Hereditary Hemorrhagic Telangiectasia (HHT) — Disease Characteristics Research Report

1. Disease information

1.1 Concise overview (current understanding)

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs), with recurrent epistaxis as the most common clinical manifestation and a major cause of iron-deficiency anemia and reduced quality of life. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2, ahmad2024managingepistaxisin pages 1-2)

Authoritative definitions emphasize autosomal dominant inheritance and vascular malformations: a 2024 JCI review describes HHT as an “inherited vascular disorder” transmitted “in an autosomal dominant manner” and characterized by mucocutaneous telangiectases and visceral AVMs (lungs, liver, brain). (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

1.2 Key identifiers (as found in retrieved sources)

Because the current tool run focused on primary literature and trial registries (not OMIM/Orphanet/MeSH/ICD web records), only a subset of identifiers were explicitly present in retrieved texts.

• Orphanet (ORPHA): ORPHA:774 (explicitly stated in a 2024 Orphanet Journal of Rare Diseases paper). URL: https://doi.org/10.1186/s13023-024-03493-3 (published Dec 2024). (villanueva2024minimalencephalopathyin pages 1-2)
• OMIM disease subtype identifiers (explicit in retrieved review):
• HHT1: OMIM 187300
• HHT2: OMIM 600376
• Juvenile polyposis/HHT (JP-HHT): OMIM 175050
• HHT5: OMIM 615506 URL: https://doi.org/10.1172/jci176379 (published Feb 2024). (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)
• OMIM gene identifiers (explicit in retrieved pediatric review):
• ENG (Endoglin; locus given as 9q34.11 with OMIM subtype context)
• ACVRL1 (12q13.13; OMIM 601284)
• SMAD4 (18q21.2; OMIM 600993)
• GDF2 (10q11.22; OMIM 605120) URL: https://doi.org/10.3390/pediatric15010011 (published Feb 2023). (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

Not found explicitly in the retrieved text excerpts during this run (and therefore not asserted here): MONDO ID, MeSH Unique ID, ICD-10/ICD-11 codes.

1.3 Synonyms / alternative names

Synonyms supported by retrieved primary/review sources include: - Osler-Weber-Rendu syndrome (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2) - Rendu–Osler–Weber syndrome (ROW) (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

1.4 Evidence source type

The report integrates (i) aggregated disease-level resources (peer-reviewed reviews and cohort/registry analyses) and (ii) patient-level/clinical study evidence, including randomized controlled trial evidence (NEJM PATH-HHT) and observational studies. (alsamkari2024pomalidomideforepistaxis pages 1-3, alvarezhernandez2023tacrolimusasa pages 1-2, criscuolo2025hereditaryhemorrhagictelangiectasia pages 1-6)

1.5 Quick-reference identifiers/criteria table

Table: This table summarizes the core naming, identifiers, major causal genes, and clinical diagnostic criteria for hereditary hemorrhagic telangiectasia from the retrieved sources. It is useful as a compact reference for populating standardized disease knowledge-base fields.

2. Etiology

2.1 Disease causal factors

HHT is primarily a Mendelian autosomal dominant disease caused by heterozygous pathogenic variants in genes encoding components of an endothelial BMP/TGF-β signaling axis: - ENG (endoglin; HHT1) - ACVRL1 (ALK1; HHT2) - SMAD4 (JP-HHT) - GDF2 (BMP9; HHT5 / HHT-like phenotype) This etiology is summarized in 2023–2024 reviews, which describe HHT as caused by loss-of-function mutations in the BMP9/BMP10–ENG–ALK1–SMAD4 signaling pathway in endothelial cells. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2, tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

A 2024 JCI review explicitly attributes HHT to “loss-of-function mutations” in the “endothelial BMP9-10/ENG/ALK1/SMAD4 signaling pathway.” (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

2.2 Risk factors

Genetic risk factors (causal genes; relative frequency)

A 2023 pediatric-focused review reports that >95% of patients have causal variants in ENG or ACVRL1, with SMAD4 in a minority (~2%) associated with a juvenile polyposis/HHT overlap, and GDF2 causative in very rare reported cases. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

Variant classes in HHT include missense, splice-site, and copy-number (deletions/duplications) changes; the same review notes variant types including “missense, splice site, deletions, and duplications.” (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

Environmental/physiologic triggers as “second hits”

While the germline mutation is present in every cell, HHT lesions are typically focal, implying local triggers. A key contemporary concept is that focal lesion formation may require additional pro-angiogenic/pro-inflammatory triggers. The 2024 JCI review notes that preclinical data support triggers such as VEGF, LPS, or wounding, which can promote AVM formation in susceptible (Eng+/– or Alk1+/–) settings, and that VEGF blockade can reduce AVMs in models. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3)

