Hereditary Hemorrhagic Telangiectasia

Mendelian MONDO:0019180 Pathograph 12 Vascular Malformation Bleeding Disorder

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal dominant vascular dysplasia caused by loss-of-function mutations in genes encoding proteins of the BMP/TGF-beta signaling pathway. Up to 90% of cases are caused by mutations in ENG (endoglin, HHT1) or ACVRL1 (ALK1, HHT2), with SMAD4 and GDF2 less frequently responsible. The disease is characterized by mucocutaneous telangiectases causing recurrent epistaxis and gastrointestinal bleeding, and arteriovenous malformations (AVMs) in the lungs, liver, and brain that can cause serious complications including stroke, brain abscess, and high-output cardiac failure. Estimated prevalence is approximately 1 in 5,000.

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2
Definitions
1
Inheritance
6
Pathophys.
15
Phenotypes
12
Pathograph
4
Genes
8
Treatments
4
Subtypes
1
Trials
1
References
3
Deep Research
📘

Definitions

2
Clinical syndrome definition for hereditary hemorrhagic telangiectasia
HHT is an inherited vascular dysplasia caused by haploinsufficiency of BMP signaling pathway components and characterized by recurrent mucocutaneous bleeding together with organ AVMs.
CASE_DEFINITION General clinical framing of hereditary hemorrhagic telangiectasia
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway."
Defines HHT as an autosomal dominant vascular dysplasia caused by loss-of-function of BMP-pathway genes.
Curaçao clinical diagnostic criteria framework
Clinical diagnosis uses the Curaçao criteria: recurrent spontaneous epistaxis, characteristic mucocutaneous telangiectases, visceral AVMs, and an affected first-degree relative. Three criteria establish definite HHT and two support possible HHT.
DIAGNOSTIC_CRITERIA Clinical diagnosis of suspected hereditary hemorrhagic telangiectasia
Show evidence (2 references)
PMID:33801690 SUPPORT Human Clinical
"Diagnosing HHT can be done through genetic testing or by the use of the clinical Curaçao Criteria framework."
Establishes the Curaçao framework as a standard clinical diagnostic approach for HHT.
PMID:33801690 SUPPORT Human Clinical
"A diagnosis of HHT is considered confirmed if at least three criteria are present, and possible with two criteria, as listed above [6]."
Supports the clinical threshold for definite versus possible HHT diagnosis.
👪

Inheritance

1
Autosomal dominant HP:0000006
HHT is transmitted as an autosomal dominant disorder caused by heterozygous loss-of-function variants in BMP/TGF-beta pathway genes, most commonly ENG or ACVRL1.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway."
Directly supports autosomal dominant inheritance of HHT.
◆

Subtypes

4
HHT Type 1 (ENG) MONDO:0008535
ENG link
ENG-related subtype with higher prevalence of pulmonary and cerebral AVMs, mucocutaneous telangiectasia, and epistaxis than HHT2.
Show evidence (1 reference)
PMID:20345718 SUPPORT Human Clinical
"HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1)."
Defines ENG-related HHT1 as the subtype caused by pathogenic ENG variants.
HHT Type 2 (ACVRL1) MONDO:0010880
ACVRL1 link
ACVRL1-related subtype with greater hepatic AVM burden and higher risk of pulmonary hypertension than HHT1.
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"HHT type 2 is caused by a mutation in the ACVRL1-gene (cytogenetic location 12q13.13; OMIM600376, encoding for the ALK1 protein) and has a higher prevalence of hepatic AVMs compared to HHT type 1 [2,9,11]."
Defines ACVRL1-related HHT2 and its stronger hepatic AVM phenotype.
Juvenile Polyposis/HHT Syndrome (SMAD4) MONDO:0008278
SMAD4 link
Rare syndromic subtype in which juvenile polyposis co-occurs with HHT vascular features.
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"Mutations in the SMAD4 gene (cytogenetic location 18q21.2; OMIM175050) can cause a rare syndrome that is a combination of juvenile polyposis and HHT."
Supports a clinically distinct SMAD4 overlap subtype combining HHT with juvenile polyposis.
HHT Type 5 (GDF2) MONDO:0014217
GDF2 link
Rare BMP9/GDF2-related subtype with an HHT-like vascular phenotype.
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"HHT type 5 is caused by a mutation in the Growth Differentiation Factor 2 gene (GDF-2) that codes for the Bone Morphogenetic Protein 9 (BMP9) (OMIM615506) which expresses an HHT-like phenotype and is therefore classified as HHT type 5 [14,15]."
Supports a rare GDF2/BMP9-related HHT-like molecular subtype.
⚙

Pathophysiology

6
Impaired BMP/TGF-beta Signaling in Vascular Endothelium
Loss-of-function mutations in ENG or ACVRL1 disrupt BMP/TGF-beta signaling in vascular endothelial cells. Endoglin and ALK1 are co-receptors essential for proper angiogenesis, vessel maturation, and stabilization. Their loss leads to dysregulated angiogenesis and formation of fragile, abnormal vascular structures including telangiectases and arteriovenous malformations.
endothelial cell link
BMP signaling pathway link angiogenesis link
Downstream
Defective Endothelial Tubulogenesis and Pericyte Recruitment Impaired ALK1/endoglin signaling compromises endothelial maturation and mural-cell recruitment during angiogenesis.
VEGF-Triggered AVM Formation Haploinsufficient endothelium becomes vulnerable to angiogenic triggers such as injury or VEGF stimulation.
Show evidence (3 references)
PMID:39788978 SUPPORT Human Clinical
"Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway."
Confirms HHT as caused by loss-of-function in BMP pathway genes.
PMID:33801690 SUPPORT Human Clinical
"All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization."
Confirms the role of TGF-beta pathway in angiogenesis and vessel maturation relevant to HHT pathophysiology.
PMID:28796572 SUPPORT Human Clinical
"Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease."
Confirms haploinsufficiency as the pathogenic mechanism in HHT.
Defective Endothelial Tubulogenesis and Pericyte Recruitment
ENG and ACVRL1 deficiency alters endothelial tubulogenesis and mural-cell recruitment, producing abnormal endothelial hyperplasia and unstable vascular morphogenesis that predispose to telangiectases and AVMs.
endothelial cell link pericyte link
Downstream
Chronic Bleeding from Telangiectases Fragile mucocutaneous and gastrointestinal telangiectases bleed recurrently.
Vascular Shunting Through Visceral AVMs Abnormally direct artery-to-vein connections in lung, liver, and CNS create clinically important shunts.
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"Mutations in ENG and ACVRL-1 disrupt TGF-β signaling, altering EC tubulogenesis and pericyte recruitment, causing abnormal endothelial hyperplasia and abnormal vascular morphogenesis in HHT [2,18]."
Links ENG/ACVRL1 haploinsufficiency to failed endothelial tubulogenesis and pericyte recruitment in HHT vascular lesions.
VEGF-Triggered AVM Formation
HHT vascular lesions show organ specificity and appear to require local angiogenic or injury-related triggers, consistent with a second-hit model in which VEGF stimulation or tissue damage precipitates AVM formation in haploinsufficient endothelium.
endothelial cell link
angiogenesis link
Downstream
Vascular Shunting Through Visceral AVMs Triggered AVM growth creates clinically relevant pulmonary and systemic shunts.
Show evidence (1 reference)
PMID:33801690 SUPPORT Model Organism
"Several studies with knock-out (KO) animal models (KO ENG and ACRVL-1) have shown that a local external trigger such as damage or stimulation of VEGF causes the formation of AVMs [8,48,53]."
Supports a second-hit model in which local angiogenic triggers such as VEGF stimulation precipitate AVM formation.
Somatic Second-Hit Mutation and AVM Formation
While germline haploinsufficiency underlies HHT, focal lesion formation follows a two-hit model analogous to tumor suppressor genes. Somatic second-hit loss-of-function mutations in ENG or ACVRL1 have been identified in telangiectasias and solid organ AVMs, leading to biallelic loss. This explains the focal nature of vascular lesions despite systemic haploinsufficiency and why only specific vascular beds develop AVMs.
endothelial cell link
Downstream
Impaired BMP/TGF-beta Signaling in Vascular Endothelium Complete biallelic loss of ENG or ACVRL1 in focal endothelial clones abolishes BMP/TGF-beta signaling locally, triggering AVM formation.
Show evidence (2 references)
PMID:39062925 SUPPORT Human Clinical
"Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias."
Confirms somatic second-hit mutations in HHT causative genes in telangiectasia lesions.
PMID:39062925 SUPPORT Human Clinical
"This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations."
Extends the two-hit model to nasal telangiectasias and solid organ AVMs including brain, lung, liver, and gallbladder.
Chronic Bleeding from Telangiectases
Recurrent epistaxis and gastrointestinal telangiectatic bleeding cause chronic iron loss, iron deficiency, and symptomatic anemia in many adults with HHT.
Downstream
Epistaxis Nasal telangiectases cause recurrent spontaneous nosebleeds.
Gastrointestinal Hemorrhage Gastrointestinal telangiectases cause chronic or severe GI bleeding.
Iron Deficiency Anemia Chronic blood loss depletes iron stores and leads to anemia.
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
Connects recurrent telangiectatic bleeding with iron deficiency and anemia in adult HHT.
Vascular Shunting Through Visceral AVMs
Pulmonary AVMs create right-to-left shunts that bypass capillary filtration, whereas systemic AVMs, especially hepatic lesions, create left-to-right shunts with high cardiac output and downstream embolic or hemodynamic complications.
Downstream
Ischemic Stroke Right-to-left shunting through pulmonary AVMs permits paradoxical emboli and septic emboli to reach the brain.
Dyspnea Pulmonary shunting reduces gas exchange efficiency and contributes to exertional dyspnea.
High-output cardiac failure Systemic AVMs, particularly hepatic shunts, can drive chronic high-output circulatory stress and eventual heart failure.
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess) and..."
Summarizes the major organ-specific shunt physiology and its key neurologic and hemodynamic consequences in HHT.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hereditary Hemorrhagic Telangiectasia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Blood 3
Epistaxis VERY_FREQUENT Epistaxis (HP:0000421)
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
Recurrent epistaxis is the most frequent HHT manifestation.
Iron Deficiency Anemia Iron deficiency anemia (HP:0001891)
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
Directly supports iron deficiency anemia as a major adult HHT consequence of chronic telangiectatic bleeding.
Gastrointestinal Hemorrhage FREQUENT Gastrointestinal hemorrhage (HP:0002239)
Show evidence (1 reference)
PMID:20345718 SUPPORT Human Clinical
"Gastrointestinal telangiectases are frequent and may cause severe bleeding."
GI bleeding from telangiectases is a well-recognized HHT complication.
Cardiovascular 4
Mucocutaneous Telangiectases VERY_FREQUENT Telangiectasia (HP:0001009)
Show evidence (1 reference)
PMID:20345718 SUPPORT Human Clinical
"Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by severe and recurrent nosebleeds, mucocutaneous telangiectases, and, in some cases, life-threatening visceral arteriovenous malformations"
Mucocutaneous telangiectases are a defining feature of HHT.
Ischemic Stroke Stroke (HP:0001297)
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
Pulmonary AVMs cause paradoxical embolization leading to stroke or brain abscess.
High-output cardiac failure Congestive heart failure (HP:0001635)
Show evidence (2 references)
PMID:33801690 SUPPORT Human Clinical
"Post-capillary PH arises from a hyperdynamic state caused by an increased cardiac output (CO), which can cause heart failure in the long term"
Supports heart failure as a downstream consequence of chronic high-output physiology in HHT-associated shunting states.
PMID:33801690 SUPPORT Human Clinical
"Within HHT, the increased CO (sometimes up to three times normal) is frequently caused by the HAVM-related shunt"
Links the high-output state specifically to hepatic AVM-related shunting in HHT.
Pulmonary Arterial Hypertension OCCASIONAL Pulmonary arterial hypertension (HP:0002092)
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway."
Confirms pulmonary arterial hypertension as a recognized complication in HHT, driven by TGF-beta pathway disruption.
Respiratory 2
Dyspnea Dyspnea (HP:0002094)
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"Diagnosing PH in HHT can be challenging. Symptoms of HHT, such as fatigue, dyspnea and exercise intolerance, resemble those of PH due to anemia, hypoxemia associated with PAVMs, inadequate sleep due to epistaxis, and the psychological burden of a chronic illness [2,6,75]."
Supports dyspnea as a clinically important respiratory manifestation in HHT, often driven by pulmonary AVM-related hypoxemia or pulmonary vascular complications.
Hemoptysis OCCASIONAL Hemoptysis (HP:0002105)
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"PAVMs can further result in rare but severe complications like massive hemoptysis, hemothorax, cerebrovascular events, and abscesses"
Hemoptysis is a recognized severe complication of pulmonary AVMs in HHT.
Constitutional 1
Fatigue FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"Symptoms of HHT, such as fatigue, dyspnea and exercise intolerance, resemble those of PH due to anemia, hypoxemia associated with PAVMs, inadequate sleep due to epistaxis, and the psychological burden of a chronic illness"
Directly names fatigue as a symptom of HHT driven by anemia and hypoxemia.
Other 5
Pulmonary Arteriovenous Malformation FREQUENT Pulmonary arteriovenous malformation (HP:0006548)
Show evidence (2 references)
PMID:39788978 SUPPORT Human Clinical
"Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
Confirms pulmonary AVMs as a major HHT manifestation with right-to-left shunting complications.
PMID:30251589 SUPPORT Human Clinical
"The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2."
Confirms higher prevalence of pulmonary AVMs in HHT1.
Cerebral Arteriovenous Malformation OCCASIONAL Cerebral arteriovenous malformation (HP:0002408)
Show evidence (2 references)
PMID:20345718 SUPPORT Human Clinical
"life-threatening visceral arteriovenous malformations of various types, including pulmonary, hepatic, cerebral, and spinal"
Cerebral AVMs are a recognized visceral manifestation of HHT.
PMID:20301525 SUPPORT Human Clinical
"Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic."
GeneReviews confirms brain AVMs as a major HHT complication.
Transient Ischemic Attack OCCASIONAL Transient ischemic attack (HP:0002326)
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
Ischemic cerebrovascular events including TIA result from paradoxical embolization through pulmonary AVMs.
Brain Abscess OCCASIONAL Brain abscess (HP:0030049)
Show evidence (2 references)
PMID:39788978 SUPPORT Human Clinical
"right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
Brain abscess results from paradoxical embolization through pulmonary AVMs.
PMID:30251589 SUPPORT Human Clinical
"Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications."
Uppsala cohort shows high prevalence of cerebral complications including brain abscess.
Hepatic Arteriovenous Malformation FREQUENT Hepatic arteriovenous malformation (HP:0006574)
Show evidence (2 references)
PMID:30251589 SUPPORT Human Clinical
"The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2."
Confirms hepatic AVMs are enriched in HHT2 patients.
PMID:20301525 SUPPORT Human Clinical
"Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic."
Hepatic AVMs are a major visceral manifestation of HHT.
🧬

