Search Results (84)

Background/Objectives: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by recurrent epistaxis, anemia, and visceral arteriovenous malformations. Epistaxis is the most frequent and disabling manifestation, with limited effective pharmacological options. Propranolol, a non-selective beta-blocker with vasoconstrictive and antiangiogenic properties, has shown benefit in other vascular anomalies but remains scarcely studied in HHT. This study aimed to evaluate the effect of oral propranolol on nasal bleeding in patients with HHT. Methods: A retrospective observational study including 151 adults with HHT (44 treated with propranolol, 107 untreated) was conducted using data from an Institutional HHT Registry from a referral center. Baseline demographic and clinical variables were recorded. Outcomes at 6 months included changes in hemoglobin, adherence to nasal hygiene, use of bleeding-related therapies, and improvement in epistaxis frequency and intensity according to the Sadick–Bergler scale. Logistic regression models were adjusted for confounders and indication bias using inverse probability of treatment weighting (IPTW). Results: After IPTW adjustment, propranolol was significantly associated with reduced frequency of epistaxis (adjusted OR: 3.8; 95% CI: 1.3–11.2; p = 0.016), while no effect was observed on intensity. Hemoglobin levels increased modestly in both groups without a significant difference. Patients without propranolol showed greater antifibrinolytic use, whereas adherence to nasal care remained stable among treated patients. Conclusions: Oral propranolol reduced nasal bleeding frequency in HHT, even among patients with greater baseline severity. Given its accessibility, safety, and potential to lessen treatment burden, it may represent a valuable adjunct therapy. This study represents the largest cohort of HHT patients treated with propranolol reported to date. Randomized trials including standardized bleeding scores and patient-reported outcomes are warranted to confirm clinical and quality-of-life benefits. Full article

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu–Osler–Weber syndrome, is a disorder of angiogenesis characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. This rare autosomal dominant disorder is caused by pathogenic variants in the ENG and ACVRL1 genes, and only 1–3% of case variants occur in SMAD4. HHT clinical manifestations include telangiectasias, epistaxis, and arteriovenous malformations in multiple organ systems. Clinical diagnosis is based on Curaçao Criteria. Here, we describe a pauci-symptomatic 10-year-old girl with an orbital and sinus infectious disease. Her clinical history was unremarkable, except for sporadic, self-limiting epistaxis episodes. She showed finger clubbing and low oxygen saturation levels on pulse oximetry, suggesting a chronic lung disease, and a large lung arteriovenous malformation. She also developed acute neurological symptoms, with evidence of multiple cerebral abscess lesions on MRI. HHT was therefore suspected and confirmed by genetic analysis, which revealed a de novo pathogenic variant in the ENG gene [c.1183G>T p.(Glu395Ter)] found in only 15% of the reads from NGS analysis, performed on peripheral blood lymphocytes, indicating a possible mutational mosaicism. This case outlines that HHT could present with unusual clinical symptoms highlighting the importance of diagnosis using both clinical criteria and genetic test. Full article

Arteriovenous malformations (AVMs) are fast-flow vascular malformations formed by direct artery-to-vein shunts without an intervening capillary bed, which increases the risk of hemorrhage and organ-specific damage. A synthesis of recent advances shows that AVMs arise from interplay between germline susceptibility (ENG, ACVRL1, SMAD4, RASA1, EPHB4), somatic mosaicism (KRAS, MAP2K1, PIK3CA), perturbed signaling (TGF-β/BMP, Notch, VEGF, PI3K/AKT, RAS/MAPK), hemodynamic stress, and inflammation. Multimodal imaging—digital subtraction angiography (DSA), MRI/MRA with perfusion and susceptibility sequences, CTA, Doppler ultrasound, and 3D rotational angiography—underpins diagnosis and risk stratification, while arterial spin labeling and 4D flow techniques refine hemodynamic assessment. Management is individualized and multidisciplinary, combining endovascular embolization, microsurgical resection, and stereotactic radiosurgery (SRS); a non-surgical approach and monitoring remain reasonable for some asymptomatic AVMs. Device and technique innovations (detachable-tip microcatheters, pressure-cooker approaches, and newer liquid embolics such as PHIL and Squid) have broadened candidacy, and precision-medicine strategies, including pathway-targeted pharmacotherapy, are emerging for syndromic and somatic-mutation–driven AVMs. Animal models and computational/radiomics tools increasingly guide hypothesis generation and treatment selection. We outline practical updates and future priorities: integrated genomic-imaging risk scores, genotype-informed medical therapy, rational hybrid sequencing, and long-term outcome standards focused on hemorrhage prevention and quality of life. Full article

Background: Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular bleeding disorder. The most common symptoms are recurrent, severe nosebleeds that occasionally necessitate intervention by an ENT (Ear, Nose, and Throat) specialist, as well as iron-deficiency anemia. Telangiectasia is typically located in the nasal cavity, lips, tongue, fingertips, and the gastrointestinal mucosa. Arteriovenous malformations (AVMs) are located in internal organs (brain, lungs, liver, etc.). The family history is positive for HHT. The diagnosis is based on the Curacao criteria. The endoglin and activin receptor-like kinase 1 genes (ENG and ACVRL1) are the most common mutation sites, leading to elevated endothelial growth factor (VEGF) levels. Methods: We conducted a retrospective analysis in the Department of Internal Medicine, Division of Hematology, and Center of Expertise for Rare Diseases at the University of Debrecen, spanning the period from 2010 to 2025. Records of patients referred with HHT were reviewed concerning demographic data, clinical presentations, laboratory findings, and treatment approaches. To evaluate management options, epistaxis severity was assessed using the Epistaxis Severity Score (ESS). Results: 48 HHT patients (21 male and 27 female) were included in this retrospective study. Genetic testing was positive in each case, showing mutations in the ENG (HHT1 subgroup) or ACVRL1 (HHT2 subgroup) genes. Most of the patients are followed-up with in our department. ESS was calculated at baseline and 6 months after antiangiogenic treatment by two independent physicians. Detailed computed tomography (CT) was performed in all patients. Seven patients were administered desmopressin, a synthetic analog of antidiuretic hormone (ADH), based on our previous experience in reducing bleeding in von Willebrand disease. Antiangiogenic therapy with thalidomide (50 mg oral tablets) was used in 24 patients, while bevacizumab was administered to 5 patients. Most patients experienced a remarkable decrease in epistaxis severity and a reduction in the need for transfusions (ESS before treatment: HHT1 patients, 4.15 ± 1.91 vs. ESS after treatment, 2.62 ± 0.99; HHT2 patients, 3.79 ± 3.19 vs. 2.02 ± 1.91). Subgroup analysis using paired ESS data showed a significant reduction in ESS in both HHT1 and HHT2 patients (p = 0.003 and p = 0.043, respectively). Bevacizumab further reduced the ESS, but the few cases were not suitable for statistical analysis. Serum iron levels significantly increased after antiangiogenic treatment in the HHT2 group (p = 0.01). Conclusions: HHT is a rare vascular bleeding disorder. Daily nosebleeds impair the patients’ quality of life and sometimes lead to severe transfusion-dependent iron-deficient anemia. Frequent hospitalization places a significant burden on the healthcare system. Thus, we have used treatment options for HHT patients that primarily act by inhibiting VEGF, and these treatment modalities have yielded successful results in our hands. Full article

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease, is an autosomal dominant vascular disorder caused most commonly by pathogenic variants in the ENG and ACVRL1/ALK1 genes. It is characterized by mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in various organs, leading to recurrent epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Diagnosis relies on the Curaçao Criteria, which include recurrent nosebleeds, characteristic telangiectasias, visceral AVMs, and family history. This review aims to present current therapeutic approaches and emerging treatment strategies for HHT. Traditional surgical and laser-based methods are increasingly complemented or replaced by targeted pharmacological interventions. Antiangiogenic agents such as bevacizumab and thalidomide have demonstrated efficacy in reducing bleeding frequency and transfusion requirements, although adverse effects may limit long-term use. Novel therapies under investigation target molecular pathways involved in vascular remodeling, including tyrosine kinase inhibitors (sorafenib, nintedanib), anti-ANGPT2 antibodies, and modulators of BMP9/ALK1 signaling (tacrolimus, sirolimus). Preclinical and early clinical studies suggest that these agents may provide disease-modifying benefits. Continued research should focus on optimizing treatment efficacy, reducing toxicity, and developing individualized therapeutic regimens based on genetic and clinical characteristics. Full article

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a vascular disorder with a global prevalence ranging from 1:5000 to 1:8000. It most commonly manifests through nosebleeds, which can be frequent and severe, exposing patients to major iron losses, anemia, and considerable physical and emotional distress. To date, no drug has received the FDA or EMA approval for preventing or treating HHT associated epistaxis, limiting access to therapies and intensifying the burden on patients and clinicians. Based on peer-reviewed evidence, the Second International HHT Guidelines provided a stepwise approach to help physicians manage HHT-related epistaxis highlighting the role of anti-fibrinolytic and systemic antiangiogenic drugs. However, experience from clinical practice and trials indicates marked variability in patient responses, and none of the recommended approaches has demonstrated sufficient placebo-controlled efficacy to gain regulatory approval. Striking insights in HHT physiopathology shed light on complex dysregulated signaling pathways with a triggering role not only by angiogenesis as widely recognized, but also by inflammation, injury and other stimuli, pointing to novel therapeutic targets. This review outlines current recommendations for preventing and managing nosebleeds in HHT patients, highlights the latest insights into the development of telangiectasic lesions, and discusses potential therapeutic treatments currently under clinical investigation. Full article