2.3 Protective factors

This tool run did not retrieve primary evidence for protective factors (genetic or environmental) that reduce HHT risk itself; HHT is typically present from birth due to inherited pathogenic variants. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2, tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

2.4 Gene–environment / gene–trigger interactions

Current mechanistic understanding supports a gene–trigger interaction framework where germline haploinsufficiency sets susceptibility, and local angiogenic/inflammatory stimuli contribute to lesion formation (“second hit” paradigm). (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3, whitehead2024investigationofthe pages 1-2)

3. Phenotypes

3.1 Core phenotype spectrum

HHT is clinically characterized by: - Recurrent spontaneous epistaxis (often earliest and most common symptom) - Mucocutaneous telangiectases (lips/oral cavity/tongue/fingers/nasal mucosa) - Visceral AVMs (lungs, liver, brain; also GI and spinal lesions) These are formalized in the Curaçao diagnostic criteria. (ahmad2024managingepistaxisin media 4cb59254, danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

A 2024 narrative review reiterates that recurrent epistaxis occurs in “nearly all affected individuals.” (ahmad2024managingepistaxisin pages 1-2)

3.2 Phenotype characteristics (onset, frequency, progression)

Epistaxis

• Frequency: in a national registry cohort (Uruguay, 2025 preprint), epistaxis affected 88.9% of adults. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 1-6)
• Age of onset: in the Uruguay cohort, mean onset was 17.6 years, with 61.3% onset before age 20. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 23-28)
• Pediatric onset: a pediatric review reports epistaxis median onset 5 years (range 0.25–15) in one series and that epistaxis is present in ~90% before age 30. (danesino2023hereditaryhemorrhagictelangiectasia pages 2-4)

Suggested HPO terms: - Epistaxis HP:0000425 (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

Telangiectases

• In the Uruguay cohort, mucocutaneous telangiectasias were observed in ~90%. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)
• Pediatric review: telangiectases appear at typical sites and “about one third of cases” report appearance before age 20. (danesino2023hereditaryhemorrhagictelangiectasia pages 4-6)

Suggested HPO terms: - Telangiectasia HP:0000954; mucocutaneous telangiectasia (as concept) (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

Visceral AVMs (lung/brain/liver/GI)

The 2024 JCI review highlights lung/liver/brain as major visceral sites. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

Recent cohort data (Uruguay registry): - Pulmonary AVMs: 20% - Cerebral AVMs: 15.7% - Hepatic AVMs: 18.9% - Gastrointestinal telangiectasias: upper GI 34.4%, lower GI 15.6% (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

Suggested HPO terms: - Pulmonary arteriovenous malformation HP:0002116 (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11) - Cerebral arteriovenous malformation HP:0002501 (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11) - Hepatic arteriovenous malformation HP:0011792 (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11) - Gastrointestinal hemorrhage HP:0002104 and related GI telangiectasia concepts (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

Anemia and iron deficiency

In the Uruguay cohort, severe anemia was reflected by low hemoglobin values; overall lowest median hemoglobin was 7 g/dL (range 5–12), with correlation by epistaxis severity (e.g., severe epistaxis lowest Hb median 5.5 g/dL). (criscuolo2025hereditaryhemorrhagictelangiectasia pages 23-28)

Suggested HPO terms: - Iron deficiency anemia HP:0002901 (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

3.3 Quality-of-life impact

HHT epistaxis is directly linked to reduced HRQoL; in the NEJM PATH-HHT trial, the abstract explicitly states epistaxis “results in iron deficiency anemia and reduced health-related quality of life (HRQoL).” (alsamkari2024pomalidomideforepistaxis pages 1-3)

In a large cross-sectional HRQoL study (Orphanet J Rare Dis, published Mar 2025), among respondents the most common symptoms were epistaxis (92%) and fatigue (79%), and severe epistaxis was associated with higher depression/anxiety/fatigue measures. URL: https://doi.org/10.1186/s13023-025-03620-8. (gong2025quantifyingtheburden pages 1-2)

4. Genetic / molecular information

4.1 Causal genes (and subtype mapping)

Core causal genes and subtype mapping (from 2023–2024 reviews): - ENG → HHT1 (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2) - ACVRL1 (ALK1) → HHT2 (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2) - SMAD4 → JP-HHT (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2) - GDF2 (BMP9) → HHT5 / HHT-like (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

