HHT1 is caused by pathogenic variants in the ENG gene on chromosome 9. ENG encodes endoglin, a membrane glycoprotein that functions as a co-receptor for transforming growth factor-beta family ligands. ClinGen has classified ENG with DEFINITIVE evidence for its causal role in HHT. Loss of functional endoglin disrupts normal vascular angiogenesis and vessel wall integrity, resulting in the formation of fragile abnormal arteriovenous connections characteristic of the disease. GeneReviews data indicate that essentially all known HHT pathogenic variants in ENG are null alleles acting through loss-of-function. No absolute genotype-phenotype correlations between specific pathogenic variants and clinical outcomes have been established.

HHT1 is inherited in an autosomal dominant manner. Penetrance is near-complete by late adulthood. Average age of onset is late childhood for epistaxis and early adulthood for mucocutaneous telangiectases. Expressivity is variable among affected individuals, even within the same family.

Clinical diagnosis of HHT relies on published consensus criteria (the Curaçao criteria), which evaluate four domains: recurrent epistaxis (typically four or more events per year), multiple telangiectases at characteristic sites (lips, oral cavity, fingers, nose), visceral AVMs (pulmonary, cerebral, hepatic, spinal, or gastrointestinal), and family history of a first-degree relative with a confirmed HHT diagnosis. Meeting three or more criteria establishes the clinical diagnosis; two criteria places the diagnosis as possible or suspected. Application of these criteria to children often underestimates affected status, as many features develop progressively during childhood and adolescence.

Molecular diagnosis involves identification of a heterozygous germline pathogenic variant in ENG by molecular genetic testing. Multigene panels including ENG and other HHT-associated genes are a common approach; exome or genome sequencing may be used in panels that require it. Identification of a variant of uncertain significance in ENG does not establish or rule out the diagnosis.

No targeted therapies are specifically FDA-approved for HHT. Several agents are used in the management of HHT manifestations based on published clinical evidence, all in an off-label capacity.

Tranexamic acid, an antifibrinolytic agent, is supported by randomized controlled trial data showing reduced epistaxis severity and is used for HHT-related epistaxis and gastrointestinal bleeding. Bevacizumab, an anti-angiogenic monoclonal antibody targeting vascular endothelial growth factor, is administered intravenously and is supported by multiple retrospective studies demonstrating reduced epistaxis frequency and improved hemoglobin levels. Pomalidomide, an immunomodulatory drug, demonstrated epistaxis severity reduction in one published randomized controlled trial. Pazopanib, a tyrosine kinase inhibitor, has shown epistaxis reduction in retrospective and prospective studies; a placebo-controlled randomized trial was ongoing at the time of GeneReviews data capture.

Supportive and procedural approaches for epistaxis management documented in GeneReviews include topical moisturizing therapies, humidification, ablation techniques (laser, radiofrequency, electrosurgery, sclerotherapy), and, in selected cases, septodermoplasty. Pulmonary AVMs of appropriate size are managed by embolization. Anemia arising from chronic blood loss is addressed with iron replacement or transfusion as clinically indicated.

HHT1 is near-fully penetrant by late adulthood, and clinical features are age-related, with manifestations typically accumulating over a lifetime. The most clinically serious complications arise from visceral AVMs: pulmonary AVMs can cause stroke through paradoxical embolism or produce significant hypoxemia; cerebral AVMs carry risk of intracranial hemorrhage; and hepatic AVMs can lead to high-output cardiac failure or, less commonly, liver failure. Anemia from recurrent blood loss is a common chronic morbidity affecting approximately half of individuals. Because essentially all HHT pathogenic variants are null alleles and no absolute genotype-phenotype correlations have been established, genotype-based prognostic prediction is not currently possible. Clinical variability is substantial among individuals sharing the same pathogenic variant, including within the same family.

HHT1 is the subject of active clinical investigation across multiple programs internationally. Investigational agents under clinical study documented in GeneReviews and active trial records include ALN-6400, an RNA interference agent designed to reduce plasminogen levels as a hemostatic approach; nintedanib, a tyrosine kinase inhibitor targeting VEGF and related receptors; tacrolimus and sirolimus, which engage Smad1/5/8 signaling downstream of the endoglin pathway; VAD044 (engasertib), an investigational AKT pathway inhibitor; and DIAG723, a novel agent in early-phase study. Bevacizumab and pazopanib continue to be evaluated in prospective trials.

Registry studies including the Comprehensive HHT Outcomes Registry of the United States (CHORUS) are collecting longitudinal outcomes data across HHT-affected populations. Observational studies in Denmark, Germany, France, and the United Kingdom are evaluating neurovascular manifestations, hemostatic management, and quality of life. Active trials span Phase 1 through observational designs and include sites in North America, Europe, and Australia.