Historically, the factor(s) that stimulate vascular malformation genesis in hereditary hemorrhagic telangiectasia (HHT) has been hotly debated. Once heterozygous loss-of-function germline mutations in ENG, ACVRL1, or SMAD4 were discovered in individuals with HHT, haploinsufficiency, a 50% reduction in the encoded protein, was proposed as the molecular mechanism of HHT. However, the focal and discrete nature of HHT-associated vascular malformations suggested to others that vascular malformation genesis requires an additional, local trigger. In this review, we discuss the evidence for the Knudsonian two-hit mutation mechanism of vascular malformation pathogenesis in HHT, where the inherited, heterozygous mutation is augmented by an acquired somatic mutation in the remaining normal copy of the gene. We consider the mechanisms of HHT–vascular malformation development in the broader context of the emerging role of somatic mutations in both sporadic and inherited vascular malformations. We discuss different mechanisms of biallelic gene inactivation in HHT, difficulties with the detection of all possible mechanisms of biallelic inactivation, and issues related to the somatic mosaic nature of the lesion. We then discuss the critical importance of non-genetic factors on the pathogenesis of HHT-associated vascular malformations. Finally, we discuss the implications of the two-hit mutation mechanism for the design of novel treatments for HHT. Full article

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by pathogenic variants in ENG (HHT1) and ACVRL1 (HHT2), with distinct phenotypic expressions. Background/Objectives: This study investigates the genotype–phenotype correlations, including comparing the quality of life by phenotype, conducting a cardiovascular risk assessment, and evaluating the impact of mutation type on its clinical manifestations and prognosis. Methods: A cross-sectional study was conducted on 85 HHT patients, stratified into HHT1 (ENG, n = 43) and HHT2 (ACVRL1, n = 42). Their clinical and biochemical parameters, arteriovenous malformations (AVMs), epistaxis severity, quality of life, and cardiovascular risk were assessed. Genetic variants were classified as truncating or non-truncating. The statistical analyses included logistic regression and survival analysis. Results: The onset of epistaxis occurred earlier in HHT1 (log-rank p = 0.011), whereas its severity (p = 0.006) and iron deficiency were greater in HHT2 (p = 0.043). Pulmonary AVMs were significantly more frequent in HHT1 (58.1% vs. 9.5%, p < 0.01), contributing to a potential decrease in survival, despite the greater hemorrhagic burden in HHT2. Truncating mutations were independently associated with anemia (p < 0.05). Cardiovascular risk (measured using the SCORE2 scale) was low to moderate, and quality of life (measured using the EQ-5D-5L scale) was most impaired in patients with severe epistaxis (p = 0.031) or anemia (p = 0.026). Truncating mutations influence the severity of anemia independently of genotype. Limitations: The principal limitations include the small sample size and the bias generated by this being a paper based on another prospective study with a methodology designed for different objectives. Conclusions: These findings underscore the need for personalized management strategies based on genotype and mutation type. Further prospective studies are warranted to validate these associations and optimize the risk stratification in HHT. Full article

Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between a pulmonary artery and pulmonary vein that bypass the capillary bed, resulting in right-to-left shunting. The majority of PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease. Asymptomatic children with either a confirmed diagnosis of HHT or who are at risk of HHT from positive family history, as well as those with signs or symptoms concerning for HHT and/or PAVMs, should undergo screening for PAVMs at the time of clinical presentation or diagnosis. Screening in children can use a conservative approach (pulse oximetry, exercise intolerance testing, and chest radiograph) or transthoracic contrast echocardiography with agitated saline (TTCE). Pediatric patients with large or physiologically significant PAVMs should be treated with transcatheter embolization. Close follow-up is required after treatment to evaluate for interval growth of other PAVMs or reperfusion of the treated PAVMs. Full article