4.2 Pathogenic variant classes and functional consequences

• Disease mechanism is largely loss of function. The 2024 JCI review frames causal variants as “loss-of-function” in the BMP9/BMP10–ENG–ALK1–SMAD4 axis. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)
• Variant classes include missense, splice-site, frameshift/nonsense (premature termination), and copy-number variants (deletions/duplications). (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2, shovlin2020mutationalandphenotypic pages 9-10)
• A 2023 genetic analysis highlighted a subset of ACVRL1 missense variants that produce ALK1 protein that reaches the endothelial cell surface but “fails to signal” (kinase-inactive), suggesting functionally distinct pathogenic mechanisms within the same gene. (jain2023pathogenicvariantfrequencies pages 1-2)

Somatic vs germline and “two-hit” lesions: - A 2024 tissue sequencing study reports very-low-level somatic second-hit mutations in nasal telangiectasias and solid organ AVMs, consistent with “somatic biallelic second-hit mutations” contributing to lesion formation. (whitehead2024investigationofthe pages 1-2)

4.3 Penetrance and expressivity

HHT shows age-dependent penetrance and variable expressivity. - A 2023 review states penetrance is “above 95% after age 40” and notes underdiagnosis because full signs may appear later in life. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

4.4 Modifier genes

Evidence for modifier loci is emerging. A 2023 genetic review notes independent variants in PTPN14 and ADAM17 associated with pulmonary AVMs (as modifier associations), alongside broad variability and incomplete genotype–phenotype predictability for traits like epistaxis severity. (jain2023pathogenicvariantfrequencies pages 2-4)

4.5 Epigenetics and chromosomal abnormalities

No specific epigenetic signatures or recurrent chromosomal abnormalities were retrieved in this tool run.

5. Environmental information

HHT is not an infectious disease; no infectious triggers were retrieved.

Environmental/physiologic triggers are best conceptualized as lesion-promoting angiogenic/inflammatory stimuli (e.g., VEGF, wounding, LPS in models) superimposed on genetic susceptibility. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3)

6. Mechanism / pathophysiology

6.1 Core pathway and causal chain

The mechanistic backbone is impaired endothelial signaling through the BMP9/BMP10–ENG–ALK1–SMAD4 axis (vascular quiescence and stability). Loss-of-function variants reduce pathway signaling, predisposing to abnormal angiogenesis and AVM development. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

A 2024 review describes AVM morphogenesis as starting with “focal dilatations of postcapillary venules” that expand to include capillaries and connect to dilated arterioles, forming direct arteriovenous shunts. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

6.2 Two-hit/somatic mosaic model

Focal lesion distribution despite germline heterozygosity supports a two-hit concept: - Reviews cite evidence of low-frequency somatic mutations in vascular lesions leading to biallelic loss of ENG/ACVRL1. (shovlin2020mutationalandphenotypic pages 23-24) - A 2024 targeted tissue study provides direct support, reporting somatic second-hit mutations in nasal telangiectasia and solid organ AVMs at very low mosaic levels (down to ~1%). (whitehead2024investigationofthe pages 1-2, whitehead2024investigationofthe pages 2-3)

6.3 Angiogenic mediators and inflammation

The mutated BMP/ENG/ALK1/SMAD4 pathway crosstalks with pro-angiogenic pathways (notably VEGF), and anti-VEGF strategies can reduce lesions in models and improve bleeding clinically. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3)

6.4 Cell types and ontology suggestions

Primary implicated cell type: - Endothelial cell (CL:0000115) — central to ENG/ALK1/BMP9 signaling and lesion formation. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

Other relevant cell/tissue features: - Perivascular lymphocytic infiltrates suggest immune involvement at lesions. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3)

Suggested GO biological process terms (high-level, mechanism-aligned): - angiogenesis (GO:0001525) - blood vessel morphogenesis (GO:0048514) - endothelial cell proliferation (GO:0001935) - regulation of BMP signaling pathway (GO:0030510) - regulation of TGF-β receptor signaling pathway (GO:0017015)

7. Anatomical structures affected

7.1 Organ level (primary sites)

Major anatomic targets include: - Nasal mucosa (epistaxis) - Skin/oral mucosa (telangiectases) - Lung, liver, brain (visceral AVMs) - Gastrointestinal tract (telangiectases/bleeding) (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2, ahmad2024managingepistaxisin media 4cb59254)

Suggested UBERON concepts (examples for knowledge base mapping): - nasal mucosa (UBERON:0001826) - lung (UBERON:0002048) - liver (UBERON:0002107) - brain (UBERON:0000955) - gastrointestinal tract (UBERON:0001555)

7.2 Tissue/cell level

• Vascular endothelium is the key affected tissue; defective endothelial signaling leads to abnormal angiogenesis and shunting. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

