scholarly journals Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

2020 ◽  
Vol 9 (11) ◽  
pp. 3571
Author(s):  
Carmelo Bernabeu ◽  
Pinar Bayrak-Toydemir ◽  
Jamie McDonald ◽  
Michelle Letarte
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Somatic Mutations ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Vascular Lesions ◽  
Mechanical Trauma ◽  
Internal Organs ◽  
Second Hit ◽  
Functional Mechanisms

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.

scholarly journals Hereditary Hemorrhagic Telangiectasia: A Genetic Disorder with Oral Manifestations

2014 ◽  
Vol 3 (1) ◽  
pp. 49-52
Author(s):  
Apollonia Desiate ◽  
Stefania Cantore ◽  
Andrea Ballini
Keyword(s):  
Family History ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Oral Manifestations ◽  
Systemic Diseases ◽  
Recurrent Epistaxis ◽  
History Of ◽  
Broad Understanding

ABSTRACT The case of a 74-year-old man who was diagnosed as having hereditary hemorrhagic telangiectasia (HHT), with telangiectasies localized in oral district is presented. This condition is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia in which telangiectasia, arteriovenous malformations and aneurysms may be widely distributed throughout the cardiovascular system. It is usually recognized as a ‘triad’ of telangiectasia, recurrent epistaxis and a family history of the disorder. The nature of the practice of dentistry necessitates a broad understanding of the systemic diseases reflected in the oral cavity. Hereditary hemorrhagic telangiectasia is one such disease. How to cite this article Ballini A, Cantore S, Desiate A. Hereditary Hemorrhagic Telangiectasia: A Genetic Disorder with Oral Manifestations. Int J Experiment Dent Sci 2014; 3(1): 49-52.

Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing

2021 ◽  
pp. ASN.2021050690
Author(s):  
Zhengmao Zhang ◽  
Hanwen Bai ◽  
Jon Blumenfeld ◽  
Andrew Ramnauth ◽  
Irina Barash ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Fragile Sites ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Polycystic Kidney ◽  
Second Hit ◽  
Kidney Cyst ◽  
Kidney Cysts ◽  
Autosomal Dominant Polycystic Kidney

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). Methods: To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. Results: Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic "second hit" alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 16.7% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another ~18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14.4% of these cysts harbored copy number neutral LOH events, while the other 3.3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic "second hit" alterations occurred at the same germline mutated PKD1/2 gene. Conclusions: These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.

scholarly journals De novo arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia

2016 ◽  
Vol 17 (3) ◽  
pp. 330-335 ◽  
Author(s):  
Yusuke Shimoda ◽  
Toshiya Osanai ◽  
Naoki Nakayama ◽  
Satoshi Ushikoshi ◽  
Masaaki Hokari ◽  
...  
Keyword(s):  
Family History ◽  
Arteriovenous Malformation ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
De Novo ◽  
The Family ◽  
Systemic Disorder ◽  
History Of ◽  
Cerebral Avms

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant systemic disorder characterized by the enlargement of capillaries, recurrent nosebleeds, and multiple arteriovenous malformations (AVMs). Although cerebral AVMs are traditionally considered to be congenital lesions, some reports have described de novo AVMs, which suggests that the authors believed them to be dynamic conditions. In this article, the authors describe the case of a 5-year-old boy with HHT in whom a de novo cerebral AVM was detected after a negative MRI result at 5 months. To the authors’ knowledge, this is the first report of a de novo AVM in a patient with HHT. In patients with a family history of HHT, de novo AVMs are possible, even when no lesions are detected at the first screening. Therefore, regular screenings need to be performed, and the family should be informed that AVMs could still develop despite normal MRI results.

scholarly journals Genetic testing for hereditary hemorrhagic telangiectasia

2018 ◽  
Vol 2 (s1) ◽  
pp. 32-34
Author(s):  
Yeltay Rakhmanov ◽  
Paolo Enrico Maltese ◽  
Stefano Paolacci ◽  
Carla Marinelli ◽  
Raul Ettore Mattassi ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Clinical Trials ◽  
Differential Diagnosis ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
De Novo ◽  
Incomplete Penetrance ◽  
Gene Test ◽  
Vascular Dysplasia

Abstract Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by telangiectases and arteriovenous malformations. These lesions cause bleeding, particularly in the nose, gastrointestinal tract and brain. HHT has incomplete penetrance, variable expressivity and genetic heterogeneity. De novo mutations associated with the onset of sporadic HHT have been reported. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Significant Hematochezia and Intracranial Bleeding in Neonatal Hereditary Hemorrhagic Telangiectasia

2019 ◽  
Vol 09 (01) ◽  
pp. e10-e14 ◽  
Author(s):  
Matthew Merves ◽  
Kimberly Parsons ◽  
Adina Alazraki ◽  
Jonathan Meisel ◽  
Cary Sauer ◽  
...  
Keyword(s):  
High Risk ◽  
Gastrointestinal Bleeding ◽  
Intracranial Hemorrhage ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
Clinical Course ◽  
Vascular Dysplasia ◽  
Prenatal Imaging ◽  
Delivery Options

AbstractHereditary hemorrhagic telangiectasia (HHT) is an underreported autosomal dominant vascular dysplasia. Neonatal presentations of HHT are rare, as this disorder typically presents in adolescence or beyond with epistaxis. We report a female neonate with hematochezia on the 1st day of life secondary to multiple gastrointestinal arteriovenous malformations (AVMs) along with intracranial hemorrhage. We describe her clinical course and management, as well as her novel family mutation in ENG. This is the first reported HHT case with significant gastrointestinal bleeding in the newborn. We review neonatal HHT and raise the consideration for more directed prenatal imaging and delivery options for fetuses at high risk of HHT.

