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BackgroundHereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) can be caused by SMAD4 pathogenic variants. SMAD4 is a common transcription factor of the BMP/TGFβ signalling pathway. In this study, we developed a cell-based functional assay to address the pathogenicity of SMAD4 variants identified in the French HHT cohort.Methods SMAD4 variants were generated by site-directed mutagenesis. A functional assay was developed in a cell line that does not express SMAD4, and the different SMAD4 variants were tested for their capacity to activate the BMP and TGFβ response using luciferase reporter assays.ResultsTwelve SMAD4 variants were identified and studied. We were able to develop a robust functional assay for these variants. All the expressed variants resulted in loss of function (LOF) in response to BMP9 or TGFβ1 stimulation. SMAD4 variants within the MH2 domain expressed SMAD4 mutated proteins that were unable to hetero-oligomerise with other SMADs, which could explain their LOF. Finally, we tested primary human endothelial cells isolated from patients with HHT carrying SMAD4 heterozygous pathogenic variants and observed that they behaved like the control cells at rest or when stimulated with BMP9.ConclusionWe developed a SMAD4 functional assay that allows discrimination between benign and pathogenic SMAD4 variants. We demonstrated that the underlying molecular mechanism of this pathogenicity is due mostly to a loss of hetero-oligomerisation. This assay will be transferable to clinical genetic laboratories and will improve the diagnosis of patients with HHT–JPS.

Hereditary hemorrhagic telangiectasia is a rare vascular genetic disease. Epistaxis is the most frequent and disabling manifestation, and timolol appears to be a new therapeutic option as non-selective beta-blockers have in vitro and in vivo anti-angiogenic properties. Our main objective was to evaluate the efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. This study is a single-center, randomized, phase 2, double-blind placebo-controlled study with an allocation ratio of 1:1. It was proposed to patients with hereditary hemorrhagic telangiectasia monitored at the French Reference Center, and we included patients aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis. The treatment was self-administered by the patient with a posology of one spray (50 microL) of timolol 0.5% or placebo in each nostril twice a day for 28 consecutive days. The primary efficacy endpoint was mean monthly epistaxis duration, assessed by monitoring epistaxis grids. A total of 58 patients were randomized and treated. The baseline characteristics were similar in the 2 groups. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 26 patients receiving the drug in comparison with the placebo group (p = 0.54). Toxicity was low and no severe adverse events were reported. One limitation is that we included all HHT patients with nosebleeds and did not take into account history of nasal surgery or nasal crusts. Timolol, administered by nasal spray at a dose of 0.25 mg in each nostril twice a day for 28 consecutive days, did not improve epistaxis in patients with hereditary hemorrhagic telangiectasia at 4 months after the beginning of the treatment.

Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a disorder of development of the vasculature characterized by telangiectases and arteriovenous malformations in specific locations. It is one of most common monogenic disorders, but affected individuals are frequently not diagnosed. The most common features of the disorder, nosebleeds, and telangiectases on the lips, hands, and oral mucosa are often quite subtle. Optimal management requires an understanding of the specific presentations of these vascular malformations, especially their locations and timing during life. Telangiectases in the nasal and gastrointestinal mucosa and brain arteriovenous malformations generally present with hemorrhage. However, complications of arteriovenous malformations in the lungs and liver are generally the consequence of blood shunting through these abnormal blood vessels, which lack a capillary bed and thus result in a direct artery-to-vein connection. Mutations in at least five genes are thought to result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) cause approximately 85% of cases. The frequency of arteriovenous malformations in particular organs and the occurrence of certain rare symptoms are dependent on the gene involved. Molecular genetic testing is used to establish the genetic subtype of hereditary hemorrhagic telangiectasia in a clinically affected individual and family, and for early diagnosis to allow for appropriate screening and preventive treatment.

Background Hereditary Hemorrhagic Telangiectasia is an autosomal dominant vascular disorder with clinical features of recurrent epistaxis, mucocutaneous telangiectasias, or visceral arteriovenous malformations, yet its early signs may be overlooked in children. Case presentation We report a family in which a fifteen-year-old boy and his mother presented for genetic evaluation of recurrent epistaxis, after his previously well seven-year-old sister demised suddenly from likely spontaneous atraumatic intracranial hemorrhage (diagnosed clinically without confirmatory post-mortem imaging), following a brief history of headache and vomiting. The mother had a background of infrequent nosebleeds and a family history of recurrent epistaxis in multiple maternal relatives. Genetic testing identified heterozygosity for NM_001114753.3(ENG): c.1134G > A (p.Ala378=) , a ClinVar classified pathogenic variant, confirming the diagnosis of hereditary hemorrhagic telangiectasia. Cascade testing for her two surviving children was done. Her fifteen-year-old son tested positive and was found on subsequent screening to have intracranial vascular malformations which were treated presymptomatically with gamma knife surgery. Her other son tested negative. Conclusion This case emphasizes the importance of prompt recognition of hereditary hemorrhagic telangiectasia in children presenting with recurrent epistaxis and highlights the need for thorough family history. Pediatricians play a crucial role in early diagnosis and referral for genetic testing with subsequent surveillance imaging. Early identification may possibly reduce the risk of unfavorable outcomes such as intracranial hemorrhage. This case emphasizes the need for heightened awareness of hereditary hemorrhagic telangiectasia in pediatric practice and supports the value of integrating genetic cascade testing and organ-specific screening in at-risk children, even before symptoms appear.

Hereditary hemorrhagic telangiectasia (HHT), also called Osler–Weber–Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.

EPHB4 variants were recently reported to cause capillary malformation–arteriovenous malformation 2 (CM-AVM2). CM-AVM2 mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia (HHT), as clinical features include capillary malformations (CMs), telangiectasia, and arteriovenous malformations (AVMs). Epistaxis, another clinical feature that overlaps with HHT, was reported in several cases. Based on the clinical overlap of CM-AVM2 and HHT, we hypothesized that patients considered clinically suspicious for HHT with no variant detected in an HHT gene (ENG, ACVRL1, or SMAD4) may have an EPHB4 variant. Exome sequencing or a next-generation sequencing panel including EPHB4 was performed on individuals with previously negative molecular genetic testing for the HHT genes and/or RASA1. An EPHB4 variant was identified in ten unrelated cases. Seven cases had a pathogenic EPHB4 variant, including one with mosaicism. Three cases had an EPHB4 variant of uncertain significance. The majority had epistaxis (6/10 cases) and telangiectasia (8/10 cases), as well as CMs. Two of ten cases had a central nervous system AVM. Our results emphasize the importance of considering CM-AVM2 as part of the clinical differential for HHT and other vascular malformation syndromes. Yet, these cases highlight significant differences in the cutaneous presentations of CM-AVM2 versus HHT.

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 .

Background and aimsHereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%–5% of patients, HHT is caused by pathogenic germline variants (PVs) in SMAD4, and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum of SMAD4-associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs in SMAD4 and compare the findings with current literature.MethodsThe study is a retrospective nationwide study with all known Danish patients with PVs in SMAD4. In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital.ResultsTwenty-nine patients with PVs in SMAD4 (83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities.ConclusionWe present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.

The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution.