networks co-opting neural molecular mechanisms to ensure close proximity and adequate delivery of oxygen and nutrients to nervous tissue. As our understanding of these biologic pathways and their phenotypic manifestations continues to advance, identification of where pathways go awry will provide critical insight into central and peripheral nervous system pathology.
Collapse
Affiliation(s)
- Nicholas T Gamboa
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Philipp Taussky
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Min S Park
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - William T Couldwell
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Mark A Mahan
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - M Yashar S Kalani
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
| |
Collapse
|
|
30
|
Health screening behaviors among adults with hereditary hemorrhagic telangiectasia in North America. Genet Med 2016; 19:659-666. [PMID: 27735923 PMCID: PMC5391304 DOI: 10.1038/gim.2016.161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 08/30/2016] [Indexed: 12/24/2022] Open
Abstract
PURPOSE This study aimed to identify factors that influence screening behaviors of adults with hereditary hemorrhagic telangiectasia (HHT). METHODS Participants with a self-reported diagnosis of HHT were recruited from the HHT Foundation International, Inc.; the "HHT Awareness" Facebook group; and six HHT clinics. A cross-sectional mixed methods survey was administered to investigate the relationships among the Health Belief model constructs, the domains of illness representations, and HHT-specific screening behaviors consistent with recommended guidelines. RESULTS A total of 320 participants reported rates of cerebral arteriovenous malformation (AVM) screenings, pulmonary AVM screenings, and HHT annual checkups that were 82.0, 67.1, and 56.5%, respectively. Logistical regression analysis showed that perceived barriers (β = -0.114, P < 0.001), perceived susceptibility (β = 0.117, P < 0.05), treatment control (β = 0.078, P < 0.05), and emotional representations (β = 0.067, P < 0.05) were significant predictors of HHT screening. Open-ended responses revealed perceived barriers to screening, including a lack of health-care providers (HCPs) familiar with and/or knowledgeable about HHT. CONCLUSION Our results reveal suboptimal screening rates among adults with HHT and identify several factors influencing these behaviors. We suggest that there is a need for increased provider education regarding HHT as well as approaches that providers can use to improve screening adherence.Genet Med advance online publication 13 October 2016.
Collapse
|
|
31
|
Thomas JM, Surendran S, Abraham M, Rajavelu A, Kartha CC. Genetic and epigenetic mechanisms in the development of arteriovenous malformations in the brain. Clin Epigenetics 2016; 8:78. [PMID: 27453762 PMCID: PMC4957361 DOI: 10.1186/s13148-016-0248-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 07/12/2016] [Indexed: 12/05/2022] Open
Abstract
Vascular malformations are developmental congenital abnormalities of the vascular system which may involve any segment of the vascular tree such as capillaries, veins, arteries, or lymphatics. Arteriovenous malformations (AVMs) are congenital vascular lesions, initially described as “erectile tumors,” characterized by atypical aggregation of dilated arteries and veins. They may occur in any part of the body, including the brain, heart, liver, and skin. Severe clinical manifestations occur only in the brain. There is absence of normal vascular structure at the subarteriolar level and dearth of capillary bed resulting in aberrant arteriovenous shunting. The causative factor and pathogenic mechanisms of AVMs are unknown. Importantly, no marker proteins have been identified for AVM. AVM is a high flow vascular malformation and is considered to develop because of variability in the hemodynamic forces of blood flow. Altered local hemodynamics in the blood vessels can affect cellular metabolism and may trigger epigenetic factors of the endothelial cell. The genes that are recognized to be associated with AVM might be modulated by various epigenetic factors. We propose that AVMs result from a series of changes in the DNA methylation and histone modifications in the genes connected to vascular development. Aberrant epigenetic modifications in the genome of endothelial cells may drive the artery or vein to an aberrant phenotype. This review focuses on the molecular pathways of arterial and venous development and discusses the role of hemodynamic forces in the development of AVM and possible link between hemodynamic forces and epigenetic mechanisms in the pathogenesis of AVM.
Collapse
Affiliation(s)
- Jaya Mary Thomas
- Cardiovascular Disease Biology Program, Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud, Thiruvananthapuram, Kerala India
| | - Sumi Surendran
- Cardiovascular Disease Biology Program, Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud, Thiruvananthapuram, Kerala India
| | - Mathew Abraham
- Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala India
| | - Arumugam Rajavelu
- Cardiovascular Disease Biology Program, Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud, Thiruvananthapuram, Kerala India ; Tropical Disease Biology Program, Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud, Thiruvananthapuram, Kerala India
| | - Chandrasekharan C Kartha
- Cardiovascular Disease Biology Program, Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud, Thiruvananthapuram, Kerala India
| |
Collapse
|
|
32
|
Hunter BN, Timmins BH, McDonald J, Whitehead KJ, Ward PD, Wilson KF. An evaluation of the severity and progression of epistaxis in hereditary hemorrhagic telangiectasia 1 versus hereditary hemorrhagic telangiectasia 2. Laryngoscope 2016; 126:786-90. [PMID: 26372311 PMCID: PMC4792805 DOI: 10.1002/lary.25604] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2015] [Indexed: 11/10/2022]
Abstract
OBJECTIVES/HYPOTHESIS Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia whose hallmark symptom is spontaneous recurrent epistaxis. Two major genetic subtypes of this syndrome are HHT1 and HHT2. Severity of epistaxis ranges from occasional low-volume bleeding to frequent large-volume hemorrhage. This study evaluated the severity and progression of epistaxis in HHT1 versus HHT2. STUDY DESIGN Retrospective cohort study. METHODS A retrospective chart review was performed for 183 genotyped HHT patients seen at our center from 2010 to 2013. Data collected included epistaxis severity score (ESS), age of epistaxis onset, number and type of treatments, age at which treatments were sought, complete blood count values, ferritin, number of telangiectases, blood transfusions, iron therapy history, and patient demographics. RESULTS 115 subjects with HHT2 were compared to 68 with HHT1. Subjects with HHT2 had a higher ESS compared to HHT1 (P = .043) and a later age of onset of epistaxis (P = .005). HHT2 subjects were more likely to use oral iron (P = .032) and were more likely to seek interventions to control their epistaxis (P = .029). CONCLUSIONS HHT2 is associated with more severe epistaxis and a subsequent higher rate of interventions, requiring more aggressive therapy as compared to HHT1. LEVEL OF EVIDENCE 4.
Collapse
Affiliation(s)
| | | | - Jamie McDonald
- University of Utah School Departments of Pathology and Radiology, SLC, UT, USA
| | - Kevin J. Whitehead
- University of Utah Division of Cardiovascular Medicine, Pediatric Cardiology, Molecular Medicine Program, SLC, UT, USA
| | - P. Daniel Ward
- University of Utah Division of Otolaryngology--Head & Neck Surgery, SLC, UT, USA
| | - Kevin F. Wilson
- University of Utah Division of Otolaryngology--Head & Neck Surgery, SLC, UT, USA
| |
Collapse
|
|
33
|
Karlsson T, Cherif H. Effect of Intravenous Iron Supplementation on Iron Stores in Non-Anemic Iron-Deficient Patients with Hereditary Hemorrhagic Telangiectasia. Hematol Rep 2016; 8:6348. [PMID: 27103980 PMCID: PMC4815949 DOI: 10.4081/hr.2016.6348] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 03/05/2016] [Accepted: 03/08/2016] [Indexed: 01/01/2023] Open
Abstract
In hereditary hemorrhagic telangiectasia (HHT), frequent episodes of nasal and gastrointestinal bleeding commonly lead to iron-deficiency with or without anemia. In the retrospective study presented here we assessed the iron stores, as determined by analysis of plasma ferritin, during oral and intravenous iron supplementation, respectively, in a population of iron-deficient non-anemic HHT patients who were inadequately iron-repleted by oral supplementation. A switch from oral to intravenous iron supplementation was associated with a significant increase in ferritin in this patient population.
Collapse
Affiliation(s)
- Torbjörn Karlsson
- Department of Hematology and Center for Osler's Disease, Uppsala University Hospital , Uppsala, Sweden
| | - Honar Cherif
- Department of Hematology and Center for Osler's Disease, Uppsala University Hospital , Uppsala, Sweden
| |
Collapse
|
|
34
|
Timmins BH, Hunter BN, Wilson KF, Ward PD. Treatment of severe refractory epistaxis in hereditary hemorrhagic telangiectasia using a two-flap nasal closure method. Int Forum Allergy Rhinol 2016; 6:544-8. [PMID: 26751606 DOI: 10.1002/alr.21703] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 10/29/2015] [Accepted: 11/10/2015] [Indexed: 11/09/2022]
Abstract
BACKGROUND Nasal closure has been shown to effectively manage severe epistaxis refractory to other treatments in patients with hereditary hemorrhagic telangiectasia (HHT). The nasal closure procedure may be underutilized because of its surgical complexity and flap breakdown. METHODS This work is a retrospective review of 13 HHT patients treated for severe epistaxis with nasal closure between 2005 and 2013. Operating room (OR) time, need for revision surgery, preprocedure, and postprocedure epistaxis severity score (ESS), complete blood count values, and Glasgow Benefit Inventory (GBI) questionnaire results were collected for each patient. The technique is described. We characterize a typical nasal closure patient and compare outcomes based on our experience with the traditional 3-flap closure and a simplified 2-flap nasal closure procedure. RESULTS The average candidate for nasal closure in this series had an ESS of 7.88, hemoglobin (Hgb) of 8.3 g/dL, and received multiple transfusions, iron therapy, and cautery/coagulation procedures. Average ESS subsequent to nasal closure using the 2-flap method is 0.92 and mean GBI score is 56.3. Comparison of 5 patients who underwent the traditional 3-flap nasal closure procedure and 8 patients receiving the 2-flap nasal closure showed no significant difference in postoperative ESS or GBI metrics. Mean operating room times of the traditional and simplified methods were 3.12 hours and 1.44 hours (p = 0.0001). Mean time to first revision for 8 nasal closure patients was 21.5 months. CONCLUSION In short-term follow-up, the 2-flap procedure showed comparable effectiveness with significantly reduced complexity and operative time compared to the traditional nasal closure method.
Collapse
Affiliation(s)
| | | | - Kevin F Wilson
- Division of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, UT
| | - P Daniel Ward
- Division of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, UT.,Facial Plastic and Reconstructive Surgery, University of Utah, Salt Lake City, UT
| |
Collapse
|
|
35
|
Masiello R, Iadevaia C, Grella E, Tranfa C, Cerqua F, Rossi G, Santoro G, Amato B, Rocca A, De Dona R, Lavoretano S, Perrotta F. A case of Multiple Unilateral Pulmonary arteriovenous Malformation Relapse: Efficacy of embolization treatment. Open Med (Wars) 2015; 10:513-518. [PMID: 28352746 PMCID: PMC5368875 DOI: 10.1515/med-2015-0087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 11/04/2015] [Indexed: 01/05/2023] Open
Abstract
Pulmonary arteriovenous Malformations (PAVMs) are a rare vascular alteration characterized by abnormal communications between the pulmonary arteries and veins resulting in an extracardiac right-to-left (R-L) shunt. The majority of PAVMs are associated with an autosomal dominant vascular disorder also known as Osler-Weber-Rendu Syndrome. PAVMs appearance can be both single and multiple. Clinical manifestations include hypoxemia, dyspnea cyanosis, hemoptysis and cerebrovascular ischemic events or abscesses. We report a case of an 18 year old female with severe respiratory failure caused by a relapse of multiple unilateral pulmonary arterovenous fistula. Symptoms at admission include dyspnea, cyanosis and clubbing. The patient underwent pulmonary angio-TC scan, brain CT and echocardiography. The thoracic angio-CT scan showed the presence of PAVMs of RUL and RLL; a marked increase of right bronchial artery caliber and its branches with an aneurismatic dilatation was also observed. The patient underwent percutaneous transcatheter embolization using Amplatzer Vascular Plug IV; a relevant clinical and functional improvement was subsequently recorded. Embolization is effective in the treatment of relapsing PAVMS.