Genetic Associations

4
ENG (Pathogenic Mutations)
Autosomal dominant inheritance
Show evidence (3 references)
PMID:20345718 SUPPORT Human Clinical
"HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1)."
Confirms ENG mutations as the cause of HHT type 1.
PMID:39062925 SUPPORT Human Clinical
"Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation."
Somatic second-hit mutations in ENG identified in telangiectasia and AVM tissues, supporting biallelic loss as mechanism for focal lesion formation.
PMID:20301525 SUPPORT Human Clinical
"HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability and age-related penetrance of individual manifestations."
Confirms autosomal dominant inheritance with age-related penetrance.
ACVRL1 (Pathogenic Mutations)
Autosomal dominant inheritance
Show evidence (2 references)
PMID:20345718 SUPPORT Human Clinical
"HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1)."
Confirms ACVRL1 mutations as the cause of HHT type 2.
PMID:30251589 SUPPORT Human Clinical
"Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2."
Confirms genotype-phenotype correlations for ACVRL1 mutations including hepatic AVM enrichment.
SMAD4 (Pathogenic Mutations)
Autosomal dominant inheritance
Show evidence (2 references)
PMID:39788978 SUPPORT Human Clinical
"Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT."
Confirms SMAD4 as a less frequent HHT gene.
PMID:20345718 SUPPORT Human Clinical
"mutations in MADH4 (encoding SMAD4), which cause a juvenile polyposis/HHT overlap syndrome, have been described"
Confirms the JP-HHT overlap syndrome phenotype.
GDF2 (Pathogenic Mutations)
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"HHT type 5 is caused by a mutation in the Growth Differentiation Factor 2 gene (GDF-2) that codes for the Bone Morphogenetic Protein 9 (BMP9) (OMIM615506) which expresses an HHT-like phenotype and is therefore classified as HHT type 5 [14,15]."
Supports GDF2/BMP9 as a rare molecular cause of an HHT-like subtype.
💊

Treatments

8
Epistaxis Management
Action: supportive care MAXO:0000950
Management of epistaxis focuses on local bleeding control with escalation to procedural or surgical approaches for refractory disease.
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members."
Supports epistaxis control as a core therapeutic goal in HHT.
Iron Replacement Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: iron ↗
Iron supplementation (oral or intravenous) is essential for managing iron deficiency anemia from chronic bleeding.
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members."
Supports active treatment of iron deficiency, with or without anemia, as a central HHT management goal.
Tranexamic Acid
Action: Pharmacotherapy NCIT:C15986
Agent: tranexamic acid ↗
Oral tranexamic acid is a first-line targeted therapy for epistaxis and gastrointestinal bleeding in HHT. It acts as an antifibrinolytic agent to stabilize clots at telangiectatic bleeding sites.
Show evidence (1 reference)
PMID:20301525 SUPPORT Human Clinical
"Oral tranexamic acid or intravenous bevacizumab for epistaxis and GI bleeding"
GeneReviews lists tranexamic acid as a targeted therapy for HHT epistaxis and GI bleeding.
Embolization of Pulmonary AVMs
Action: surgical procedure MAXO:0000004
Transcatheter embolization is the standard treatment for pulmonary AVMs to prevent paradoxical embolization and stroke.
Show evidence (1 reference)
PMID:33801690 SUPPORT Human Clinical
"The international clinical guidelines for diagnosis and management of HHT recommend treating PAVMs with transcatheter embolotherapy through the use of detachable coils or plugs, frequently preventing surgery [4]."
Supports transcatheter embolotherapy as standard interventional management for pulmonary AVMs in HHT.
Antiangiogenic Therapy (Bevacizumab)
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: bevacizumab ↗
Systemic antiangiogenic therapy with bevacizumab is being investigated for severe HHT manifestations including refractory epistaxis, GI bleeding, and hepatic AVMs.
Show evidence (2 references)
PMID:37592715 SUPPORT Human Clinical
"Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted."
Randomized phase 2 trial of bevacizumab in severe HHT bleeding showing improved hemoglobin levels at 6 months.
PMID:20301525 SUPPORT Human Clinical
"Oral tranexamic acid or intravenous bevacizumab for epistaxis and GI bleeding"
GeneReviews lists bevacizumab as a targeted therapy for HHT epistaxis and GI bleeding.
Pomalidomide Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: pomalidomide ↗
Pomalidomide can reduce moderate-to-severe epistaxis burden and improve disease-specific quality of life in HHT patients with refractory bleeding.
Show evidence (1 reference)
PMID:39292928 SUPPORT Human Clinical
"Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity."
A randomized placebo-controlled trial supports pomalidomide as an evidence-backed option for refractory HHT epistaxis.
Tacrolimus
Action: Pharmacotherapy NCIT:C15986
Agent: tacrolimus ↗
Low-dose oral tacrolimus has shown promise in treating refractory epistaxis and gastrointestinal bleeding in HHT. The mechanistic rationale is that tacrolimus increases endoglin and ALK1 expression in endothelial cells, partially compensating for haploinsufficiency.
Show evidence (3 references)
PMID:36142926 SUPPORT Human Clinical
"Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT."
Open-label pilot study in 25 HHT patients showing significant improvement in hemoglobin and reduction in transfusion needs with oral tacrolimus.
PMID:38068462 SUPPORT Human Clinical
"Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT."
Observational study in 11 refractory HHT patients showing significant reduction in epistaxis severity score and increase in hemoglobin with low-dose tacrolimus.
PMID:36142926 SUPPORT In Vitro
"In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression."
Mechanistic rationale for tacrolimus in HHT — increases expression of the haploinsufficient proteins.
Genetic Counseling
Action: genetic counseling MAXO:0000079
Genetic counseling and cascade screening of at-risk family members is recommended given the autosomal dominant inheritance.
Show evidence (1 reference)
PMID:39788978 SUPPORT Human Clinical
"Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members."
Genetic counseling and family evaluation are recommended management goals.
🔬

Clinical Trials

1
NCT04646356 PHASE_II COMPLETED
Open-label Phase II trial investigating the effectiveness of oral low-dose tacrolimus for recurrent epistaxis in HHT. Primary outcome is reduction of epistaxis severity (minutes of bleeding per week).
Target Phenotypes: Epistaxis ↗
Show evidence (1 reference)
clinicaltrials:NCT04646356 SUPPORT
"This study will investigate the effectiveness of oral low-dose tacrolimus for the treatment of recurrent nasal hemorrhage in HHT subjects."
Phase II trial evaluating tacrolimus for epistaxis in HHT.
{ }