Background/Objectives: Pathogenic variants in the growth differentiation factor 2 (GDF2) gene have been linked to a hereditary hemorrhagic telangiectasia (HHT)-like syndrome, yet their clinical significance remains under investigation. This study reports seven pediatric patients with GDF2 variants from a single center. Methods: We identified children with GDF2 pathogenic variants and variants of uncertain significance (VUS) from the Children’s Hospital of Philadelphia Comprehensive HHT Program and cross-referenced the list with a full-text query by GDF2 gene name on >53,000,000 visits to ensure complete ascertainment. Medical records were reviewed retrospectively, and variables of interest were abstracted. Results: The median age at genetic testing was 12 years (range 1.75–16). Reasons for genetic testing included telangiectasias, pulmonary hypertension, familial testing, respiratory symptoms, seizures, developmental disabilities, and lung arteriovenous malformations (AVMs). Four patients had missense VUS, including two novel VUS (c.34C>G; p.Leu12Val, c.41C>T; p.Ser14Phe), while three had pathogenic deletions. All patients experienced epistaxis, starting at a median age of 6 years (range 2–12). Three had telangiectasias. One patient had both a GDF2 VUS and a de novo partial endoglin (ENG) gene deletion. While this patient’s symptoms of HHT are likely related to her ENG variant, synergy cannot be excluded, and two first-degree family members with clinically significant epistaxis also have the same GDF2 VUS. Notably, two patients had visceral AVMs—one with a lung AVM and another with a vein of Galen malformation. Conclusions: Interpretation of GDF2 VUS and their relationship to clinical symptoms is challenging given the rarity of these genetic variants and the inadequate diagnostic utility of the current clinical criteria for HHT in the pediatric population. Further research with larger cohorts is necessary to improve the genotype–phenotype correlation in GDF2-related HHT. Carefully collected clinical information with longitudinal follow-up may also assist in refining classification of GDF2 VUS as benign or pathogenic in the future. Full article

Objective: The aim of this study was to evaluate patients with hereditary hemorrhagic telangiectasia (HHT) for the potential reperfusion of pulmonary arteriovenous malformations (PAVM) treated by catheter embolization using coils or embolization plugs and to analyze causes of possible reperfusion in order to further improve treatment. Methods: This retrospective study analyzed the data of 345 patients who underwent screening for pulmonary arteriovenous malformations in cases of suspected or confirmed HHT (Osler’s disease). Of these, 118 patients with PAVM that underwent catheter embolization and had at least one follow-up study were included in our study and evaluated for potential reperfusion. Screening and follow-up for the detection of PAVM was performed by dynamic and high-resolution contrast-enhanced magnetic resonance angiography (MRA). The average follow-up time was 6.2 years. Results: Reperfusion was detected in 43 of 118 patients at follow-up. Thirty-five of these patients showed a recanalization of the treated vessel and in eleven patients the formation of collateral vessels resupplying the PAVM were identified as the cause of reperfusion. The average time between embolization and detected reperfusion was 5.6 years. The recanalization of both coils and plugs was observed. The recanalization of coils could be attributed in most cases to an insufficient packing density of the implanted coils. In addition, an enlarged diameter of the feeding artery was confirmed as a risk factor for reperfusion. Conclusions: As the reperfusion of embolized pulmonary arteriovenous malformations can occur after a long time interval post-treatment, regular lifelong follow-up studies after embolization are essential to detect reperfusion at an early stage and avoid serious complications like a brain abscess or stroke through prompt re-embolization. After coil embolization, attention should be paid to sufficiently dense packing to achieve adequate and permanent occlusion. Full article

Background/Objectives: Angiogenesis is involved in the pathogenesis of hereditary hemorrhagic telangiectasia (HHT). VEGF, ANG2, TGFβ1, and ENG are the most studied angiogenic factors, but their clinical significance in blood samples is still not completely defined. The genetic study of HHT mutations is the test of choice for diagnosing the disease, but this route is expensive, and the causative mutation is not found in up to 10% of cases. Therefore, the use of angiogenic biomarkers could facilitate a cheaper and easier approach to the diagnosis of HHT. To determine the diagnostic and prognostic value of the VEGFA, TGFβ1, ANG2, and ENG plasmatic concentrations in patients with HHT. Methods: All the participants were clinically evaluated and the concentrations of these angiogenic factors were measured using MILLIPLEX^®MAP immunoassays in plasma samples collected from 44 patients with HHT and 19 controls. To evaluate the diagnostic validity of these parameters, we estimated the maximum Youden index of the ROC curve and evaluated their diagnostic value using multiple logistic regression. Results: Patients with HHT had increased blood levels of TGFβ1 and decreased ENG compared to the control group. We could not identify any angiogenic markers related to the clinical severity or epistaxis. TGFβ1 and ENG exhibited a higher discriminant capacity for HHT, especially patients with HHT1, and it was possible to develop signatures of these factors with diagnostic value. Conclusions: We identified several angiogenic factors that may be important diagnostic biomarkers for HHT and propose that the combination of TGFβ1 and ENG could represent a signature with diagnostic value for this disease. Full article