Collapse
Affiliation(s)
- Rossella Masiello
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| | - Carlo Iadevaia
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| | - Edoardo Grella
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| | - Carmelindo Tranfa
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| | - Francesco Cerqua
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| | - Giovanni Rossi
- U.O.C. Radiology A.O.R.N dei Colli - Monaldi Hospital, Naples, Italy
| | - Giuseppe Santoro
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| | - Bruno Amato
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Italy
| | - Aldo Rocca
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Italy
| | - Roberta De Dona
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Sabrina Lavoretano
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Fabio Perrotta
- Department of Cardio-Thoracic and Respiratory Sciences - Second University of Naples - Monaldi Hospital, Naples, Italy
| |
Collapse
|
|
36
|
Lacout A, Marcy PY, El Hajjam M, Lacombe P. Metformin as possible therapy of pulmonary arterio venous malformation in HHT patients. Med Hypotheses 2015; 85:245-8. [DOI: 10.1016/j.mehy.2015.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 05/02/2015] [Indexed: 01/14/2023]
|
|
37
|
Bruno W, Fornarini G, Ghiorzo P. Signs and genetics of rare cancer syndromes with gastroenterological features. World J Gastroenterol 2015; 21:8985-8993. [PMID: 26290627 PMCID: PMC4533032 DOI: 10.3748/wjg.v21.i30.8985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 05/26/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023] Open
Abstract
Although the genetic bases of most hereditary cancer syndromes are known, and genetic tests are available for them, the incidence of the most rare of these syndromes is likely underestimated, partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs, though not necessarily tumors, that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis, and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.
Collapse
|
|
38
|
Heimdal K, Dalhus B, Rødningen O, Kroken M, Eiklid K, Dheyauldeen S, Røysland T, Andersen R, Kulseth M. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in
ACVRL1. Clin Genet 2015; 89:182-6. [DOI: 10.1111/cge.12612] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 05/04/2015] [Accepted: 05/11/2015] [Indexed: 11/27/2022]
Affiliation(s)
- K. Heimdal
- Department of Medical GeneticsOslo University Hospital Oslo Norway
| | - B. Dalhus
- Department for Medical BiochemistryUniversity of Oslo Oslo Norway
- Department for MicrobiologyOslo University Hospital Oslo Norway
| | - O.K. Rødningen
- Department of Medical GeneticsOslo University Hospital Oslo Norway
| | - M. Kroken
- Department of Medical GeneticsOslo University Hospital Oslo Norway
| | - K. Eiklid
- Department of Medical GeneticsOslo University Hospital Oslo Norway
| | - S. Dheyauldeen
- Department for OtorhinolaryngologyOslo University Hospital Oslo Norway
| | - T. Røysland
- Department for OtorhinolaryngologyOslo University Hospital Oslo Norway
- Department for OtorhinolaryngologyInnlandet Hospital Gjøvik Norway
| | - R. Andersen
- Department of Radiology and Nuclear MedicineOslo University Hospital Oslo Norway
| | - M.A. Kulseth
- Department of Medical GeneticsOslo University Hospital Oslo Norway
| |
Collapse
|
|
39
|
Yuan D, Yin X, Dai Y, Li B, Liang K, Wei G. [Gene analysis in a family of hereditary hemorrhagic telangiectasia]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2015; 36:112-5. [PMID: 25778885 PMCID: PMC7342162 DOI: 10.3760/cma.j.issn.0253-2727.2015.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE To investigate the clinical feature of a family with hereditary hemorrhagic telangiectasia (HHT), and to study the mutation of its related genes. METHODS Medical histories of the family were analyzed to detect HHT patients according to the diagnostic criteria. ENG and ALK-1 genes of the proband and her two daughters were analyzed. DNA from the three patients' peripheral blood was extracted. The exons 2-10 and their intron-exon boundaries of ALK1 were amplified with PCR, and then the PCR products were sequenced and analyzed to identify the mutation. RESULTS There were 11 people in 41 family members of 4 generations were diagnosed as HHT. The proband and her two daughters suffered from multiple organ damage, the younger daughter appeared only imaging features instead of corresponding clinical symptoms. A missense mutation at the 1321 bp of cDNA (c.1321G>A) was detected in the exon 9 of ALK1, which resulted in valine 441 to methionine replacement in ALK-1 protein (p.Val441Met). CONCLUSION A Chinese family with HHT was studied and a missense mutation (c.1321G>A, p.Val441Met) of ALK-1 was discovered. This mutation is the genetic basis of the family with HHT and is reported for the first time in China. This research will not only help to further investigate molecular mechanism of pathogenesis of HTT, but also provide evidences and references for the following gene screening and genetic counseling on HTT family members.
