Hereditary Hemorrhagic Telangiectasia

Executive Summary

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular disorder affecting approximately 1 in 5,000 individuals worldwide (MONDO:0008535). It is caused by loss-of-function mutations in the BMP9/10-ALK1-ENG-SMAD4 signaling pathway, which normally maintains vascular quiescence. HHT is the second most common inherited bleeding disorder worldwide (after von Willebrand disease) and is characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs) that lead to chronic bleeding, iron deficiency anemia, and organ-specific complications including stroke, brain abscess, high-output cardiac failure, and pulmonary hemorrhage. Despite its prevalence, HHT remains significantly underdiagnosed, with 63% of patients not diagnosed until mid-to-late adulthood despite symptom onset typically by age 13. A paradigm shift in treatment is underway, with antiangiogenic therapies (particularly pomalidomide, the first drug to show efficacy in a Phase 3 RCT) offering disease-modifying potential, though no FDA/EMA-approved HHT-specific therapy exists yet.

1. Disease Identity and Classification

2. Genetic Basis

2.1 Causative Genes

HHT is caused by heterozygous loss-of-function mutations in genes encoding components of the BMP9/10 signaling pathway:

• ENG and ACVRL1 mutations account for ~97% of genetically confirmed cases.
• ENG mutations are widely distributed across the gene without mutational hot spots; truncating mutations are associated with more severe phenotypes than missense mutations.
• ACVRL1 mutations cluster in exons 5-10 (the serine/threonine kinase domain).
• SMAD4 mutations produce the unique Juvenile Polyposis-HHT overlap syndrome (JP-HHT).
• Approximately 10-15% of clinically diagnosed HHT patients remain genetically unresolved, suggesting additional undiscovered loci.

2.2 Inheritance and Penetrance

• Inheritance: Autosomal dominant with highly variable expressivity
• Penetrance: Age-dependent; ~90% penetrant for epistaxis by age 40
• De novo mutations: Rare but documented
• Visceral AVMs accumulate throughout the lifetime
• Significant intrafamilial variability suggests modifier genes and/or stochastic somatic events

2.3 Mutation Spectrum

• Haploinsufficiency is the predominant mechanism for both ENG and ALK1 mutations
• Mutation types include: missense, nonsense, splice-site, frameshift, and large deletions/duplications
• No common founder mutation worldwide; however, population-specific founder effects exist (see Epidemiology)

3. Molecular Pathogenesis

3.1 The BMP9/10-ALK1-ENG-SMAD4 Signaling Pathway

The core disease pathway operates as follows:

1. Circulating ligands BMP9 and BMP10 (encoded by GDF2) bind to the co-receptor Endoglin (ENG) on endothelial cell surfaces
2. Endoglin facilitates ligand presentation to the signaling receptor ALK1 (ACVRL1)
3. ALK1 phosphorylates downstream SMAD1/5/8, which complex with SMAD4
4. The SMAD complex translocates to the nucleus to activate transcriptional programs for vascular quiescence

This pathway actively: - Suppresses PI3K/AKT/mTOR signaling (which drives angiogenesis) - Maintains Notch signaling (essential for arterial-venous identity) - Antagonizes VEGF-driven angiogenesis - Regulates casein kinase 2 (CK2) expression

3.2 Two-Hit Pathogenesis Model

HHT pathogenesis follows a two-hit model, explaining why patients with systemic heterozygous mutations develop focal vascular lesions:

Hit 1 (Germline): Inherited heterozygous loss-of-function mutation in ENG, ACVRL1, SMAD4, or GDF2.

Hit 2 (Somatic): Loss of heterozygosity (LOH) or somatic second mutation in endothelial cells, resulting in biallelic loss and complete pathway inactivation at focal sites.

Environmental Triggers (required for AVM development): - VEGF upregulation from angiogenic stimuli (wounding, inflammation, infection) - Hemodynamic shear stress and blood flow - Hormonal changes (pregnancy, puberty)

3.3 Molecular Consequences of Pathway Loss

When the BMP9/10-ALK1-ENG-SMAD4 pathway is inactivated: - Unopposed VEGF-driven angiogenesis occurs - PI3K/AKT activation drives endothelial cell proliferation - Loss of arterial-venous specification (Notch pathway downregulation) - Endothelial cells lose capillary identity and enter the cell cycle - Direct arteriovenous connections form (AVMs), bypassing normal capillary beds

RNA-seq analysis of BMP9-knockout mice identified >2,000 differentially expressed genes in liver sinusoidal endothelial cells, confirming massive transcriptional dysregulation.