Background/Objectives: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal blood vessel formation, leading to recurrent epistaxis, cutaneous and mucosal telangiectases, and visceral arteriovenous malformations (AVMs). Hepatic involvement may result in complications such as high-output heart failure, portal hypertension, and biliary ischemia. We report an uncommon case of ischemic cholecystitis in a patient with HHT. Methods: A 57-year-old male with HHT type 1, including gastric telangiectases and hepatic AVMs, presented with anemia, melena, epigastric pain, and a history of recurrent epistaxis. Imaging revealed gastric telangiectases and liver AVMs, consistent with HHT. Following an episode of severe epistaxis and aspiration pneumonia, the patient developed right upper quadrant pain. Results: Abdominal CT and ultrasound identified thickening of the gallbladder wall, segmental enhancement defects, and a perivesicular fluid effusion, suggestive of acalculous cholecystitis. A laparoscopic cholecystectomy was performed, revealing ischemic cholecystitis with necrotic gallbladder walls. Conclusions: This case underscores the potential for ischemic cholecystitis in patients with HHT and liver involvement, particularly under conditions of acute hemodynamic instability. Clinicians should be vigilant in recognizing this rare complication, especially in patients with established HHT and associated hepatic vascular anomalies. Full article

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder leading to frequent bleeding in several organs. As HHT diagnosis is demanding and depends on clinical criteria, liquid biopsy would be beneficial. Exosomes from biofluids are nano-sized vesicles for intercellular communication. Their cargo and characteristics represent biomarkers for many diseases. Here, exosomes of HHT patients were examined regarding their biosignature. Methods: Exosomes were isolated from the plasma of 20 HHT patients and 17 healthy donors (HDs). The total exosomal protein was quantified, and specific proteins were analyzed using Western blot and antibody arrays. Human umbilical vein endothelial cells (HUVECs) co-incubated with exosomes were functionally examined via immunofluorescence, proliferation, and scratch assay. Results: The levels of the angiogenesis-regulating protein Thrombospondin-1 were significantly higher in HHT compared to HD exosomes. Among HHT, but not HD exosomes, a negative correlation between total exosomal protein and soluble Endoglin (sENG) levels was found. Other exosomal proteins (ALK1, ALK5) and the particle concentration significantly correlated with disease severity parameters (total consultations/interventions, epistaxis severity score) in HHT patients. Functionally, HUVECs were able to internalize both HD and HHT exosomes, inducing a similar change in the F-Actin structure and a reduction in migration and proliferation. Conclusions: This study provided first insights into the protein cargo and function of HHT-derived exosomes. The data indicate changes in sENG secretion via exosomes and reveal exosomal Thrombospondin-1 as a potential biomarker for HHT. Several exosomal characteristics were pointed out as potential liquid biomarkers for disease severity, revealing a possible new way of diagnosis and prognosis of HHT. Full article

Background: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations and telangiectases, in which the endothelium and immune system play a role in the pathophysiology. Therefore, treatments with antiangiogenic properties which are also regarded as immunomodulators were demonstrated to play an important role in treatment. This systematic review aimed to gather the accumulated information of the use of thalidomide and its analogs in the treatment of HHT. Methods: In this systematic review, publications that were published up to March 2024 and met the inclusion criteria were compiled using the keywords ‘thalidomide’, ‘lenalidomide’, ‘pomalidomide’, ‘immunomodulatory drugs’ and ‘HHT’ in Medline and Scholars databases. Results: A total of 53 articles were evaluated and 15 were included in the study. Thalidomide was the predominant used agent and was observed to be used in patients with ages ranging from 37 to 77 years, with doses ranging from 50 to 200 mg daily, and the mean follow-up period was observed to be 6–60 months. Assessments regarding efficacy were based on the epistaxis severity score (ESS), hemoglobin level, and transfusion independence. While thalidomide showed significant efficacy, it also had an adverse event rate of any severity of up to 85% of patients. Use of lenalidomide to control bleeding in HHT was reported in a single case report, while the use of pomalidomide was observed to be investigated in Phase 1 and Phase 2 studies in patients aged 48 to 70 years, with doses ranging from 1 to 5 mg daily for 6–24 months. This treatment was reported to provide significant improvement in hemoglobin levels and ESS. Adverse events of any severity were observed at a frequency of 60–66%. Conclusions: Antiangiogenic agents such as thalidomide, lenalidomide, and pomalidomide may be effective in managing HHT. However, further studies are needed to optimize the timing, dose, and sequence. Full article