8. Temporal development

8.1 Onset

• Epistaxis often begins in childhood/adolescence (mean onset ~17.6 years in one cohort; median 5 years in a pediatric series). (criscuolo2025hereditaryhemorrhagictelangiectasia pages 23-28, danesino2023hereditaryhemorrhagictelangiectasia pages 2-4)

8.2 Progression

• Penetrance is age-dependent and becomes essentially complete in adulthood (>95% after age 40). (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)
• Visceral lesions can be present early (including in children) and may cause sudden complications. (danesino2023hereditaryhemorrhagictelangiectasia pages 4-6)

9. Inheritance and population

9.1 Inheritance

Autosomal dominant inheritance is consistently reported across 2023–2024 sources. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2, tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)

9.2 Epidemiology and population statistics

• General prevalence estimates in recent reviews: “up to 1 in 5,000 individuals” (JCI review, Feb 2024). (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2)
• A 2023 review states “a reasonable general estimate of the prevalence is 1 in 5000” and that HHT “affects at least one million people worldwide.” (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)
• Country-level registry estimate (Uruguay, Aug 2025 preprint): prevalence 3.83 per 100,000 (95% CI 3.26–4.61), female:male ratio 1.73:1, mean age 48.2 ± 18.3 years, diagnostic delay 5.7 ± 10.6 years, and low screening adherence (complete screening ~21%). URL: https://doi.org/10.1101/2025.08.18.25333772. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

Founder effects are noted in reviews, including a founder effect reported in the Netherlands Antilles. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)

10. Diagnostics

10.1 Clinical criteria: Curaçao criteria

The Curaçao criteria and thresholds are explicitly laid out in a 2024 review’s Table 1 (cropped below). (ahmad2024managingepistaxisin media 4cb59254)

Key criteria: 1) recurrent spontaneous epistaxis 2) multiple telangiectases at characteristic sites 3) visceral lesions (GI telangiectasia; pulmonary/hepatic/cerebral/spinal AVMs) 4) first-degree family history Definite: 3 criteria; Possible/Suspected: 2; Unlikely: <2. (ahmad2024managingepistaxisin media 4cb59254)

10.2 Genetic testing

Multiple sources state that identifying a heterozygous pathogenic variant in HHT genes is diagnostic/confirmatory. - A 2024 epistaxis-focused review states that “identification of a heterozygous pathogenic variant in ACVRL1, ENG, GDF2, and SMAD4 genes is diagnostic.” (ahmad2024managingepistaxisin pages 1-2)

Pediatric considerations: - Curaçao criteria sensitivity is lower in early childhood; a pediatric review reports sensitivity 42% in ages 0–5 vs 91% in 16–21, with high specificity, and notes nasal endoscopy improves sensitivity. (danesino2023hereditaryhemorrhagictelangiectasia pages 2-4)

10.3 Imaging and screening implementation (real-world)

Registry data provide real-world implementation gaps: in Uruguay, only ~21% completed recommended screening (bubble echocardiography + brain imaging + hepatic Doppler), and many had only partial imaging workups. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

11. Outcome / prognosis

11.1 Complications (morbidity)

Major complications arise from visceral AVMs: - Pulmonary AVMs can lead to paradoxical emboli causing stroke and brain abscess; this is emphasized in mechanistic reviews and confirmed by cohort complication data. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2, criscuolo2025hereditaryhemorrhagictelangiectasia pages 23-28) - In the Uruguay cohort, pulmonary AVM-related complications included ischemic stroke 12.2%, TIA 11.1%, brain abscess 2.2%. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 23-28)

11.2 Quality-of-life outcomes

The 2024 NEJM PATH-HHT trial showed improvement in disease-specific QoL with reduced epistaxis (see Treatment). (alsamkari2024pomalidomideforepistaxis pages 1-3)

Mortality and formal survival statistics were not retrieved in the current tool run.

12. Treatment

12.1 Supportive and interventional care (core real-world approaches)

Treatment is typically symptom- and complication-directed: iron replacement and transfusion for chronic bleeding anemia; endoscopic/surgical management for epistaxis; and embolization or other interventions for AVMs depending on location and risk. A 2024 epistaxis review describes a “stepwise approach” escalating from conservative measures to more invasive procedures. (ahmad2024managingepistaxisin pages 1-2)

12.2 Pharmacotherapy and targeted/anti-angiogenic strategies (recent developments)

Pomalidomide (PATH-HHT; randomized placebo-controlled)

High-quality recent evidence is provided by the PATH-HHT trial (NEJM, Sep 2024): - Design: randomized 2:1 pomalidomide 4 mg daily vs placebo for 24 weeks; n=144 randomized. - Primary endpoint: change in Epistaxis Severity Score (ESS); ≥0.71 considered clinically significant. - Result: mean ESS difference vs placebo at 24 weeks −0.94 (95% CI −1.57 to −0.31; p=0.004). - HRQoL: HHT-specific QoL score improved (mean difference −1.4; 95% CI −2.6 to −0.3). - Safety: neutropenia, constipation, rash were more common; grade ≥3 adverse events 47% vs 24%; VTE 4% vs 2%. URL: https://doi.org/10.1056/NEJMoa2312749 (published Sep 2024). (alsamkari2024pomalidomideforepistaxis pages 1-3, alsamkari2024pomalidomideforepistaxis pages 6-8)

MAXO suggestions: - immunomodulatory drug therapy; treatment of epistaxis; treatment of chronic anemia (conceptual MAXO mapping).