4. Epidemiology

4.1 Prevalence

4.2 Geographic Variation in Subtype Distribution

• HHT2 (ACVRL1) predominates in Southern Europe (Italy, France, Spain)
• HHT1 (ENG) predominates in Northern Europe and East Asia (Japan)
• The ratio varies significantly by region and is likely influenced by founder effects

4.3 Founder Effects

The most dramatic example is the Netherlands Antilles, where 7 of 10 studied families share an ENG exon 1 splice-site mutation, likely introduced into the African slave population by a Dutch colonizer during the colonial era. This single ancestral mutation accounts for the ~1:1,300 prevalence — the highest in the world.

4.4 Diagnostic Delay

Despite symptom onset typically by age 13, 63% of patients are not diagnosed until mid-to-late adulthood (CHORUS registry, n=600), representing a median diagnostic delay of ~25-35 years. This delay reflects: - Low clinical awareness among general practitioners - Gradual, progressive symptom development - Attribution of epistaxis to benign causes - Insufficient family history screening

5. Clinical Manifestations

5.1 Diagnostic Criteria (Curaçao Criteria)

Clinical diagnosis is based on the Curaçao criteria. Meeting 3 or more = definite HHT, 2 = possible HHT:

1. Spontaneous, recurrent epistaxis
2. Mucocutaneous telangiectases at characteristic sites (lips, oral cavity, fingers, nose)
3. Visceral AVMs (pulmonary, hepatic, cerebral, spinal, GI)
4. First-degree relative with HHT

Important limitations: Curaçao criteria are specific but not sensitive in children due to age-dependent development of features. Genetic testing is recommended for all ages, especially in children of affected families, and can provide definitive diagnosis.

5.2 Prevalence of Clinical Features (CHORUS Registry, n=600)

5.3 Genotype-Phenotype Correlations

6. Organ-Specific Complications

6.1 Pulmonary AVMs and Paradoxical Embolism

PAVMs create right-to-left shunts that bypass the pulmonary capillary filter, causing: - Hypoxemia from deoxygenated blood bypassing the lungs - Paradoxical embolism → ischemic stroke (11% arterial TE), TIA - Brain abscess (5-13% of PAVM patients) from infected emboli - Hemothorax/hemoptysis especially during pregnancy - Antibiotic prophylaxis during dental procedures is recommended for PAVM patients

6.2 Hepatic AVMs

Three types of hepatic shunting cause distinct clinical syndromes: 1. Hepatic artery → Hepatic vein (arteriosystemic): High-output cardiac failure 2. Hepatic artery → Portal vein (arterioportal): Portal hypertension 3. Portal vein → Hepatic vein (portosystemic): Hepatic encephalopathy

Most hepatic AVMs are asymptomatic. Bevacizumab can reduce cardiac index. Liver transplantation is reserved for severe cases. Hepatic AVM embolization is contraindicated due to risk of hepatic necrosis.

6.3 Brain AVMs

• Present in 9-16% of HHT patients (predominantly HHT1)
• Intracranial hemorrhage risk ~0.7% per year
• Often multiple and cortical in location
• Spinal AVMs reported in HHT2
• Screening recommended in childhood (can identify treatable lesions)

6.4 GI Bleeding

• Chronic GI bleeding in ~30% of adults, increasing with age
• Contributes to worsening anemia on top of epistaxis
• May require endoscopic treatment (argon plasma coagulation)

6.5 Manganese Deposition

HHT patients with hepatic AVMs show T1-hyperintensity of basal ganglia on MRI due to manganese deposition, associated with tremor, restless leg syndrome, and memory problems.

7. Special Populations

7.1 JP-HHT Overlap Syndrome (SMAD4 Mutations)

SMAD4 mutations produce a unique and particularly dangerous overlap of: - Juvenile Polyposis Syndrome: Colonic polyps (87%), gastric polyps (67%), tubular adenomas (50%) - HHT vascular malformations: PAVMs (42%), epistaxis, telangiectases - High cancer risk: Colorectal cancer in 25% at median age 33 years - High surgical rate: Colectomy (43%), gastrectomy (42%) - Overall mortality: 14% in available cohorts

All patients with SMAD4 mutations require dual surveillance: GI cancer screening AND vascular AVM screening.

7.2 Pregnancy and HHT

Pregnancy represents a high-risk period for HHT women: - Maternal mortality: ~1.0% per pregnancy (vs ~0.02% general population — 50-fold increase) - Severe complications: 2.7-6.8% of pregnancies - Most complications from PAVM rupture (hemothorax, hemoptysis, severe hypoxemia) - Complications occur mainly in 2nd/3rd trimester in undiagnosed/unscreened patients - Pre-conception PAVM screening and embolization is strongly recommended

7.3 Pediatric HHT

• Curaçao criteria are insensitive in children
• Genetic testing recommended for all at-risk children
• Early screening for pulmonary and brain AVMs recommended
• PAVMs can develop throughout life; repeated screening every 5 years recommended
• AVFs in children are highly suggestive of HHT

