The packet lists ENG, located on chromosome 9, as the associated gene. ClinGen classifies the ENG gene-disease relationship as definitive. The inheritance pattern recorded in the packet is autosomal dominant, and GeneReviews likewise describes HHT as inherited in an autosomal dominant manner. GeneReviews states that most individuals diagnosed with HHT have an affected parent, and that a proband rarely has the disorder as the result of a de novo germline or postzygotic mosaic pathogenic variant. It also notes that a proband may appear to be the only affected family member because of unrecognized disease in relatives, reduced penetrance, early death of a parent before symptom onset, or late onset in an affected parent. GeneReviews reports that essentially all known HHT pathogenic variants are null alleles and that no absolute genotype-phenotype correlations exist between clinical phenotypes and specific variants or variant types.

GeneReviews describes consensus clinical diagnostic criteria, the revised Curacao criteria, which comprise four elements: recurrent nosebleeds (typically four or more per year); multiple telangiectases at characteristic sites (lips, oral cavity, fingers, nose); visceral AVM (typically pulmonary, cerebral, hepatic, spinal, or gastrointestinal); and a family history, defined as a first-degree relative diagnosed by these criteria. According to GeneReviews, a clinical diagnosis can be established in a proband meeting three or more criteria, and the diagnosis is considered possible or suspected with two criteria. GeneReviews notes that applying the clinical criteria to children at risk often fails to identify affected children, because epistaxis, telangiectases, and symptoms of visceral AVMs are frequently absent in childhood. A molecular diagnosis is described as the identification of a germline heterozygous pathogenic or likely pathogenic variant in an HHT-associated gene by molecular genetic testing, using multigene panel testing or comprehensive genomic testing such as exome or genome sequencing. GeneReviews states that a heterozygous variant of uncertain significance neither establishes nor rules out the diagnosis.

The packet contains no FDA-approved treatment records and no orphan-drug records for this condition. GeneReviews states that, to date, no targeted therapies are FDA approved specifically for use in individuals with HHT. Its management section describes supportive care aimed at quality of life, function, and reduction of complications, typically through multidisciplinary care by specialists in relevant fields, and notes that published guidelines are considered supplementary to the judgment of an expert in clinical management of HHT, as typically seen at HHT Centers of Excellence. For nosebleeds, GeneReviews lists humidification, topical moisturizing therapy, and hemostatic products, with ablation therapies (laser treatment, radiofrequency ablation, electrosurgery, sclerotherapy) and surgical options such as septodermoplasty or Young's nasal closure described for epistaxis that does not respond to topical measures. Anemia is described as sometimes requiring iron replacement therapy or, less commonly, blood transfusion. GeneReviews also lists targeted therapies used off label: the antifibrinolytic tranexamic acid and the antiangiogenic agents bevacizumab, pomalidomide, and pazopanib, each with supporting evidence ranging from randomized trials to retrospective studies. GeneReviews notes that use of the antiangiogenic agents in children is limited. Its surveillance discussion covers evaluations for anemia, pulmonary AVMs, cerebral AVMs, and hepatic AVMs.

The packet does not certify life-expectancy or overall outcome data. GeneReviews describes the average age of onset as late childhood for epistaxis and early adulthood for mucocutaneous telangiectases, and states that HHT is near fully penetrant by late adulthood. GeneReviews also notes that features of HHT are age-related, with telangiectases first appearing before age 20 years in 30% of affected individuals and by age 40 years in two thirds. Pulmonary artery hypertension is listed at approximately 1%-2% of individuals.

ClinicalTrials.gov records linked to this condition in the packet indicate that several clinical trials are currently registered. Examples include NCT06659640, a phase 1 study of ALN-6400 in healthy volunteers and patients with HHT sponsored by Alnylam Pharmaceuticals (active, not recruiting); NCT07623525, a phase 1 study of DIAG723 in adults with HHT sponsored by Diagonal Therapeutics (recruiting); NCT04404881, a phase 2 study of bevacizumab (active, not recruiting); NCT03850964, a phase 2 study of pazopanib on HHT-related epistaxis and anemia sponsored by Cure HHT (active, not recruiting); and NCT04976036, a phase 2 study of nintedanib for epistaxis (recruiting). Registry and observational records include the Comprehensive HHT Outcomes Registry of the United States (CHORUS). GeneReviews lists therapies under investigation as ALN-6400, an RNA interference agent designed to lower plasminogen levels; nintedanib, a tyrosine kinase inhibitor; tacrolimus; sirolimus; and VAD044 (engasertib), an AKT pathway inhibitor, and notes that results from larger controlled trials are needed. The ClinicalTrials.gov search page for this condition lists current records.