Collapse
Affiliation(s)
- Dong Yuan
- Mudanjiang First People's Hospital of Heilongjiang Province, Mudanjiang Institute of Blood Diseases, Mudanjiang 157011, China
| | - Xiaohua Yin
- Mudanjiang First People's Hospital of Heilongjiang Province, Mudanjiang Institute of Blood Diseases, Mudanjiang 157011, China
| | - Yuhong Dai
- Mudanjiang First People's Hospital of Heilongjiang Province, Mudanjiang Institute of Blood Diseases, Mudanjiang 157011, China
| | - Bing Li
- Mudanjiang First People's Hospital of Heilongjiang Province, Mudanjiang Institute of Blood Diseases, Mudanjiang 157011, China
| | - Keji Liang
- Mudanjiang First People's Hospital of Heilongjiang Province, Mudanjiang Institute of Blood Diseases, Mudanjiang 157011, China
| | - Guangyi Wei
- Mudanjiang First People's Hospital of Heilongjiang Province, Mudanjiang Institute of Blood Diseases, Mudanjiang 157011, China
| |
Collapse
|
|
40
|
Hsu CCT, Kwan GNC, Thompson SA, Evans-Barns H, van Driel ML. Embolisation for pulmonary arteriovenous malformation. Cochrane Database Syst Rev 2015; 1:CD008017. [PMID: 25634560 DOI: 10.1002/14651858.cd008017.pub4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Pulmonary arteriovenous malformations are abnormal direct connections between the pulmonary artery and pulmonary vein which result in a right-to-left shunt. They are associated with substantial morbidity and mortality mainly from the effects of paradoxical emboli. Potential complications include stroke, cerebral abscess, pulmonary haemorrhage and hypoxaemia. Embolisation is an endovascular intervention based on the occlusion of the feeding arteries the pulmonary arteriovenous malformations thus eliminating the abnormal right-to-left-shunting. OBJECTIVES To determine the efficacy and safety of embolisation in patients with pulmonary arteriovenous malformations including a comparison with surgical resection and different embolisation devices. SEARCH METHODS We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register; date of last search: 31 March 2014.We also searched the following databases: the Australian New Zealand Clinical Trials Registry; ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Register; International Clinical Trials Registry Platform Search Portal (last searched 1 July 2014).We checked cross-references and searched references from review articles. SELECTION CRITERIA Trials in which individuals with pulmonary arteriovenous malformations were randomly allocated to embolisation compared to no treatment, surgical resection or embolisation using a different embolisation device. DATA COLLECTION AND ANALYSIS Studies identified for potential inclusion were independently assessed for eligibility by two authors, with excluded studies further checked by a third author. No trials were identified for inclusion in the review and hence no analysis was performed. MAIN RESULTS There were no randomised controlled trials included in the review; one ongoing trial has been identified which may be eligible for inclusion in the future. AUTHORS' CONCLUSIONS There is no evidence from randomised controlled trials for embolisation of pulmonary arteriovenous malformations. However, randomised controlled trials are not always feasible on ethical grounds. Accumulated data from observational studies suggest that embolisation reduces morbidity. A standardised approach to reporting with long-term follow-up through registry studies can help to strengthen the evidence for embolisation in the absence of randomised controlled trials.
Collapse
Affiliation(s)
- Charlie C-T Hsu
- Department of Medical Imaging, Princess Alexandra Hospital, 199 Ipswich Road, Brisbane, Queensland, Australia, 4102
| | | | | | | | | |
Collapse
|
|
41
|
McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 2015; 6:1. [PMID: 25674101 PMCID: PMC4306304 DOI: 10.3389/fgene.2015.00001] [Citation(s) in RCA: 223] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 01/05/2015] [Indexed: 01/02/2023] Open
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs) in particular locations described in consensus clinical diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β) signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao) diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS) HHT panel is proposed.