8. Diagnosis

8.1 Clinical Diagnosis

• Curaçao criteria: ≥3 of 4 criteria = definite HHT; 2 = possible
• Limitations in pediatric population (age-dependent features)

8.2 Genetic Testing

• Recommended for all suspected cases and at-risk family members
• Sequencing of ENG, ACVRL1, SMAD4 (and GDF2 if negative)
• Includes deletion/duplication analysis (MLPA)
• Positive genetic test is definitive regardless of age or symptoms

8.3 Screening Protocols (2020 International Guidelines)

The Second International HHT Guidelines (2020) recommend: - Pulmonary AVMs: Contrast echocardiography (bubble study); CT chest if positive - Brain AVMs: MRI brain at diagnosis (all ages) - Hepatic AVMs: Doppler ultrasound if symptomatic - Repeat screening: PAVMs every 5 years even if initially negative - Antibiotic prophylaxis: For dental procedures in patients with PAVMs

9. Treatment and Therapeutic Landscape

9.1 Current Standard of Care

Mild bleeding: - Nasal humidification, topical care - Antifibrinolytics (tranexamic acid — oral or topical)

Moderate-to-severe bleeding: - Iron replacement (oral and/or IV) - Systemic antiangiogenic therapy (off-label): - Bevacizumab (IV anti-VEGF) — most evidence for hepatic AVMs and severe epistaxis - Pomalidomide (oral immunomodulatory/antiangiogenic) — positive Phase 3 RCT - Pazopanib (oral VEGF receptor TKI) - Thalidomide (oral; limited by toxicity) - Laser ablation, cauterization for nasal telangiectases - Endoscopic APC for GI telangiectases

Visceral AVMs: - Pulmonary AVMs: Transcatheter embolization - Brain AVMs: Embolization, surgery, or radiosurgery at specialized centers - Hepatic AVMs: Bevacizumab as medical therapy; liver transplant for severe cases (embolization contraindicated)

9.2 Landmark Pomalidomide Phase 3 Trial (2024)

The first positive Phase 3 RCT for any HHT therapy: - Design: Randomized, placebo-controlled; n=144 (2:1 ratio) - Intervention: Pomalidomide 4 mg daily for 24 weeks - Primary outcome: Change in Epistaxis Severity Score (ESS, 0-10 scale) - Result: Mean ESS difference -0.94 points (95% CI -1.57 to -0.31; P=0.004) - Clinical significance: Exceeds the minimal clinically important difference of 0.71 points - Trial stopped early for efficacy at planned interim analysis - Also improved HHT-specific quality of life

This positions pomalidomide as a potential first-ever FDA-approved therapy for HHT.

9.3 Emerging Therapies and Pipeline

• Aflibercept: VEGF/PlGF trap; effective after bevacizumab resistance
• Standardized outcome criteria now established (2025 GRMAB consensus) to facilitate future trials
• ALK1 overexpression: Preclinical mouse data showing therapeutic potential
• Novel HHT-specific therapies in development following pathway understanding
• Tacrolimus (FK506): Under investigation as ALK1 activator

9.4 Unmet Needs

• No FDA- or EMA-approved HHT-specific therapy (as of 2025)
• No cure; all therapies are symptom-modifying
• Need for biomarkers to predict AVM development and progression
• Need for therapies that prevent new AVM formation
• Insufficient clinical awareness causing diagnostic delay

10. Sex Differences

Clinically significant sex differences exist in HHT (n=242; 142 women, 100 men): - Women have more hepatic AVMs (28.2% vs 13%), pulmonary AVMs (35.2% vs 23%), and require invasive treatment more often (28.2% vs 16%) - Men have more duodenal telangiectases (21% vs 9.8%) and more ED visits - Women have higher hepatic involvement scores (3.38±1.2 vs 2.03±1.2) - Splenic artery aneurysms are more common in women (OR=2.12, P=0.04) - These differences are maintained across both HHT1 and HHT2 subtypes - Hormonal influences on angiogenesis may explain female preponderance of visceral AVMs

11. Prognosis and Survival

• HHT-associated PAH: 1-year survival 77.8%, 3-year survival 53.3% — significantly worse than matched idiopathic PAH (P=0.047)
• Liver transplantation: 86% post-transplant survival with resolution of heart failure
• Pregnancy: ~1% maternal mortality per pregnancy (50x general population)
• Splenic artery aneurysms: 24.7% of HHT patients vs 5.4% controls (P<0.001), suggesting a systemic arteriopathy beyond AVMs
• Subaortic membranes: Novel cardiac finding in HHT-HOCF patients (exclusively female, mean cardiac output 12.1 L/min)