Source YAML

click to show 
name: Hereditary Hemorrhagic Telangiectasia
creation_date: "2026-03-06T00:00:00Z"
updated_date: "2026-04-24T16:00:00Z"
description: >
  Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu
  disease, is an autosomal dominant vascular dysplasia caused by loss-of-function
  mutations in genes encoding proteins of the BMP/TGF-beta signaling pathway.
  Up to 90% of cases are caused by mutations in ENG (endoglin, HHT1) or ACVRL1
  (ALK1, HHT2), with SMAD4 and GDF2 less frequently responsible. The disease is
  characterized by mucocutaneous telangiectases causing recurrent epistaxis and
  gastrointestinal bleeding, and arteriovenous malformations (AVMs) in the lungs,
  liver, and brain that can cause serious complications including stroke, brain
  abscess, and high-output cardiac failure. Estimated prevalence is approximately
  1 in 5,000.
category: Mendelian
definitions:
- name: Clinical syndrome definition for hereditary hemorrhagic telangiectasia
  definition_type: CASE_DEFINITION
  description: >
    HHT is an inherited vascular dysplasia caused by haploinsufficiency of BMP
    signaling pathway components and characterized by recurrent mucocutaneous
    bleeding together with organ AVMs.
  scope: General clinical framing of hereditary hemorrhagic telangiectasia
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway."
    explanation: Defines HHT as an autosomal dominant vascular dysplasia caused by loss-of-function of BMP-pathway genes.
- name: Curaçao clinical diagnostic criteria framework
  definition_type: DIAGNOSTIC_CRITERIA
  description: >
    Clinical diagnosis uses the Curaçao criteria: recurrent spontaneous
    epistaxis, characteristic mucocutaneous telangiectases, visceral AVMs, and
    an affected first-degree relative. Three criteria establish definite HHT and
    two support possible HHT.
  scope: Clinical diagnosis of suspected hereditary hemorrhagic telangiectasia
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosing HHT can be done through genetic testing or by the use of the clinical Curaçao Criteria framework."
    explanation: Establishes the Curaçao framework as a standard clinical diagnostic approach for HHT.
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A diagnosis of HHT is considered confirmed if at least three criteria are present, and possible with two criteria, as listed above [6]."
    explanation: Supports the clinical threshold for definite versus possible HHT diagnosis.
disease_term:
  preferred_term: Hereditary Hemorrhagic Telangiectasia
  term:
    id: MONDO:0019180
    label: hereditary hemorrhagic telangiectasia
synonyms:
- HHT
- Osler-Weber-Rendu disease
- Rendu-Osler-Weber disease
parents:
- Vascular Malformation
- Bleeding Disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    HHT is transmitted as an autosomal dominant disorder caused by heterozygous
    loss-of-function variants in BMP/TGF-beta pathway genes, most commonly ENG
    or ACVRL1.
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway."
    explanation: Directly supports autosomal dominant inheritance of HHT.
prevalence:
- population: Global
  percentage: "0.02"
  notes: Estimated prevalence of approximately 1 in 5,000 persons.
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons"
    explanation: Provides a direct prevalence estimate for HHT in the general population.
progression:
- phase: Childhood epistaxis-predominant phase
  age_range: Childhood
  notes: >
    Children commonly present first with isolated epistaxis, whereas severe
    complications in childhood are usually due to large pulmonary or central
    nervous system AVMs.
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children usually experience isolated epistaxis; in rare cases, childhood complications occur from large AVMs in the lungs or central nervous system."
    explanation: Supports a typical childhood phase dominated by epistaxis with rarer early visceral AVM complications.
- phase: Adult chronic bleeding and visceral AVM complication phase
  age_range: Adolescence to adulthood
  notes: >
    Adult disease burden more often reflects iron deficiency and anemia from
    recurrent epistaxis or gastrointestinal telangiectases together with
    complications from pulmonary, hepatic, and central nervous system AVMs.
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
    explanation: Supports the adult shift toward chronic bleeding, iron deficiency, and anemia as dominant manifestations.
has_subtypes:
- name: HHT1
  display_name: HHT Type 1 (ENG)
  classification: molecular
  subtype_term:
    preferred_term: hereditary hemorrhagic telangiectasia type 1
    term:
      id: MONDO:0008535
      label: telangiectasia, hereditary hemorrhagic, type 1
  description: >
    ENG-related subtype with higher prevalence of pulmonary and cerebral AVMs,
    mucocutaneous telangiectasia, and epistaxis than HHT2.
  genes:
  - preferred_term: ENG
    term:
      id: hgnc:3349
      label: ENG
  evidence:
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1)."
    explanation: Defines ENG-related HHT1 as the subtype caused by pathogenic ENG variants.
- name: HHT2
  display_name: HHT Type 2 (ACVRL1)
  classification: molecular
  subtype_term:
    preferred_term: hereditary hemorrhagic telangiectasia type 2
    term:
      id: MONDO:0010880
      label: telangiectasia, hereditary hemorrhagic, type 2
  description: >
    ACVRL1-related subtype with greater hepatic AVM burden and higher risk of
    pulmonary hypertension than HHT1.
  genes:
  - preferred_term: ACVRL1
    term:
      id: hgnc:175
      label: ACVRL1
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT type 2 is caused by a mutation in the ACVRL1-gene (cytogenetic location 12q13.13; OMIM600376, encoding for the ALK1 protein) and has a higher prevalence of hepatic AVMs compared to HHT type 1 [2,9,11]."
    explanation: Defines ACVRL1-related HHT2 and its stronger hepatic AVM phenotype.
- name: SMAD4-associated juvenile polyposis/HHT overlap
  display_name: Juvenile Polyposis/HHT Syndrome (SMAD4)
  classification: molecular
  subtype_term:
    preferred_term: juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
    term:
      id: MONDO:0008278
      label: juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
  description: >
    Rare syndromic subtype in which juvenile polyposis co-occurs with HHT
    vascular features.
  genes:
  - preferred_term: SMAD4
    term:
      id: hgnc:6770
      label: SMAD4
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the SMAD4 gene (cytogenetic location 18q21.2; OMIM175050) can cause a rare syndrome that is a combination of juvenile polyposis and HHT."
    explanation: Supports a clinically distinct SMAD4 overlap subtype combining HHT with juvenile polyposis.
- name: GDF2-related HHT-like disease
  display_name: HHT Type 5 (GDF2)
  classification: molecular
  subtype_term:
    preferred_term: hereditary hemorrhagic telangiectasia type 5
    term:
      id: MONDO:0014217
      label: telangiectasia, hereditary hemorrhagic, type 5
  description: >
    Rare BMP9/GDF2-related subtype with an HHT-like vascular phenotype.
  genes:
  - preferred_term: GDF2
    term:
      id: hgnc:4217
      label: GDF2
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT type 5 is caused by a mutation in the Growth Differentiation Factor 2 gene (GDF-2) that codes for the Bone Morphogenetic Protein 9 (BMP9) (OMIM615506) which expresses an HHT-like phenotype and is therefore classified as HHT type 5 [14,15]."
    explanation: Supports a rare GDF2/BMP9-related HHT-like molecular subtype.
pathophysiology:
- name: Impaired BMP/TGF-beta Signaling in Vascular Endothelium
  description: >
    Loss-of-function mutations in ENG or ACVRL1 disrupt BMP/TGF-beta signaling
    in vascular endothelial cells. Endoglin and ALK1 are co-receptors essential
    for proper angiogenesis, vessel maturation, and stabilization. Their loss
    leads to dysregulated angiogenesis and formation of fragile, abnormal vascular
    structures including telangiectases and arteriovenous malformations.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway."
    explanation: Confirms HHT as caused by loss-of-function in BMP pathway genes.
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization."
    explanation: Confirms the role of TGF-beta pathway in angiogenesis and vessel maturation relevant to HHT pathophysiology.
  - reference: PMID:28796572
    reference_title: "Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease."
    explanation: Confirms haploinsufficiency as the pathogenic mechanism in HHT.
  downstream:
  - target: Defective Endothelial Tubulogenesis and Pericyte Recruitment
    description: >
      Impaired ALK1/endoglin signaling compromises endothelial maturation and
      mural-cell recruitment during angiogenesis.
  - target: VEGF-Triggered AVM Formation
    description: >
      Haploinsufficient endothelium becomes vulnerable to angiogenic triggers
      such as injury or VEGF stimulation.
- name: Defective Endothelial Tubulogenesis and Pericyte Recruitment
  description: >
    ENG and ACVRL1 deficiency alters endothelial tubulogenesis and mural-cell
    recruitment, producing abnormal endothelial hyperplasia and unstable vascular
    morphogenesis that predispose to telangiectases and AVMs.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: pericyte
    term:
      id: CL:0000669
      label: pericyte
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in ENG and ACVRL-1 disrupt TGF-β signaling, altering EC tubulogenesis and pericyte recruitment, causing abnormal endothelial hyperplasia and abnormal vascular morphogenesis in HHT [2,18]."
    explanation: Links ENG/ACVRL1 haploinsufficiency to failed endothelial tubulogenesis and pericyte recruitment in HHT vascular lesions.
  downstream:
  - target: Chronic Bleeding from Telangiectases
    description: >
      Fragile mucocutaneous and gastrointestinal telangiectases bleed
      recurrently.
  - target: Vascular Shunting Through Visceral AVMs
    description: >
      Abnormally direct artery-to-vein connections in lung, liver, and CNS
      create clinically important shunts.
- name: VEGF-Triggered AVM Formation
  description: >
    HHT vascular lesions show organ specificity and appear to require local
    angiogenic or injury-related triggers, consistent with a second-hit model in
    which VEGF stimulation or tissue damage precipitates AVM formation in
    haploinsufficient endothelium.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Several studies with knock-out (KO) animal models (KO ENG and ACRVL-1) have shown that a local external trigger such as damage or stimulation of VEGF causes the formation of AVMs [8,48,53]."
    explanation: Supports a second-hit model in which local angiogenic triggers such as VEGF stimulation precipitate AVM formation.
  downstream:
  - target: Vascular Shunting Through Visceral AVMs
    description: >
      Triggered AVM growth creates clinically relevant pulmonary and systemic
      shunts.
- name: Somatic Second-Hit Mutation and AVM Formation
  description: >
    While germline haploinsufficiency underlies HHT, focal lesion formation
