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Background: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life., Methods: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations)., Results: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash., Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244)., (Copyright © 2024 Massachusetts Medical Society.)

Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1 , have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations.

Objective: The brain arteriovenous malformation (BAVM) nidus compactness score (CS), determined on angiography, predicts BAVM recurrence after surgical resection among children with sporadic BAVMs. We measured the angiographic CS for BAVMs among children with hereditary hemorrhagic telangiectasia (HHT) to determine CS characteristics in this population., Methods: A pediatric interventional neuroradiologist reviewed angiograms to determine the CS of BAVMs in children with HHT recruited to the BVMC. CS is based on overall nidus and perinidal anomalous vessel compactness. CS categories included 1 = diffuse nidus, 2 = intermediate nidus, and 3 = compact nidus., Results: Forty-eight of 78 children (61.5%) with HHT and brain vascular malformations had a conventional angiogram; 47 (97.9%) angiograms were available. Fifty-four BAVMs were identified in 40 of these 47 children (85.1%). Of 54 BAVMs in children with HHT, CS was 1 in 7 (13%), 2 in 29 (53.7%), and 3 in 18 BAVMs (33.3%) compared with CS of 1 in six (26.1%), 2 in 15 (65.2%), and 3 in 2 BAVMs (8.7%) among 23 previously reported children with sporadic BAVMs, p = 0.045 (Fisher's exact). Seven children with HHT had intracranial hemorrhage: 4 had CS = 3, 1 had CS = 2, and 2 had CS = 1., Conclusions: A range of CSs exists across HHT BAVMs, suggesting it may be an angiographic measure of interest for future studies of BAVM recurrence and hemorrhage risk. Children with HHT may have more compact niduses compared to children with sporadic BAVMs. Additional research should determine whether CS affects hemorrhage risk or post-surgical recurrence risk in HHT-associated BAVMs, which could be used to direct BAVM treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Approximately 10% of people with hereditary hemorrhagic telangiectasia (HHT) have brain vascular malformations (VMs). Few reports describe de novo brain VM formation. International HHT Guidelines recommend initial brain VM screening upon HHT diagnosis in children but do not address rescreening. We aimed to confirm whether brain VMs can form de novo in patients with HHT., Methods: The Brain Vascular Malformation Consortium HHT project is a 17-center longitudinal study enrolling patients since 2010. We analyzed the database for de novo VMs defined as those detected (1) on follow-up neuroimaging in a patient without previous brain VMs or (2) in a location distinct from previously identified brain VMs and reported those in whom a de novo VM could be confirmed on central neuroimaging review., Results: Of 1909 patients enrolled, 409 (21%) had brain VMs. Seven patients were recorded as having de novo brain VMs, and imaging was available for central review in four. We confirmed that three (0.7% of individuals with brain VMs) had de novo brain VMs (two capillary malformations, one brain arteriovenous malformation) with intervals of six, nine, and 13 years from initial imaging. Two with de novo brain VMs were <18 years. The fourth patient, a child, did not have a de novo brain VM but had a radiologically confirmed increase in size of an existing brain arteriovenous malformation., Conclusions: Brain VMs can, albeit rarely, form de novo in patients with HHT. Given the potential risk of hemorrhage from brain VMs, regular rescreening in patients with HHT may be warranted., Competing Interests: Declaration of competing interest The Brain Vascular Malformation Consortium (U54NS065705) is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN) and is supported by the RDCRNData Management and Coordinating Center (DMCC) (U2CTR002818). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and NINDS. L.A.B. was supported by a BVMC fellowship, as part of the funding detailed above. L.A.B. was also supported by the Children's Hospital of Philadelphia Department of Pediatrics Chair's Initiative. M.E.F. was also supported by the Li Ka Shing Knowledge Institute. None of the funding sources directly participated in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the article for publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The Curaçao criteria are well-established diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT), but they lack details regarding a predictive presentation of epistaxis and telangiectasias. This study collects and compares data in HHT and population cohorts to inform the application of these criteria., Methods: In-person interviews regarding epistaxis and targeted examination for telangiectases in a general population cohort (n = 204) and an HHT cohort (n = 432) were conducted., Results: Frequency of epistaxis, rather than intensity or duration, was the best discriminator of HHT. A cutoff of ≥4 nosebleeds per year alone yielded a diagnostic sensitivity of 97%, and specificity of 84%. The mean number of telangiectases at the sites investigated was 0.4 in the general population cohort and 26.5 in the HHT cohort. The most distinctive sites for telangiectases in HHT were lips and palmar fingers, whereas telangiectases of the face and dorsum of the hand were comparable in both cohorts., Conclusion: We propose that the Curaçao criteria be modified to include the following cutoffs: (1) epistaxis frequency of ≥4 nosebleeds per year and (2) telangiectasia count of at least 2 in characteristic locations (palmar aspect of fingers, lips, and oral cavity), and that cutaneous telangiectases at other sites not be considered relevant for diagnostic purposes., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Published by Elsevier Inc.)

Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Description: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications., Methods: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved., Recommendations: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Background: The location of telangiectases in hereditary hemorrhagic telangiectasia (HHT), as set forth in the consensus diagnostic (Curaçao) criteria, is based primarily on adults., Objective: Document the locations and numbers of telangiectases in a cohort of pediatric patients with HHT., Methods: A retrospective chart review using a standardized data collection form for site and number of telangiectases was performed for pediatric patients with HHT (age, 0-18 years) from 2005 to 2016., Results: Of 90 pediatric patients with HHT, 71% had one or more telangiectases. Of all the telangiectases counted (N = 319), cutaneous telangiectases were more common (73%) than oral telangiectases (27%). The hands were the most frequent site, accounting for 33% of all telangiectases. Adolescents were more likely than children to have cutaneous telangiectases (85% vs 50% [Q = 0.005]). The most frequent sites in children younger than 10 years were the hands excluding the fingers (27%), fingers (25%), and face (23%). Only 23% of subjects (21 of 90) presented with multiple (≥3) telangiectases at locations considered characteristic for the current consensus diagnosis guidelines (lips, oral cavity, and fingers)., Limitations: Ascertainment bias based on recruitment., Conclusions: In this pediatric population, telangiectases at sites not included as "characteristic" by the Curaçao diagnostic criteria were common. The Curaçao criteria in regard to both number and location of telangiectases may be inadequate in the pediatric HHT population., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Hereditary 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., Methods: DNA 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., Results: Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1 intron 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 ACVRL1 intron 9 that disrupted splicing., Conclusions: Despite 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 ACVRL1 intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives/hypothesis: Our objective was to describe epistaxis onset and severity in pediatric hereditary hemorrhagic telangiectasia (HHT) patients and study the cumulative incidence of epistaxis by age of onset within each genetic subtype., Study Design: Retrospective cohort chart review., Methods: Charts were reviewed of patients age 0 to 18 years with a clinical or genetic diagnosis of HHT who were evaluated at a tertiary multidisciplinary HHT clinic from January 2010 to June 2016. The epistaxis severity score (ESS), a validated tool for assessing epistaxis severity, was used to assess epistaxis. Statistical analyses were conducted on the full HHT cohort as well as subgroups stratified by the HHT causative gene (HHT1 = ENG and HHT2 = ACVRL1)., Results: Sixty-nine pediatric subjects were identified; 60 had HHT confirmed by genetic testing, and nine (from families with known mutations) met published clinical diagnostic criteria alone. Fifty-nine (85%) had onset of epistaxis. The median age of onset of epistaxis was 5 years (interquartile range [IQR]: 2-9 years). The median ESS for the entire cohort was 1.6 (IQR: 0-2.6). The median ESS was higher in HHT1 versus HHT2 (2.3 vs. 1.1, P = .002), and age of epistaxis onset was earlier in HHT1 (3 vs. 5 years, P = .03). Sex and age were not associated with ESS., Conclusions: Epistaxis may present early in HHT, but is typically mild in the pediatric period. Severity in the pediatric population is worse in patients with HHT1. By recognizing the significance of even mild, infrequent epistaxis in a child with a family history of HHT, and understanding that not all HHT patients have epistaxis during childhood, community providers and otolaryngologist can assist in the early detection of HHT., Level of Evidence: 4 Laryngoscope, 128:1714-1719, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Hereditary hemorrhagic telangiectasia (HHT) is characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectases, and multisystem arteriovenous malformations (AVMs). Brain AVMs typically present at birth and are identified in approximately 10-20% of patients with HHT. A retrospective review was undertaken of all HHT patients with known single or multiple brain AVMs treated at our institution. Thirty-nine patients with brain AVM(s) were diagnosed with HHT. Most patients presented with at least one Curaçao criterion. A total of 78 brain AVMs were identified in 39 patients. Two-thirds of patients had solitary brain AVMs, whereas 33% of patients harbored at least two lesions (range: 2-16). Brain AVMs of the supratentorial cerebral hemispheres comprised 83% of all lesions, whereas infratentorial lesions accounted for only 17%. Of the 55 brain AVMs assigned Spetzler-Martin grading, the majority of patients were Grade 1 (73%), and 23% and 4% were Grades 2 and 3, respectively. Patients were treated with surgery alone (51%), embolization alone (6%), embolization followed by surgery (9%), stereotactic radiosurgery (11%), stereotactic radiosurgery followed by surgery (3%), or observation (20%). Of patients who underwent genetic analysis, 62% possessed mutations in ENG (HHT type 1), whereas 38% had mutations in ACVRL1 (HHT type 2). This robust patient cohort of brain AVMs in 39 patients with HHT advances the collective understanding of this disease's varied presentation, diagnostic workup, genetic underpinnings, and available treatment options., (Copyright © 2018. Published by Elsevier Ltd.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain., Objective: To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis., Design, Setting, and Participants: The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014., Interventions: Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline)., Main Outcomes and Measures: The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure., Results: Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits., Conclusions and Relevance: Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency., Trial Registration: clinicaltrials.gov Identifier: NCT01408030.

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., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Vascular malformations are a disruption of the normal vascular pattern in which it is expected that a capillary network of microscopic vessels lies interposed between high-pressure arteries that deliver blood and thin-walled veins that collect low-pressure blood for return to the heart. In the case of arteriovenous malformations, arteries or arterioles connect directly to the venous collection system, bypassing any capillary bed. Clinical consequences result from rupture and hemorrhage, from dramatically increased blood flow, or from the loss of capillary functions such as nutrient exchange and filtering function. These malformations can occur sporadically or as a component of inherited vascular malformation syndromes. In these and other hereditary vascular malformation syndromes, genetic studies have identified proteins and pathways involved in vascular morphogenesis and development. A common theme observed is that vascular malformations result from disruption in pathways involved in vascular stability. Here we review the vascular malformations and pathways involved in hereditary hemorrhagic telangiectasia, capillary malformation-arteriovenous malformation, cerebral cavernous malformations, and mucocutaneous venous malformations.