12. Endoglin (CD105) as a Cancer Biomarker

The same protein mutated in HHT1 (endoglin/CD105) plays a major role in cancer biology: - Selectively highly expressed on tumor vasculature across multiple cancer types - Correlates with poor survival in cancer patients - Soluble endoglin elevated in metastatic colorectal cancer - Anti-endoglin antibody TRC105 (Carotuximab) developed as anti-cancer therapy - This creates a translational bridge: HHT research informs cancer biology and vice versa - Anti-angiogenic drugs used in HHT (bevacizumab) are established cancer therapies

13. Clinical Management Challenges

The Thrombosis-Bleeding Paradox

HHT presents a unique clinical paradox: patients have an inherited bleeding disorder yet face elevated thrombotic risk: - VTE: 7% (CHORUS registry) - Arterial thromboembolism: 11% (paradoxical embolism through PAVMs) - Atrial fibrillation: Common in high-output cardiac states from hepatic AVMs

Anticoagulation is frequently indicated but poorly tolerated — the majority of HHT-AF patients require premature dose-reduction or discontinuation due to worsening mucosal bleeding. Emerging solutions include: - Left atrial appendage occlusion (device-based stroke prevention without long-term anticoagulation) - Concurrent antiangiogenic therapy to stabilize telangiectases while anticoagulating - Novel topical therapies (intranasal timolol gel, propranolol) to control epistaxis locally

Contraindicated/High-Risk Medications

• Anticoagulants: Classified as Level 1 pharmacotherapy risk (FDA-driven) for HHT
• Antiplatelet agents: Poorly tolerated; worsens bleeding
• Hepatic AVM embolization: Contraindicated due to hepatic necrosis risk
• Bevacizumab in pregnancy: Teratogenic; timing considerations for women of childbearing age

Differential Diagnosis

Conditions that may mimic HHT include: - CREST syndrome/scleroderma (telangiectases, but different pattern and associated features) - Capillary malformation-AVM syndrome (CM-AVM) caused by RASA1 or EPHB4 mutations - Ataxia-telangiectasia (telangiectases + neurological features) - Sporadic AVMs (lack family history and systemic features) - Drug-induced telangiectases (e.g., trastuzumab emtansine can mimic HHT)

14. Key Findings Summary

11. Limitations

• This report is based on published literature and public databases; no primary patient data were analyzed
• Prevalence estimates may underrepresent true burden due to underdiagnosis
• Genotype-phenotype correlations are population-dependent and may not apply universally
• Treatment efficacy data is largely from uncontrolled studies except the pomalidomide RCT
• Long-term natural history data from registries (CHORUS) is still being accumulated
• Biomarker discovery for HHT remains an active area of research with limited validated markers

12. Future Directions

1. FDA/EMA approval of pomalidomide or other antiangiogenic agents for HHT
2. Biomarker development for predicting AVM formation and monitoring treatment response
3. Gene therapy approaches to restore pathway function
4. Comparative clinical trials enabled by newly standardized outcome criteria
5. Improved screening programs to reduce the 25-35 year diagnostic delay
6. Mechanistic studies of modifier genes and stochastic factors driving variable expressivity
7. Precision medicine approaches matching therapy to genotype

References (Key PMIDs)

• PMID: 37695357 — 14th HHT International Scientific Conference summary
• PMID: 38357927 — HHT signaling insights to therapeutic advances (2024 review)
• PMID: 41843464 — CHORUS registry initial report (2026)
• PMID: 39292928 — Pomalidomide Phase 3 RCT (2024)
• PMID: 32894695 — Second International HHT Guidelines (2020)
• PMID: 38864625 — How I treat bleeding in HHT (2024)
• PMID: 29976569 — SMAD4 prevents flow-induced AVMs via CK2
• PMID: 38502919 — BMP9 as key player in endothelial identity
• PMID: 17388964 — HHT clinical features in ENG and ALK1 carriers
• PMID: 41915210 — Genotype-phenotype correlations for CVMs (2026)
• PMID: 31910869 — HHT and pregnancy review
• PMID: 38627541 — JP-HHT outcomes in Scotland
• PMID: 10982033 — Netherlands Antilles founder effect
• PMID: 40648852 — Somatic mutation in HHT pathogenesis
• PMID: 40662351 — Standardization of HHT outcome criteria (2025)
• PMID: 32122373 — Gender differences in HHT severity
• PMID: 29480092 — HHT-PAH clinical characteristics and prognosis
• PMID: 31971937 — Splenic artery aneurysms in HHT
• PMID: 33375670 — Endoglin targeting: lessons learned (cancer)
• PMID: 33054561 — Subaortic membranes in HHT-HOCF
• PMID: 37340288 — Antithrombotic therapy for AF in HHT
• PMID: 41527333 — Pharmacotherapy risks in rare genetic diseases (2026)

Report generated through systematic literature review and biomedical database analysis. 16 key findings confirmed with cited evidence from 110+ publications across 5 visualizations.