    follows a two-hit model analogous to tumor suppressor genes. Somatic
    second-hit loss-of-function mutations in ENG or ACVRL1 have been identified
    in telangiectasias and solid organ AVMs, leading to biallelic loss. This
    explains the focal nature of vascular lesions despite systemic
    haploinsufficiency and why only specific vascular beds develop AVMs.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:39062925
    reference_title: "Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias."
    explanation: Confirms somatic second-hit mutations in HHT causative genes in telangiectasia lesions.
  - reference: PMID:39062925
    reference_title: "Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations."
    explanation: Extends the two-hit model to nasal telangiectasias and solid organ AVMs including brain, lung, liver, and gallbladder.
  downstream:
  - target: Impaired BMP/TGF-beta Signaling in Vascular Endothelium
    description: >
      Complete biallelic loss of ENG or ACVRL1 in focal endothelial clones
      abolishes BMP/TGF-beta signaling locally, triggering AVM formation.
- name: Chronic Bleeding from Telangiectases
  description: >
    Recurrent epistaxis and gastrointestinal telangiectatic bleeding cause
    chronic iron loss, iron deficiency, and symptomatic anemia in many adults
    with HHT.
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
    explanation: Connects recurrent telangiectatic bleeding with iron deficiency and anemia in adult HHT.
  downstream:
  - target: Epistaxis
    description: >
      Nasal telangiectases cause recurrent spontaneous nosebleeds.
  - target: Gastrointestinal Hemorrhage
    description: >
      Gastrointestinal telangiectases cause chronic or severe GI bleeding.
  - target: Iron Deficiency Anemia
    description: >
      Chronic blood loss depletes iron stores and leads to anemia.
- name: Vascular Shunting Through Visceral AVMs
  description: >
    Pulmonary AVMs create right-to-left shunts that bypass capillary filtration,
    whereas systemic AVMs, especially hepatic lesions, create left-to-right
    shunts with high cardiac output and downstream embolic or hemodynamic
    complications.
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess) and left-to-right through systemic AVMs (causing high cardiac output)."
    explanation: Summarizes the major organ-specific shunt physiology and its key neurologic and hemodynamic consequences in HHT.
  downstream:
  - target: Ischemic Stroke
    description: >
      Right-to-left shunting through pulmonary AVMs permits paradoxical emboli
      and septic emboli to reach the brain.
  - target: Dyspnea
    description: >
      Pulmonary shunting reduces gas exchange efficiency and contributes to
      exertional dyspnea.
  - target: High-output cardiac failure
    description: >
      Systemic AVMs, particularly hepatic shunts, can drive chronic high-output
      circulatory stress and eventual heart failure.
phenotypes:
- category: Hematologic
  name: Epistaxis
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Recurrent spontaneous nosebleeds are the most common manifestation, affecting
    over 90% of patients. Epistaxis typically begins in childhood and can range
    from mild to severe enough to cause iron deficiency anemia.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
    explanation: Recurrent epistaxis is the most frequent HHT manifestation.
- category: Hematologic
  name: Iron Deficiency Anemia
  description: >
    Chronic blood loss from recurrent epistaxis and gastrointestinal
    telangiectases commonly produces iron deficiency anemia in adults with HHT.
  phenotype_term:
    preferred_term: iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases."
    explanation: Directly supports iron deficiency anemia as a major adult HHT consequence of chronic telangiectatic bleeding.
- category: Dermatologic
  name: Mucocutaneous Telangiectases
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Small dilated blood vessels on the skin and mucous membranes, particularly
    on the lips, tongue, fingertips, and nasal mucosa. They are a hallmark
    diagnostic feature of HHT.
  phenotype_term:
    preferred_term: Telangiectasia
    term:
      id: HP:0001009
      label: Telangiectasia
  evidence:
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by severe and recurrent nosebleeds, mucocutaneous telangiectases, and, in some cases, life-threatening visceral arteriovenous malformations"
    explanation: Mucocutaneous telangiectases are a defining feature of HHT.
- category: Gastrointestinal
  name: Gastrointestinal Hemorrhage
  frequency: FREQUENT
  description: >
    Gastrointestinal telangiectases can cause chronic bleeding and iron deficiency
    anemia, particularly in older patients.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal telangiectases are frequent and may cause severe bleeding."
    explanation: GI bleeding from telangiectases is a well-recognized HHT complication.
- category: Neurologic
  name: Ischemic Stroke
  description: >
    Pulmonary AVMs allow paradoxical embolization through right-to-left shunting,
    causing ischemic stroke.
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
    explanation: Pulmonary AVMs cause paradoxical embolization leading to stroke or brain abscess.
- category: Cardiovascular
  name: High-output cardiac failure
  description: >
    Hepatic and other systemic AVMs can generate a chronic hyperdynamic state
    with increased cardiac output that progresses to congestive heart failure in
    a subset of patients.
  phenotype_term:
    preferred_term: high-output cardiac failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-capillary PH arises from a hyperdynamic state caused by an increased cardiac output (CO), which can cause heart failure in the long term"
    explanation: Supports heart failure as a downstream consequence of chronic high-output physiology in HHT-associated shunting states.
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within HHT, the increased CO (sometimes up to three times normal) is frequently caused by the HAVM-related shunt"
    explanation: Links the high-output state specifically to hepatic AVM-related shunting in HHT.
- category: Respiratory
  name: Dyspnea
  description: >
    Pulmonary AVMs affect approximately 15-50% of HHT patients and can cause
    dyspnea, hypoxemia, and hemoptysis.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosing PH in HHT can be challenging. Symptoms of HHT, such as fatigue, dyspnea and exercise intolerance, resemble those of PH due to anemia, hypoxemia associated with PAVMs, inadequate sleep due to epistaxis, and the psychological burden of a chronic illness [2,6,75]."
    explanation: Supports dyspnea as a clinically important respiratory manifestation in HHT, often driven by pulmonary AVM-related hypoxemia or pulmonary vascular complications.
- category: Respiratory
  name: Pulmonary Arteriovenous Malformation
  frequency: FREQUENT
  subtype: HHT1
  description: >
    Pulmonary AVMs are present in approximately 15-50% of HHT patients, with
    higher prevalence in HHT1 (ENG mutations). They create right-to-left shunts
    that bypass the pulmonary capillary bed, leading to hypoxemia and risk of
    paradoxical embolization.
  phenotype_term:
    preferred_term: Pulmonary arteriovenous malformation
    term:
      id: HP:0006548
      label: Pulmonary arteriovenous malformation
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
    explanation: Confirms pulmonary AVMs as a major HHT manifestation with right-to-left shunting complications.
  - reference: PMID:30251589
    reference_title: "Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2."
    explanation: Confirms higher prevalence of pulmonary AVMs in HHT1.
- category: Respiratory
  name: Hemoptysis
  frequency: OCCASIONAL
  description: >
    Hemoptysis can occur from pulmonary AVMs or from bronchial telangiectases.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAVMs can further result in rare but severe complications like massive hemoptysis, hemothorax, cerebrovascular events, and abscesses"
    explanation: Hemoptysis is a recognized severe complication of pulmonary AVMs in HHT.
- category: Neurologic
  name: Cerebral Arteriovenous Malformation
  frequency: OCCASIONAL
  subtype: HHT1
  description: >
    Cerebral AVMs occur in approximately 10-23% of HHT patients, with higher
    prevalence in HHT1. They can cause hemorrhagic stroke, seizures, or
    headaches.
  phenotype_term:
    preferred_term: Cerebral arteriovenous malformation
    term:
      id: HP:0002408
      label: Cerebral arteriovenous malformation
  evidence:
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "life-threatening visceral arteriovenous malformations of various types, including pulmonary, hepatic, cerebral, and spinal"
    explanation: Cerebral AVMs are a recognized visceral manifestation of HHT.
  - reference: PMID:20301525
    reference_title: "Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic."
    explanation: GeneReviews confirms brain AVMs as a major HHT complication.
- category: Neurologic
  name: Transient Ischemic Attack
  frequency: OCCASIONAL
  description: >
    TIAs occur due to paradoxical embolization through pulmonary AVMs, with
    right-to-left shunting allowing venous emboli to reach the cerebral
    circulation.
  phenotype_term:
    preferred_term: Transient ischemic attack
    term:
      id: HP:0002326
      label: Transient ischemic attack
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
    explanation: Ischemic cerebrovascular events including TIA result from paradoxical embolization through pulmonary AVMs.
- category: Neurologic
  name: Brain Abscess
  frequency: OCCASIONAL
  description: >
    Brain abscesses occur in HHT patients due to paradoxical septic
    embolization through pulmonary AVMs, bypassing the normal pulmonary
    capillary filtration.
  phenotype_term:
    preferred_term: Brain abscess
    term:
      id: HP:0030049
      label: Brain abscess
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess)"
    explanation: Brain abscess results from paradoxical embolization through pulmonary AVMs.
  - reference: PMID:30251589
    reference_title: "Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications."
    explanation: Uppsala cohort shows high prevalence of cerebral complications including brain abscess.
- category: Hepatic
  name: Hepatic Arteriovenous Malformation
  frequency: FREQUENT
  subtype: HHT2
  description: >
    Hepatic AVMs are more common in HHT2 (ACVRL1 mutations) and can cause
    high-output cardiac failure, portal hypertension, or biliary ischemia.
  phenotype_term:
    preferred_term: Hepatic arteriovenous malformation
    term:
      id: HP:0006574
      label: Hepatic arteriovenous malformation
  evidence:
  - reference: PMID:30251589
    reference_title: "Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2."
    explanation: Confirms hepatic AVMs are enriched in HHT2 patients.
  - reference: PMID:20301525
    reference_title: "Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic."
    explanation: Hepatic AVMs are a major visceral manifestation of HHT.
- category: Cardiovascular