Systemic tacrolimus (observational/off-label clinical evidence; translational rationale)

A 2023 observational study (J Clin Med, Nov 2023) reports 11 refractory HHT patients treated off-label with low-dose tacrolimus (0.5–2 mg/day): epistaxis decreased significantly and hemoglobin increased significantly, with discontinuation in 2 patients. URL: https://doi.org/10.3390/jcm12237410. (alvarezhernandez2023tacrolimusasa pages 1-2)

Mechanistic rationale described includes increased endoglin/ALK1 expression and stimulation of BMP9/TGF-β1/ALK1 signaling with SMAD4 translocation and downstream gene changes (e.g., ID1), supporting endothelial pathway restoration as a therapeutic strategy. (alvarezhernandez2023tacrolimusasa pages 2-4)

MAXO suggestions: - calcineurin inhibitor therapy; treatment of epistaxis; treatment of gastrointestinal hemorrhage (conceptual).

Bevacizumab (anti-VEGF) — systemic and local

A 2024 epistaxis review summarizes evidence that systemic IV bevacizumab can yield clinically meaningful ESS improvements in large cohorts (e.g., in an analysis of 143 patients, mean ESS fell by 3.37 points and 92% had clinically meaningful ESS reduction), though adverse events can lead to discontinuation. (ahmad2024managingepistaxisin pages 3-3)

The mechanistic rationale for targeting VEGF is also supported by pathway crosstalk noted in mechanistic reviews. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3)

MAXO suggestions: - anti-VEGF therapy; treatment of epistaxis; treatment of gastrointestinal hemorrhage (conceptual).

12.3 Experimental/ongoing clinical trials (ClinicalTrials.gov)

Tacrolimus trial (NCT04646356)

• Phase II, open-label, single-group (Unity Health Toronto)
• Actual start: 2020-10-20; primary completion: 2024-01-15; completion: 2024-10-21; last update posted 2025-04-01
• Enrollment: 10
• Primary endpoint: weekly minutes of epistaxis over a long follow-up window with diary capture URL: https://clinicaltrials.gov/study/NCT04646356 (registry-derived). (NCT04646356 chunk 1)

Pazopanib randomized trial (NCT03850964)

• Phase 2/3 randomized, quadruple-masked, placebo-controlled
• Start: 2023-05-08; primary completion: 2025-11-21; estimated completion: Jul 2026
• Enrollment: 70
• Primary endpoints include ≥50% decrease in epistaxis duration and ≥2 g/dL hemoglobin increase (weeks 19–24 vs baseline) URL: https://clinicaltrials.gov/study/NCT03850964 (registry-derived). (NCT03850964 chunk 1)

13. Prevention

Primary prevention is not generally applicable for a dominantly inherited Mendelian disorder, but secondary/tertiary prevention is central.

Key tertiary prevention strategy: systematic screening and management of visceral AVMs to prevent stroke/abscess/hemorrhage and high-output cardiac failure. Implementation gaps are documented by registry data showing low adherence to recommended screening in one national cohort. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11)

14. Other species / natural disease

No naturally occurring non-human HHT cases were retrieved in this tool run.

15. Model organisms

15.1 Genetic and induced models

Mechanistic reviews report that Eng+/– or Alk1+/– mouse models can develop AVMs in the presence of angiogenic/inflammatory triggers (e.g., wounding, VEGF, LPS), supporting a two-hit paradigm and providing platforms for testing anti-VEGF interventions. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3)

15.2 Model utility and limitations

These models recapitulate key features of focal AVM formation and response to angiogenic modulation, but human lesion heterogeneity and multi-organ natural history remain incompletely modeled.

Figure/Table evidence: Curaçao criteria (cropped from a 2024 review)

The following cropped table is direct evidence for diagnostic criteria and is suitable for knowledge-base encoding. (ahmad2024managingepistaxisin media 4cb59254)

Notes on evidence gaps (limitations of this tool run)

• ICD-10/ICD-11, MeSH Unique ID, MONDO ID were not explicitly present in retrieved excerpts and therefore are not provided with citations.
• Some high-priority guideline sources (e.g., “Second International Guidelines for the Diagnosis and Management of HHT”) were not retrieved as full text in this run, limiting guideline-level specificity for screening intervals and prophylaxis recommendations.

