HHT is caused by pathogenic variants in four genes documented in this packet: ENG (encoding Endoglin), ACVRL1 (encoding ALK1), SMAD4, and GDF2 (encoding BMP9). According to GeneReviews, essentially all known HHT pathogenic variants are null alleles, and no absolute genotype-phenotype correlations exist between clinical phenotypes and specific pathogenic variants or variant types. ClinVar documents a total of 299 pathogenic and 119 likely pathogenic variants across these genes, with 74 high-confidence variants classified. Hotspot variants documented in ClinVar for ENG (LRG_543 reference) include: Arg411Gln (c.1232G>A; 10 submissions, 3-star review), Arg374Trp (c.1120C>T; 8 submissions), Arg411Trp (c.1231C>T; 6 submissions), Arg374Gln (c.1121G>A; 6 submissions), Cys344Tyr (c.1031G>A; 5 submissions), and Arg479Ter (c.1435C>T; 5 submissions). Variant types documented in ClinVar include single nucleotide variants, duplications, deletions, insertions, and indels.

Consensus clinical diagnostic criteria for HHT — the Curaçao criteria — are documented in this packet and in GeneReviews. The four criteria are: (1) recurrent epistaxis, (2) multiple telangiectases at characteristic sites including the lips, oral cavity, fingers, and nose, (3) visceral arteriovenous malformations, and (4) positive family history of HHT. According to GeneReviews, meeting three or four criteria constitutes a definite clinical diagnosis; two criteria yields a possible diagnosis. Molecular genetic testing for pathogenic variants in ENG, ACVRL1, SMAD4, and GDF2 enables genetic confirmation, as documented in this packet. Contrast echocardiography (bubble study) for pulmonary AVM screening and brain MRI for cerebral AVM evaluation are among the diagnostic methods documented in this packet. GeneReviews notes that updated Curaçao criteria proposals are available in the published literature.

No FDA-approved targeted therapies are documented in this packet's approved_treatments field. Foundational management approaches documented in this packet include: systematic screening for visceral AVMs (pulmonary, hepatic, cerebral) at the time of diagnosis; iron supplementation and blood transfusion for chronic anemia from epistaxis and GI bleeding; embolization of pulmonary AVMs; antiangiogenic therapy with bevacizumab for severe epistaxis; and laser ablation and septodermoplasty for nasal telangiectases. According to GeneReviews treatment of manifestations section, tranexamic acid (an antifibrinolytic agent) has been used in children and adults with HHT. GeneReviews documents anticoagulants, aspirin, and nonsteroidal anti-inflammatory agents that interfere with platelet function as agents to avoid in individuals with significant epistaxis; vigorous nose blowing, heavy lifting, and straining are similarly listed as circumstances to avoid in that chapter. GeneReviews also documents that some individuals with HHT experience increased epistaxis after alcohol consumption.

According to the natural history documented in this packet, with systematic screening and management, life expectancy in HHT can be near normal. GeneReviews notes that HHT is near fully penetrant by late adulthood. The absence of absolute genotype-phenotype correlations, as documented in GeneReviews, means that clinical course cannot be reliably predicted from the specific pathogenic variant identified. Hepatic arteriovenous malformations are documented in up to 74% of individuals in this packet's characteristic findings; pulmonary and cerebral AVMs represent sources of morbidity through mechanisms including paradoxical embolism, stroke, and brain abscess, as referenced in the foundational management data in this packet.

According to GeneReviews, newer therapies designed to interfere with the development of abnormal vascular connections are being investigated, including ALN-6400 and other investigational agents under various stages of clinical study; GeneReviews notes that results from larger controlled trials are needed. Three clinical trials recently initiated or currently recruiting are documented in this packet. NCT07623525 (DIAG723 in adults with HHT) is a Phase 1 study sponsored by Diagonal Therapeutics, initiated June 2026 with planned completion December 2027. NCT07601425 (Harmony-HHT: ATV-1601) is a Phase 1 study sponsored by Atavistik Bio, initiated July 2026 with planned completion March 2030. NCT07667413 is a Phase 1 study of topical TOR-582 for treatment of epistaxis in HHT, sponsored by Columbia University, not yet recruiting as of this packet, with planned initiation October 2026 and planned completion December 2027.