  name: Pulmonary Arterial Hypertension
  frequency: OCCASIONAL
  subtype: HHT2
  description: >
    Pulmonary arterial hypertension is particularly associated with HHT2
    (ACVRL1 mutations) and can occur independently of hepatic or pulmonary
    AVMs.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway."
    explanation: Confirms pulmonary arterial hypertension as a recognized complication in HHT, driven by TGF-beta pathway disruption.
- category: Constitutional
  name: Fatigue
  frequency: FREQUENT
  description: >
    Fatigue is a common symptom in HHT, driven by chronic iron deficiency
    anemia from recurrent bleeding as well as by hypoxemia from pulmonary AVMs.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms of HHT, such as fatigue, dyspnea and exercise intolerance, resemble those of PH due to anemia, hypoxemia associated with PAVMs, inadequate sleep due to epistaxis, and the psychological burden of a chronic illness"
    explanation: Directly names fatigue as a symptom of HHT driven by anemia and hypoxemia.
genetic:
- name: ENG
  association: Pathogenic Mutations
  presence: Positive
  subtype: HHT1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >
      Age-related penetrance; most individuals manifest by age 40. Considerable
      intrafamilial variability in severity and organ involvement.
  notes: >
    ENG on chromosome 9q34 encodes endoglin, a TGF-beta co-receptor on endothelial
    cells. Loss-of-function mutations cause HHT type 1, which is associated with
    higher frequency of pulmonary and cerebral AVMs. Pathogenic variants include
    missense, nonsense, splice-site, and copy number variants.
    Somatic second-hit mutations in ENG have been identified in telangiectasias
    and solid organ AVMs, supporting a two-hit model for focal lesion formation.
  evidence:
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1)."
    explanation: Confirms ENG mutations as the cause of HHT type 1.
  - reference: PMID:39062925
    reference_title: "Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation."
    explanation: Somatic second-hit mutations in ENG identified in telangiectasia and AVM tissues, supporting biallelic loss as mechanism for focal lesion formation.
  - reference: PMID:20301525
    reference_title: "Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability and age-related penetrance of individual manifestations."
    explanation: Confirms autosomal dominant inheritance with age-related penetrance.
- name: ACVRL1
  association: Pathogenic Mutations
  presence: Positive
  subtype: HHT2
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >
    ACVRL1 on chromosome 12q13 encodes ALK1, a type I TGF-beta receptor.
    Loss-of-function mutations cause HHT type 2, which is associated with higher
    frequency of hepatic AVMs and pulmonary hypertension. Pathogenic variants
    include missense, nonsense, and splice-site mutations.
  evidence:
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor-like kinase 1)."
    explanation: Confirms ACVRL1 mutations as the cause of HHT type 2.
  - reference: PMID:30251589
    reference_title: "Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2."
    explanation: Confirms genotype-phenotype correlations for ACVRL1 mutations including hepatic AVM enrichment.
- name: SMAD4
  association: Pathogenic Mutations
  presence: Positive
  subtype: SMAD4-associated juvenile polyposis/HHT overlap
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >
    SMAD4 mutations cause a combined juvenile polyposis/HHT syndrome. Less common
    than ENG or ACVRL1 mutations. Patients require colonoscopic surveillance for
    gastrointestinal polyps in addition to standard HHT management.
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT."
    explanation: Confirms SMAD4 as a less frequent HHT gene.
  - reference: PMID:20345718
    reference_title: "Hereditary hemorrhagic telangiectasia: from molecular biology to patient care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations in MADH4 (encoding SMAD4), which cause a juvenile polyposis/HHT overlap syndrome, have been described"
    explanation: Confirms the JP-HHT overlap syndrome phenotype.
- name: GDF2
  association: Pathogenic Mutations
  presence: Positive
  subtype: GDF2-related HHT-like disease
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >
    GDF2 (encoding BMP9) mutations are a rare cause of HHT (type 5), recently
    identified. BMP9 is a ligand for the ALK1 receptor.
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HHT type 5 is caused by a mutation in the Growth Differentiation Factor 2 gene (GDF-2) that codes for the Bone Morphogenetic Protein 9 (BMP9) (OMIM615506) which expresses an HHT-like phenotype and is therefore classified as HHT type 5 [14,15]."
    explanation: Supports GDF2/BMP9 as a rare molecular cause of an HHT-like subtype.
treatments:
- name: Epistaxis Management
  description: >
    Management of epistaxis focuses on local bleeding control with escalation to
    procedural or surgical approaches for refractory disease.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members."
    explanation: Supports epistaxis control as a core therapeutic goal in HHT.
- name: Iron Replacement Therapy
  description: >
    Iron supplementation (oral or intravenous) is essential for managing iron
    deficiency anemia from chronic bleeding.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: iron
      term:
        id: CHEBI:18248
        label: iron atom
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members."
    explanation: Supports active treatment of iron deficiency, with or without anemia, as a central HHT management goal.
- name: Tranexamic Acid
  description: >
    Oral tranexamic acid is a first-line targeted therapy for epistaxis and
    gastrointestinal bleeding in HHT. It acts as an antifibrinolytic agent
    to stabilize clots at telangiectatic bleeding sites.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  evidence:
  - reference: PMID:20301525
    reference_title: "Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral tranexamic acid or intravenous bevacizumab for epistaxis and GI bleeding"
    explanation: GeneReviews lists tranexamic acid as a targeted therapy for HHT epistaxis and GI bleeding.
- name: Embolization of Pulmonary AVMs
  description: >
    Transcatheter embolization is the standard treatment for pulmonary AVMs to
    prevent paradoxical embolization and stroke.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:33801690
    reference_title: "Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The international clinical guidelines for diagnosis and management of HHT recommend treating PAVMs with transcatheter embolotherapy through the use of detachable coils or plugs, frequently preventing surgery [4]."
    explanation: Supports transcatheter embolotherapy as standard interventional management for pulmonary AVMs in HHT.
- name: Antiangiogenic Therapy (Bevacizumab)
  description: >
    Systemic antiangiogenic therapy with bevacizumab is being investigated for
    severe HHT manifestations including refractory epistaxis, GI bleeding, and
    hepatic AVMs.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: bevacizumab
      term:
        id: NCIT:C2039
        label: Bevacizumab
  evidence:
  - reference: PMID:37592715
    reference_title: "Efficacy and safety of intravenous bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: A national, randomized multicenter trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted."
    explanation: Randomized phase 2 trial of bevacizumab in severe HHT bleeding showing improved hemoglobin levels at 6 months.
  - reference: PMID:20301525
    reference_title: "Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral tranexamic acid or intravenous bevacizumab for epistaxis and GI bleeding"
    explanation: GeneReviews lists bevacizumab as a targeted therapy for HHT epistaxis and GI bleeding.
- name: Pomalidomide Therapy
  description: >
    Pomalidomide can reduce moderate-to-severe epistaxis burden and improve
    disease-specific quality of life in HHT patients with refractory bleeding.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pomalidomide
      term:
        id: CHEBI:72690
        label: pomalidomide
  evidence:
  - reference: PMID:39292928
    reference_title: "Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity."
    explanation: A randomized placebo-controlled trial supports pomalidomide as an evidence-backed option for refractory HHT epistaxis.
- name: Tacrolimus
  description: >
    Low-dose oral tacrolimus has shown promise in treating refractory epistaxis
    and gastrointestinal bleeding in HHT. The mechanistic rationale is that
    tacrolimus increases endoglin and ALK1 expression in endothelial cells,
    partially compensating for haploinsufficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tacrolimus
      term:
        id: CHEBI:61049
        label: tacrolimus (anhydrous)
  evidence:
  - reference: PMID:36142926
    reference_title: "Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT."
    explanation: Open-label pilot study in 25 HHT patients showing significant improvement in hemoglobin and reduction in transfusion needs with oral tacrolimus.
  - reference: PMID:38068462
    reference_title: "Tacrolimus as a Promising Drug for Epistaxis and Gastrointestinal Bleeding in HHT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT."
    explanation: Observational study in 11 refractory HHT patients showing significant reduction in epistaxis severity score and increase in hemoglobin with low-dose tacrolimus.
  - reference: PMID:36142926
    reference_title: "Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression."
    explanation: Mechanistic rationale for tacrolimus in HHT — increases expression of the haploinsufficient proteins.
- name: Genetic Counseling
  description: >
    Genetic counseling and cascade screening of at-risk family members is
    recommended given the autosomal dominant inheritance.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:39788978
    reference_title: "Hereditary haemorrhagic telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members."
    explanation: Genetic counseling and family evaluation are recommended management goals.
clinical_trials:
- name: NCT04646356
  phase: PHASE_II
  status: COMPLETED
  description: >
    Open-label Phase II trial investigating the effectiveness of oral low-dose
    tacrolimus for recurrent epistaxis in HHT. Primary outcome is reduction of
    epistaxis severity (minutes of bleeding per week).
  target_phenotypes:
  - preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: clinicaltrials:NCT04646356
    supports: SUPPORT
    snippet: "This study will investigate the effectiveness of oral low-dose tacrolimus for the treatment of recurrent nasal hemorrhage in HHT subjects."
    explanation: Phase II trial evaluating tacrolimus for epistaxis in HHT.
references:
- reference: PMID:20301525
  title: "Hereditary Hemorrhagic Telangiectasia."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301525
Hereditary Hemorrhagic Telangiectasia.
No top-level findings curated for this source.