References

1. (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2): Tala Al Tabosh, Mohammad Al Tarrass, Laura Tourvieilhe, Alexandre Guilhem, Sophie Dupuis-Girod, and Sabine Bailly. Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances. Journal of Clinical Investigation, Feb 2024. URL: https://doi.org/10.1172/jci176379, doi:10.1172/jci176379. This article has 67 citations and is from a highest quality peer-reviewed journal.

2. (ahmad2024managingepistaxisin pages 1-2): Youssef El Sayed Ahmad, S. Kajal, and Akaber M. Halawi. Managing epistaxis in hereditary haemorrhagic telangiectasia: a comprehensive narrative review of therapeutic horizons. The Journal of Laryngology & Otology, 139:389-394, Nov 2024. URL: https://doi.org/10.1017/s0022215124002093, doi:10.1017/s0022215124002093. This article has 1 citations.

3. (villanueva2024minimalencephalopathyin pages 1-2): B. Villanueva, A. Cañabate, R. Torres-Iglesias, P. Cerdà, E. Gamundí, Q. Ordi, E. Alba, L. A. Sanz-Astier, A. Iriarte, J. Ribas, J. Castellote, X. Pintó, and A. Riera-Mestre. Minimal encephalopathy in hereditary hemorrhagic telangiectasia patients with portosystemic vascular malformations. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03493-3, doi:10.1186/s13023-024-03493-3. This article has 2 citations and is from a peer-reviewed journal.

4. (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2): Cesare Danesino, Claudia Cantarini, and Carla Olivieri. Hereditary hemorrhagic telangiectasia in pediatric age: focus on genetics and diagnosis. Pediatric Reports, 15:129-142, Feb 2023. URL: https://doi.org/10.3390/pediatric15010011, doi:10.3390/pediatric15010011. This article has 23 citations.

5. (alsamkari2024pomalidomideforepistaxis pages 1-3): Hanny Al-Samkari, Raj S. Kasthuri, Vivek N. Iyer, Allyson M. Pishko, Jake E. Decker, Clifford R. Weiss, Kevin J. Whitehead, Miles B. Conrad, Marc S. Zumberg, Jenny Y. Zhou, Joseph Parambil, Derek Marsh, Marianne Clancy, Lauren Bradley, Lisa Wisniewski, Benjamin A. Carper, Sonia M. Thomas, and Keith R. McCrae. Pomalidomide for epistaxis in hereditary hemorrhagic telangiectasia. New England Journal of Medicine, 391:1015-1027, Sep 2024. URL: https://doi.org/10.1056/nejmoa2312749, doi:10.1056/nejmoa2312749. This article has 38 citations and is from a highest quality peer-reviewed journal.

6. (alvarezhernandez2023tacrolimusasa pages 1-2): Paloma Álvarez-Hernández, José Luis Patier, Sol Marcos, Vicente Gómez del Olmo, Laura Lorente-Herraiz, Lucía Recio-Poveda, Luisa María Botella, Adrián Viteri-Noël, and Virginia Albiñana. Tacrolimus as a promising drug for epistaxis and gastrointestinal bleeding in hht. Journal of Clinical Medicine, 12:7410, Nov 2023. URL: https://doi.org/10.3390/jcm12237410, doi:10.3390/jcm12237410. This article has 9 citations.

7. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 1-6): Z. Criscuolo, C. Chiesa, G. Losada, B. Marsiglia, L. Matta, R. Nogara, H. Pereira, S. Rodriguez, R. Mezzano, and S. Ruiz. Hereditary hemorrhagic telangiectasia in uruguay: epidemiologic and clinical features of the evaluated population. MedRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.18.25333772, doi:10.1101/2025.08.18.25333772. This article has 0 citations.

8. (gong2025quantifyingtheburden pages 1-2): Anna J. Gong, Marisabel Linares Bolsegui, Emerson E. Lee, Matthew R. Tan, Yong Zeng, Jianqiao Ma, Prateek C. Gowda, Tushar Garg, and Clifford R. Weiss. Quantifying the burden of hereditary hemorrhagic telangiectasia on quality of life and psychological health: a cross-sectional study. Orphanet Journal of Rare Diseases, Mar 2025. URL: https://doi.org/10.1186/s13023-025-03620-8, doi:10.1186/s13023-025-03620-8. This article has 2 citations and is from a peer-reviewed journal.