Collapse
Affiliation(s)
- Jamie McDonald
- Department of Radiology, Hereditary Hemorrhagic Telangiectasia Center, University of Utah Salt Lake City, UT, USA ; Department of Pathology, University of Utah Salt Lake City, UT, USA
| | - Whitney Wooderchak-Donahue
- Department of Pathology, University of Utah Salt Lake City, UT, USA ; ARUP Institute for Clinical and Experimental Pathology Salt Lake City, UT, USA
| | - Chad VanSant Webb
- ARUP Institute for Clinical and Experimental Pathology Salt Lake City, UT, USA
| | - Kevin Whitehead
- Department of Radiology, Hereditary Hemorrhagic Telangiectasia Center, University of Utah Salt Lake City, UT, USA ; Division of Cardiovascular Medicine, Department of Medicine, University of Utah Salt Lake City, UT, USA ; Program in Molecular Medicine, University of Utah Salt Lake City, UT, USA ; George E. Wahlen Veterans Affairs Medical Center Salt Lake City, UT, USA
| | - David A Stevenson
- Division of Medical Genetics, Department of Pediatrics, University of Utah Salt Lake City, UT, USA
| | - Pinar Bayrak-Toydemir
- Department of Pathology, University of Utah Salt Lake City, UT, USA ; ARUP Institute for Clinical and Experimental Pathology Salt Lake City, UT, USA
| |
Collapse
|
|
42
|
Cherif H, Karlsson T. Combination treatment with an erythropoiesis-stimulating agent and intravenous iron alleviates anaemia in patients with hereditary haemorrhagic telangiectasia. Ups J Med Sci 2014; 119:350-3. [PMID: 25188751 PMCID: PMC4248076 DOI: 10.3109/03009734.2014.955619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Patients with hereditary haemorrhagic telangiectasia (HHT) suffer from recurrent epistaxis and bleeding from gastrointestinal telangiectasias that occur despite otherwise normal haemostasis and result in iron deficiency anaemia with increasing severity. In advanced disease, anaemia may be severe, be irresponsive to iron supplementation, and may lead to red blood cell transfusion dependency. METHODS We conducted a retrospective study at our Centre for Osler's Disease to evaluate the effectiveness of adding an erythropoiesis-stimulating agent (ESA) to intravenous iron supplementation in the management of anaemic HHT patients. Blood values and treatment parameters were collected for nine months before combination therapy (iron supplementation only) and 12 months during combination therapy (iron supplementation plus ESA). RESULTS Four patients received intravenous iron and an ESA with mean weekly doses of 126 mg and 17,300 units (U), respectively. Mean haemoglobin improved significantly during combination therapy, from 106 g/L to 119 g/L (p < 0.001). CONCLUSION Anaemia can be alleviated in patients with HHT who are irresponsive to intravenous iron supplementation, by addition of an ESA. The proposed mechanism behind the iron irresponsiveness is that the anaemia is caused by a combination of recurrent haemorrhage and anaemia of chronic disease.
Collapse
Affiliation(s)
- Honar Cherif
- Department of Haematology, Uppsala University Hospital, Uppsala, Sweden
- Centre for Osler’s Disease, Uppsala University Hospital, Uppsala, Sweden
| | - Torbjörn Karlsson
- Department of Haematology, Uppsala University Hospital, Uppsala, Sweden
- Centre for Osler’s Disease, Uppsala University Hospital, Uppsala, Sweden
| |
Collapse
|
|
43
|
Thompson AB, Ross DA, Berard P, Figueroa-Bodine J, Livada N, Richer SL. Very low dose bevacizumab for the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia. ALLERGY & RHINOLOGY 2014; 5:91-5. [PMID: 25199101 PMCID: PMC4124584 DOI: 10.2500/ar.2014.5.0091] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. The genetic mutations that cause this disease result in elevated levels of vascular endothelial growth factor, which is inhibited by bevacizumab. Previous studies have shown bevacizumab treatment to be effective in reducing symptoms, but study protocols have all used oncological dosing parameters, which carry several well-described serious side effects. This study investigates whether drastically lower dosages of bevacizumab than normally used in oncological treatment could control epistaxis in patients with HHT and medically refractory epistaxis. A prospective, open-label, noncomparative study enrolled six patients receiving 0.125-mg/kg infusions of bevacizumab once every 4 weeks for a total of six infusions. Severity of epistaxis was assessed with the epistaxis severity score, and quality-of-life measures were followed with the 20-item Sino-Nasal Outcome Test and 36-item Short Form surveys. A statistically significant improvement was seen in the control of epistaxis severity and frequency, with minimal negative side effects and high patient satisfaction. Very low dose bevacizumab treatment is an effective method of controlling medically refractory epistaxis in patients with HHT and additional investigation to optimize dosing guidelines is warranted.