scholarly journals Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding

2020 ◽  
Vol 9 (6) ◽  
pp. 1766 ◽  
Author(s):  
Virginia Albiñana ◽  
Angel M. Cuesta ◽  
Isabel de Rojas-P ◽  
Eunate Gallardo-Vara ◽  
Lucía Recio-Poveda ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Blood Transfusions ◽  
Ground Zero ◽  
Internal Organs ◽  
Antifibrinolytic Agents ◽  
Estrogen Receptor Modulators ◽  
Repurposed Drugs ◽  
Receptor Modulators

The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at “ground zero” to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT.

scholarly journals Recent Advances in Basic Research for Brain Arteriovenous Malformation

2019 ◽  
Vol 20 (21) ◽  
pp. 5324 ◽  
Author(s):  
Barbosa Do Prado ◽  
Han ◽  
Oh ◽  
Su
Keyword(s):  
Arteriovenous Malformations ◽  
Somatic Mutations ◽  
Genetic Disorder ◽  
Basic Research ◽  
Science Research ◽  
Brain Arteriovenous Malformation ◽  
Therapeutic Implications ◽  
Familial Cases ◽  
Life Threatening ◽  
Brain Avms

Arteriovenous malformations (AVMs) are abnormal connections of vessels that shunt blood directly from arteries into veins. Rupture of brain AVMs (bAVMs) can cause life-threatening intracranial bleeding. Even though the majority of bAVM cases are sporadic without a family history, some cases are familial. Most of the familial cases of bAVMs are associated with a genetic disorder called hereditary hemorrhagic telangiectasia (HHT). The mechanism of bAVM formation is not fully understood. The most important advances in bAVM basic science research is the identification of somatic mutations of genes in RAS-MAPK pathways. However, the mechanisms by which mutations of these genes lead to AVM formation are largely unknown. In this review, we summarized the latest advance in bAVM studies and discussed some pathways that play important roles in bAVM pathogenesis. We also discussed the therapeutic implications of these pathways.

scholarly journals Hereditary hemorrhagic telangiectasia diagnosed by enteroscopy: a case report

2021 ◽  
Vol 49 (12) ◽  
pp. 030006052110673
Author(s):  
Margarita Rey ◽  
Johana Milena Salazar ◽  
Drixie Dalyla Leal ◽  
Fernando Sierra ◽  
Erika Pérez ◽  
...  
Keyword(s):  
Case Report ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Laboratory Tests ◽  
Autosomal Dominant ◽  
Double Balloon Enteroscopy ◽  
Multisystemic Disease ◽  
History Of ◽  
Patient’S History ◽  
Endoscopic Methods

Hereditary hemorrhagic telangiectasia (HHT) is a very rare autosomal dominant multisystemic disease. Patients with this disease usually present with punctate mucocutaneous telangiectasias and arteriovenous malformations. The diagnostic criteria currently in use are the Curaçao criteria. HHT is considered a clinical diagnosis; thus, no imaging or preclinical laboratory is mandatory, and diagnosis and management are performed according to the experience of the treating team. We herein describe a 58-year-old man with no significant medical history who presented with a 15-day history of intermittent hematochezia. He was admitted to the hospital and underwent a series of laboratory tests, including colonoscopy, which showed normal results. Therefore, the patient was discharged with a diagnosis of gastrointestinal bleeding. During his second visit to the emergency room, the doctors requested video capsule endoscopy because of the patient’s history, and a diagnosis of HHT was made. The entire approach and treatment were completed with antegrade double-balloon enteroscopy. This case highlights the importance of endoscopic methods for timely diagnosis and proper management.

Hypoxemia without Respiratory Distress: Hereditary Hemorrhagic Telangiectasia in a Child

2020 ◽  
Author(s):  
Michael D. McCann ◽  
Claire Newlon ◽  
Conrad Krawiec
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Genetic Disorder ◽  
Significant Morbidity ◽  
Younger Patients ◽  
Life Threatening ◽  
Symptoms And Signs ◽  
Over Time

AbstractHereditary hemorrhagic telangiectasia (HHT) is an underrecognized genetic disorder of vascular development in pediatric patients. Its presentation can range from mild cutaneous findings to life-threatening hemorrhage from arteriovenous malformations. Clinical diagnosis can be challenging in the pediatric population as disease manifestations evolve over time and may be difficult to identify in younger patients. This case highlights how nonspecific symptoms and signs in the preanesthesia period can be misleading, potentially placing a patient with unrecognized HHT at risk for significant morbidity and mortality.

scholarly journals A CASE OF OSLER WEBER RENDU SYNDROME AND ITS ANAESTHETIC IMPLICATIONS

2020 ◽  
pp. 189-190
Author(s):  
Vivek Chaudhary ◽  
Neha Rehalia ◽  
Monika Monika ◽  
Ashish Minhas ◽  
Dheeraj Singha
Keyword(s):  
Case Report ◽  
Gastrointestinal Tract ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Hereditary Haemorrhagic Telangiectasia ◽  
Familial Disorder ◽  
Vascular Structures ◽  
The 19Th Century ◽  
Arteries And Veins

Osler-Weber-Rendu disease or hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder. First recognised in the 19th century, this rare often undiagnosed familial disorder with abnormal vascular structures, causes bleeding from the nose and gastrointestinal tract. This condition is characterised by lack of communicating capillaries connecting arteries and veins resulting in multiple arteriovenous malformations (AVMs) and telangiectasia. We describe a case report of anaesthesia management of a patient with Osler-Weber-Rendu disease.

Sign in / Sign up

Export Citation Format

Share Document