9. (ochiai2026acaseof pages 5-6): Sawako Ochiai, Reimon Yamaguchi, Kiminobu Takeda, Naoto Oishi, Sumihito Togi, Hiroki Ura, Yo Niida, and Akira Shimizu. A case of hereditary hemorrhagic telangiectasia with <i>acvrl1</i> gene variant. Dermatology Reports, Mar 2026. URL: https://doi.org/10.4081/dr.2026.10582, doi:10.4081/dr.2026.10582. This article has 0 citations.

10. (jain2023pathogenicvariantfrequencies pages 2-4): Kinshuk Jain, Sarah C. McCarley, Ghazel Mukhtar, Anna Ferlin, Andrew Fleming, Deborah J. Morris-Rosendahl, and Claire L. Shovlin. Pathogenic variant frequencies in hereditary haemorrhagic telangiectasia support clinical evidence of protection from myocardial infarction. Journal of Clinical Medicine, 13:250, Dec 2023. URL: https://doi.org/10.3390/jcm13010250, doi:10.3390/jcm13010250. This article has 9 citations.

11. (ahmad2024managingepistaxisin media 4cb59254): Youssef El Sayed Ahmad, S. Kajal, and Akaber M. Halawi. Managing epistaxis in hereditary haemorrhagic telangiectasia: a comprehensive narrative review of therapeutic horizons. The Journal of Laryngology & Otology, 139:389-394, Nov 2024. URL: https://doi.org/10.1017/s0022215124002093, doi:10.1017/s0022215124002093. This article has 1 citations.

12. (tabosh2024hereditaryhemorrhagictelangiectasia pages 2-3): Tala Al Tabosh, Mohammad Al Tarrass, Laura Tourvieilhe, Alexandre Guilhem, Sophie Dupuis-Girod, and Sabine Bailly. Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances. Journal of Clinical Investigation, Feb 2024. URL: https://doi.org/10.1172/jci176379, doi:10.1172/jci176379. This article has 67 citations and is from a highest quality peer-reviewed journal.

13. (whitehead2024investigationofthe pages 1-2): Kevin J. Whitehead, Doruk Toydemir, Whitney Wooderchak-Donahue, Gretchen M. Oakley, Bryan McRae, Angelica Putnam, Jamie McDonald, and Pinar Bayrak-Toydemir. Investigation of the genetic determinants of telangiectasia and solid organ arteriovenous malformation formation in hereditary hemorrhagic telangiectasia (hht). International Journal of Molecular Sciences, 25:7682, Jul 2024. URL: https://doi.org/10.3390/ijms25147682, doi:10.3390/ijms25147682. This article has 16 citations.

14. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 23-28): Z. Criscuolo, C. Chiesa, G. Losada, B. Marsiglia, L. Matta, R. Nogara, H. Pereira, S. Rodriguez, R. Mezzano, and S. Ruiz. Hereditary hemorrhagic telangiectasia in uruguay: epidemiologic and clinical features of the evaluated population. MedRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.18.25333772, doi:10.1101/2025.08.18.25333772. This article has 0 citations.

15. (danesino2023hereditaryhemorrhagictelangiectasia pages 2-4): Cesare Danesino, Claudia Cantarini, and Carla Olivieri. Hereditary hemorrhagic telangiectasia in pediatric age: focus on genetics and diagnosis. Pediatric Reports, 15:129-142, Feb 2023. URL: https://doi.org/10.3390/pediatric15010011, doi:10.3390/pediatric15010011. This article has 23 citations.

16. (criscuolo2025hereditaryhemorrhagictelangiectasia pages 6-11): Z. Criscuolo, C. Chiesa, G. Losada, B. Marsiglia, L. Matta, R. Nogara, H. Pereira, S. Rodriguez, R. Mezzano, and S. Ruiz. Hereditary hemorrhagic telangiectasia in uruguay: epidemiologic and clinical features of the evaluated population. MedRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.18.25333772, doi:10.1101/2025.08.18.25333772. This article has 0 citations.

17. (danesino2023hereditaryhemorrhagictelangiectasia pages 4-6): Cesare Danesino, Claudia Cantarini, and Carla Olivieri. Hereditary hemorrhagic telangiectasia in pediatric age: focus on genetics and diagnosis. Pediatric Reports, 15:129-142, Feb 2023. URL: https://doi.org/10.3390/pediatric15010011, doi:10.3390/pediatric15010011. This article has 23 citations.