Deep Research

3
Falcon ▸
Hereditary Hemorrhagic Telangiectasia (HHT) — Disease Characteristics Research Report
Edison Scientific Literature 44 citations 2026-04-24T07:25:19.914350

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

Category Details
Disease name / synonyms Hereditary hemorrhagic telangiectasia (HHT); also Osler-Weber-Rendu syndrome, Rendu-Osler-Weber syndrome, Rendu-Osler syndrome, historical Osler's disease (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2, tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2, ahmad2024managingepistaxisin pages 1-2, gong2025quantifyingtheburden pages 1-2)
Key identifiers explicitly found HHT1: OMIM 187300; HHT2: OMIM 600376; JP-HHT: OMIM 175050; HHT5: OMIM 615506; Orphanet/ORPHA: 774 (reported in an HHT Orphanet-linked 2024 source) (tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2, ochiai2026acaseof pages 5-6, villanueva2024minimalencephalopathyin pages 1-2)
Main causal genes with OMIM gene IDs mentioned ENG (Endoglin) — OMIM 131195; ACVRL1 — OMIM 601284; SMAD4 — OMIM 600993; GDF2 — OMIM 605120 (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2)
Gene-to-subtype mapping ENG → HHT1; ACVRL1 → HHT2; SMAD4 → juvenile polyposis/HHT overlap; GDF2 → HHT5 / HHT-like phenotype (danesino2023hereditaryhemorrhagictelangiectasia pages 1-2, tabosh2024hereditaryhemorrhagictelangiectasia pages 1-2, jain2023pathogenicvariantfrequencies pages 2-4)
Core Curaçao criterion 1 Epistaxis — spontaneous, recurrent nosebleeds (ahmad2024managingepistaxisin pages 1-2, ahmad2024managingepistaxisin media 4cb59254)
Core Curaçao criterion 2 Telangiectasia — multiple, characteristic sites: lips, oral cavity, fingers, nose (ahmad2024managingepistaxisin pages 1-2, ahmad2024managingepistaxisin media 4cb59254)
Core Curaçao criterion 3 Visceral lesions — gastrointestinal telangiectasia (with/without bleeding), pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM (ahmad2024managingepistaxisin pages 1-2, ahmad2024managingepistaxisin media 4cb59254)
Core Curaçao criterion 4 Family history — first-degree relative with HHT according to these criteria (ahmad2024managingepistaxisin pages 1-2, ahmad2024managingepistaxisin media 4cb59254)
Diagnostic thresholds Definite HHT: 3 criteria present; Possible/Suspected HHT: 2 criteria present; Unlikely HHT: fewer than 2 criteria present (ahmad2024managingepistaxisin pages 1-2, ahmad2024managingepistaxisin media 4cb59254)

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

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  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

Hereditary Hemorrhagic Telangiectasia OpenScientist Report Review ▸

Hereditary Hemorrhagic Telangiectasia OpenScientist Report Review

Date: 2026-04-24

Scope

Review of the verbatim OpenScientist report at research/Hereditary_Hemorrhagic_Telangiectasia-deep-research-openscientist.md against the current curated YAML, the Falcon report, and fetched primary references used during HHT curation.