Collapse
Affiliation(s)
- Andrew B Thompson
- Department of Otolaryngology, St. Vincent's Medical Center, Bridgeport, Connecticut, USA
| | | | | | | | | | | |
Collapse
|
|
44
|
Salaria M, Taylor J, Bogwitz M, Winship I. Hereditary haemorrhagic telangiectasia, an Australian cohort: clinical and investigative features. Intern Med J 2014; 44:639-44. [DOI: 10.1111/imj.12457] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 04/16/2014] [Indexed: 12/13/2022]
Affiliation(s)
- M. Salaria
- Department of Genetics; Royal Melbourne Hospital; University of Melbourne; Melbourne Victoria Australia
| | - J. Taylor
- Department of Genetics; Royal Melbourne Hospital; University of Melbourne; Melbourne Victoria Australia
| | - M. Bogwitz
- Department of Genetics; Royal Melbourne Hospital; University of Melbourne; Melbourne Victoria Australia
| | - I. Winship
- Department of Genetics; Royal Melbourne Hospital; University of Melbourne; Melbourne Victoria Australia
- Department of Medicine; MDHS; RMH; University of Melbourne; Melbourne Victoria Australia
| |
Collapse
|
|
45
|
Lacout A, Marcy PY, Thariat J, Sellier J, El Hajjam M, Lacombe P. Roles of cyclooxygenase 2 and hepatic venous flow in patients with HHT or hepatopulmonary syndrome. Med Hypotheses 2014; 83:302-5. [PMID: 24986705 DOI: 10.1016/j.mehy.2014.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 05/27/2014] [Accepted: 06/01/2014] [Indexed: 11/24/2022]
Abstract
BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) and hepatopulmonary syndrome are disorders characterized by the development of multiple pulmonary arteriovenous malformations (PAVM). PRESENTATION OF THE HYPOTHESIS COX2 may be at the origin of a cascade of pro inflammatory events to favour angiogenesis and PAVM development. TESTING THE HYPOTHESIS HHT and hepatopulmonary syndrome mouse models may be used to show its effects on PAVM formation. Anti COX-2 therapy could also be tested in human individuals, particularly in patients presenting a hepatopulmonary syndrome or HHT with small PAVM. IMPLICATION OF THE HYPOTHESIS PAVMs are one of the main causes of morbidity in patients presenting with HHT disease, owing to the risks of rupture as well as paradoxical embolism exposing to stroke and/or cerebral abscess. Percutaneous embolization has become the treatment of choice of PAVM. Anti COX2 may prevent from PAVM development and subsequent related complications and avoid either surgery and/or percutaneous embolization and thus subsequent related complication.
Collapse
Affiliation(s)
- Alexis Lacout
- Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France.
| | - Pierre Yves Marcy
- Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France
| | - Juliette Thariat
- Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France
| | - Jacques Sellier
- Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France
| | - Mostafa El Hajjam
- Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France
| | - Pascal Lacombe
- Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France
| |
Collapse
|
|
46
|
Meurer SK, Alsamman M, Scholten D, Weiskirchen R. Endoglin in liver fibrogenesis: Bridging basic science and clinical practice. World J Biol Chem 2014; 5:180-203. [PMID: 24921008 PMCID: PMC4050112 DOI: 10.4331/wjbc.v5.i2.180] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 12/29/2013] [Accepted: 01/17/2014] [Indexed: 02/05/2023] Open
Abstract
Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membrane-bound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β (TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type I and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin (i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e., sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and -independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.