18. (shovlin2020mutationalandphenotypic pages 9-10): Claire L. Shovlin, Ilenia Simeoni, Kate Downes, Zoe C. Frazer, Karyn Megy, Maria E. Bernabeu-Herrero, Abigail Shurr, Jennifer Brimley, Dilipkumar Patel, Loren Kell, Jonathan Stephens, Isobel G. Turbin, Micheala A. Aldred, Christopher J. Penkett, Willem H. Ouwehand, Luca Jovine, and Ernest Turro. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood, 136:1907-1918, Oct 2020. URL: https://doi.org/10.1182/blood.2019004560, doi:10.1182/blood.2019004560. This article has 78 citations and is from a highest quality peer-reviewed journal.

19. (jain2023pathogenicvariantfrequencies pages 1-2): Kinshuk Jain, Sarah C. McCarley, Ghazel Mukhtar, Anna Ferlin, Andrew Fleming, Deborah J. Morris-Rosendahl, and Claire L. Shovlin. Pathogenic variant frequencies in hereditary haemorrhagic telangiectasia support clinical evidence of protection from myocardial infarction. Journal of Clinical Medicine, 13:250, Dec 2023. URL: https://doi.org/10.3390/jcm13010250, doi:10.3390/jcm13010250. This article has 9 citations.

20. (shovlin2020mutationalandphenotypic pages 23-24): Claire L. Shovlin, Ilenia Simeoni, Kate Downes, Zoe C. Frazer, Karyn Megy, Maria E. Bernabeu-Herrero, Abigail Shurr, Jennifer Brimley, Dilipkumar Patel, Loren Kell, Jonathan Stephens, Isobel G. Turbin, Micheala A. Aldred, Christopher J. Penkett, Willem H. Ouwehand, Luca Jovine, and Ernest Turro. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood, 136:1907-1918, Oct 2020. URL: https://doi.org/10.1182/blood.2019004560, doi:10.1182/blood.2019004560. This article has 78 citations and is from a highest quality peer-reviewed journal.

21. (whitehead2024investigationofthe pages 2-3): Kevin J. Whitehead, Doruk Toydemir, Whitney Wooderchak-Donahue, Gretchen M. Oakley, Bryan McRae, Angelica Putnam, Jamie McDonald, and Pinar Bayrak-Toydemir. Investigation of the genetic determinants of telangiectasia and solid organ arteriovenous malformation formation in hereditary hemorrhagic telangiectasia (hht). International Journal of Molecular Sciences, 25:7682, Jul 2024. URL: https://doi.org/10.3390/ijms25147682, doi:10.3390/ijms25147682. This article has 16 citations.

22. (alsamkari2024pomalidomideforepistaxis pages 6-8): Hanny Al-Samkari, Raj S. Kasthuri, Vivek N. Iyer, Allyson M. Pishko, Jake E. Decker, Clifford R. Weiss, Kevin J. Whitehead, Miles B. Conrad, Marc S. Zumberg, Jenny Y. Zhou, Joseph Parambil, Derek Marsh, Marianne Clancy, Lauren Bradley, Lisa Wisniewski, Benjamin A. Carper, Sonia M. Thomas, and Keith R. McCrae. Pomalidomide for epistaxis in hereditary hemorrhagic telangiectasia. New England Journal of Medicine, 391:1015-1027, Sep 2024. URL: https://doi.org/10.1056/nejmoa2312749, doi:10.1056/nejmoa2312749. This article has 38 citations and is from a highest quality peer-reviewed journal.

23. (alvarezhernandez2023tacrolimusasa pages 2-4): Paloma Álvarez-Hernández, José Luis Patier, Sol Marcos, Vicente Gómez del Olmo, Laura Lorente-Herraiz, Lucía Recio-Poveda, Luisa María Botella, Adrián Viteri-Noël, and Virginia Albiñana. Tacrolimus as a promising drug for epistaxis and gastrointestinal bleeding in hht. Journal of Clinical Medicine, 12:7410, Nov 2023. URL: https://doi.org/10.3390/jcm12237410, doi:10.3390/jcm12237410. This article has 9 citations.

24. (ahmad2024managingepistaxisin pages 3-3): Youssef El Sayed Ahmad, S. Kajal, and Akaber M. Halawi. Managing epistaxis in hereditary haemorrhagic telangiectasia: a comprehensive narrative review of therapeutic horizons. The Journal of Laryngology & Otology, 139:389-394, Nov 2024. URL: https://doi.org/10.1017/s0022215124002093, doi:10.1017/s0022215124002093. This article has 1 citations.

25. (NCT04646356 chunk 1): Tacrolimus Trial for Hereditary Hemorrhagic Telangiectasia (HHT). Unity Health Toronto. 2020. ClinicalTrials.gov Identifier: NCT04646356

26. (NCT03850964 chunk 1): Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz). Cure HHT. 2023. ClinicalTrials.gov Identifier: NCT03850964