Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy afflicting 1 in 5000 individuals, is the second-most-common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the U.S. Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS; NCT06259292), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median (range) age of 53 (0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of post-menarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring intravenous iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). This data from CHORUS, the first national registry of its kind, provides reliable, real-world estimates of the incidence, prevalence and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of over two decades, during which substantial serious, preventable HHT morbidity, including early intracranial hemorrhage, may occur.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin-ENG, activin like kinase 1 ACVRL1 aka ALK1, and SMAD4) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000. Expert clinicians and international scientists gathered in Cascais, Portugal from September 29th to October 2^nd, 2022 to present the latest scientific research in the HHT field and novel treatment strategies for people living with HHT. During the largest HHT scientific conference yet, participants included 293 in person and 46 virtually. An impressive 209 abstracts were accepted to the meeting and 59 were selected for oral presentations. The remaining 150 abstracts were presented during judged poster sessions. This review article summarizes the basic and clinical abstracts selected as oral presentations with their new observations and discoveries as well as surrounding discussion and debate. Two discussion-based workshops were also held during the conference, each focusing on mechanisms and clinical perspectives in either AVM formation and progression or current and future therapies for HHT. Our hope is that this paper will represent the current progress and the remaining unanswered questions surrounding HHT, in order to serve as an update for those within the field and an invitation to those scientists and clinicians as yet outside of the field of HHT.

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant vascular disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs), which arise due to direct connections between arteries and veins. These vascular lesions are prone to bleeding and vascular shunts, leading to recurrent epistaxis and GI bleeding, among other systemic complications. HHT is caused by heterozygous loss-of-function mutations in genes involved in the BMP9/BMP10 signaling pathway—primarily ENG, ACVRL1 (also known as ALK1), and SMAD4—which define the major HHT subtypes (HHT1, HHT2, and HHT-JP). HHT has a global prevalence of 1 in 5000 individuals, affecting approximately 1.6 million worldwide. The 15th International HHT Scientific Conference was held in Mandelieu-la-Napoule, France, bringing together over 376 attendees from around the world, including 77 trainees, to share the latest advances in HHT research and clinical care. The conference received 225 abstract submissions, of which 49 were selected for oral presentations and 176 for poster sessions. This gathering marked a significant milestone in the field, not only for its scale but also for the depth and breadth of the scientific discussions. Key highlights included new insights into AVM biology, disease mechanisms, genetic underpinnings, and emerging therapeutic strategies. In addition to oral and poster sessions, two focused workshops provided in-depth discussion on pulmonary arterial hypertension (PAH) and HHT, a rare occurrence of two disease states where treatment for one often worsens the other, and a discussion on the evolving definition of HHT and whether it should be revised in light of recent advances in research, genetic testing, and clinical evidence beyond the Curacao criteria, which were established 25 years ago. This executive summary aims to recapitulate the key scientific and clinical findings presented at the conference and to spotlight areas of continued debate and unmet need. We hope this summary will serve as a resource for experts working in the field and as an invitation for new investigators and clinicians to engage in collaborative efforts to advance the understanding and treatment of HHT.