Collapse
|
|
47
|
Tørring P, Brusgaard K, Ousager L, Andersen P, Kjeldsen A. National mutation study among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet 2013; 86:123-33. [DOI: 10.1111/cge.12269] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 08/23/2013] [Accepted: 08/29/2013] [Indexed: 12/01/2022]
Affiliation(s)
- P.M. Tørring
- HHT Centre OUH, Department of Clinical Genetics
- Department of Otorhinolaryngology
| | | | | | - P.E. Andersen
- Department of Interventional Radiology; Odense University Hospital and Institute of Clinical Research, University of Southern Denmark; Odense Denmark
| | | |
Collapse
|
|
48
|
Lacombe P, Lacout A, Marcy PY, Binsse S, Sellier J, Bensalah M, Chinet T, Bourgault-Villada I, Blivet S, Roume J, Lesur G, Blondel JH, Fagnou C, Ozanne A, Chagnon S, El Hajjam M. Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: An overview. Diagn Interv Imaging 2013; 94:835-48. [PMID: 23763987 DOI: 10.1016/j.diii.2013.03.014] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomic dominant disorder, which is characterized by the development of multiple arteriovenous malformations in either the skin, mucous membranes, and/or visceral organs. Pulmonary arteriovenous malformations (PAVMs) may either rupture, and lead to life-threatening hemoptysis/hemothorax or be responsible for a right-to-left shunting leading to paradoxical embolism, causing stroke or cerebral abscess. PAVMs patients should systematically be screened as the spontaneous complication rate is high, by reaching almost 50%. Neurological complications rate is considerably higher in patients presenting with diffuse pulmonary involvement. PAVM diagnosis is mainly based upon transthoracic contrast echocardiography and CT scanner examination. The latter also allows the planification of treatments to adopt, which consists of percutaneous embolization, having replaced surgery in most of the cases. The anchor technique consists of percutaneous coil embolization of the afferent pulmonary arteries of the PAVM, by firstly placing a coil into a small afferent arterial branch closely upstream the PAVM. Enhanced contrast CT scanner is the key follow-up examination that depicts the PAVM enlargement, indicating the various mechanisms of PAVM reperfusion. When performed by experienced operators as the prime treatment, percutaneous embolization of PAVMs, is a safe, efficient and sustained therapy in the great majority of HHT patients.
Collapse
Affiliation(s)
- P Lacombe
- Radiology department, Pluridisciplinary HHT team, Ambroise-Paré Hospital, Groupement des Hôpitaux Île-de-France Ouest, Assistance Publique-Hôpitaux de Paris, Université de Versailles-Saint-Quentin-en-Yvelines, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Lacout A, Marcy PY, Hajjam ME, Lacombe P. Pulmonary arteriovenous malformations etiologies in HHT patients and potential utility of thalidomide. Med Hypotheses 2013; 80:587-8. [DOI: 10.1016/j.mehy.2013.01.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 01/23/2013] [Accepted: 01/26/2013] [Indexed: 11/30/2022]
|
|
50
|
Cho D, Kim S, Kim M, Seo YH, Kim W, Kang SH, Park SM, Shim W. Two cases of high output heart failure caused by hereditary hemorrhagic telangiectasia. Korean Circ J 2012; 42:861-5. [PMID: 23323127 PMCID: PMC3539055 DOI: 10.4070/kcj.2012.42.12.861] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 05/22/2012] [Accepted: 05/28/2012] [Indexed: 11/24/2022] Open
Abstract
High-output cardiac failure is a rare complication of hereditary hemorrhagic telangiectasia (HHT) usually caused by shunting of blood through atriovenous malformations (AVMs) in the liver. We describe two cases of high output heart failure due to large hepatic AVMs. Clinical suspicion of HHT based on detailed history taking and physical examination is essential for early detection and proper management of heart failure associated with HHT.
Collapse
Affiliation(s)
- Donghyuk Cho
- Department of Cardiology, Korea University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | |
Collapse
|