Overall assessment

  • The report is useful as a lead-generation artifact for disease-level structure.
  • It is not safe for direct ingestion without review.
  • The strongest value was in surfacing the 2024 PATH-HHT pomalidomide trial.
  • The report also contains at least one ontology-anchor error and several claims that are plausible but too loosely sourced for direct promotion.

Findings That Held Up On Review

  • Core disease framing as an autosomal dominant vascular dysplasia involving the BMP9/BMP10-ENG-ALK1-SMAD4 axis.
  • Two-hit / focal lesion framing for AVM formation.
  • Broad genotype-phenotype split:
  • ENG enriched for pulmonary and cerebral AVMs.
  • ACVRL1 enriched for hepatic AVMs.
  • High disease-burden framing around recurrent epistaxis, iron deficiency, and visceral AVM complications.
  • Therapeutic significance of the PATH-HHT randomized trial (PMID:39292928).

Review Findings

1. Incorrect ontology anchor in the verbatim report

The OpenScientist report uses MONDO:0008535 as the HHT identifier. The current validated repo entry uses MONDO:0019180 in kb/disorders/Hereditary_Hemorrhagic_Telangiectasia.yaml. This means the verbatim report should be treated as informative text, not as ontology-safe structured input.

2. One claim was clearly worth promotion after primary-source check

The report surfaced the pomalidomide Phase 3 result. After fetching the underlying abstract (PMID:39292928), that evidence was strong enough to add a new Pomalidomide Therapy treatment entry to the HHT YAML.

3. Several claims remain "interesting but not yet curation-safe"

These may be correct, but they were not promoted from the OpenScientist report without additional source-level checking:

  • pregnancy-risk summary values
  • manganese-deposition / basal-ganglia MRI discussion
  • sex-difference claims
  • forward-looking therapeutic language such as "potential first-ever FDA-approved therapy"

These are exactly the kinds of statements that should stay in the verbatim file until a reviewer fetches and checks the underlying papers.

4. Technical note on the provider run

For this HHT job, the OpenScientist /status endpoint continued to report running even after the artifacts ZIP already contained final_report.md. The verbatim report recovered cleanly from the ZIP, but this behavior means status alone is not a reliable completion signal for eval bookkeeping.

What Was Promoted From The Review

  • PMID:39292928 was fetched and used to support Pomalidomide Therapy in the curated HHT YAML.

Specific Paper Check: PMC12274349

Paper:

  • PMC12274349
  • PMID:40681766
  • DOI: 10.1038/s42003-025-08461-6
  • Title: Overlapping upstream ORFs ending at c.125 lead to reduced Endoglin, contributing to Hereditary Hemorrhagic Telangiectasia.

Result:

  • This paper was not surfaced in the verbatim OpenScientist HHT report.
  • It was also not surfaced in the verbatim Falcon HHT report.
  • It is not currently referenced in the HHT YAML.

Evidence for that conclusion:

  • repo search across the four HHT report artifacts found no hit for PMC12274349
  • no hit for PMID:40681766
  • no hit for 10.1038/s42003-025-08461-6
  • no hit for the title string

Interpretation:

  • This omission is understandable. PMID:40681766 is a narrower 2025 molecular diagnostics / ENG 5'UTR mechanistic paper, whereas both agent reports leaned toward disease-level reviews, cohort studies, and clinically central management papers.
  • It is still potentially useful for a future refinement of the ENG genetics section, especially if we want better coverage of noncoding pathogenic mechanisms and molecular diagnosis edge cases.

Bottom Line

Keep the OpenScientist file as the verbatim eval artifact. Use the review file to record what survived cross-checking, what was promoted into YAML, and what still needs source-level verification before curation.

OpenScientist ▸
Executive Summary
openscientist-autonomous 22 citations 2026-04-24T14:34:54.610665+00:00

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

Attribute Details
Disease Name Hereditary Hemorrhagic Telangiectasia (HHT)
Synonyms Osler-Weber-Rendu syndrome/disease
MONDO ID MONDO:0008535
OMIM 187300 (HHT1), 601101 (HHT2), 175050 (JP-HHT), 615506 (HHT5), 600376 (HHT locus 3)
Orphanet ORPHA:774
Category Mendelian (autosomal dominant)
Disease Class Vascular dysplasia / inherited bleeding disorder

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:

Gene Protein Chromosome HHT Subtype OMIM Approx. % of Cases
ENG Endoglin (CD105) 9q34.11 HHT1 187300 ~39-53%
ACVRL1 ALK1 (activin receptor-like kinase 1) 12q13.13 HHT2 601101 ~31-48%
SMAD4 SMAD4/DPC4 18q21.2 JP-HHT 175050 ~2-3%
GDF2 BMP9 (bone morphogenetic protein 9) 10q11.22 HHT5 615506 ~1%
  • 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

Population Estimated Prevalence Notes
Worldwide 1:5,000 Consensus estimate
Netherlands Antilles (Curaçao) ~1:1,300 Highest known; founder effect (ENG)
Japan (Akita region) ~1:5,000-1:8,000 Predominantly HHT1/ENG
Hungary (study area) ~1:6,090-1:11,267 Population screening study
General range 1:5,000-1:10,000 Likely underestimated due to underdiagnosis

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)

Manifestation Prevalence Notes
Recurrent epistaxis 95% Most common symptom; universal feature
Mucocutaneous telangiectases >90% Lips (79%), tongue (76%), ears (61%), fingers (71%)
Iron deficiency and/or anemia 68% Often severe
Pulmonary AVMs ~50-57% Higher in HHT1 (75%) vs HHT2 (44%)
IV iron required 41% Reflecting severity of bleeding
Hepatic AVMs 60-84% Higher in HHT2
Heavy menstrual bleeding 35% Post-menarche females
Chronic GI bleeding 30% Increases with age
RBC transfusions required 25% Reflecting transfusion dependency
Arterial thromboembolism 11% Paradoxical embolism through PAVMs
Brain AVMs 9-16% Higher in HHT1 (20-36%) vs HHT2 (0-4%)
Heart failure 7% High-output from hepatic shunting
Pulmonary hypertension 7% Multiple mechanisms
Venous thromboembolism 7%
Intracranial hemorrhage 3% From brain AVMs

5.3 Genotype-Phenotype Correlations

Feature HHT1 (ENG) HHT2 (ACVRL1) JP-HHT (SMAD4)
Pulmonary AVMs 75% 44% 42%
Brain AVMs 20-36% 0-4% Present
Hepatic AVMs 60% 84% Present
Epistaxis onset Earlier Later Variable
GI polyps No No Yes (87%)
Cancer risk No No 25% CRC
Neurological events More common Less common Present
High-output HF Less common More common Present

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

# Finding Key Evidence
1 HHT caused by mutations in BMP9/10-ALK1-ENG-SMAD4 pathway 4 genes, autosomal dominant, ~1:5000 prevalence
2 Distinct genotype-phenotype correlations ENG→lung/brain AVMs; ACVRL1→liver AVMs
3 High disease burden (CHORUS, n=600) 95% epistaxis, 68% anemia, 63% late diagnosis
4 Two-hit pathogenesis model Germline + somatic LOH + environmental triggers
5 Antiangiogenic therapy paradigm shift Bevacizumab, pomalidomide, pazopanib (all off-label)
6 PAVMs cause paradoxical embolism 11% arterial TE, 5-13% brain abscess
7 Pregnancy carries 1% maternal mortality 50x general population; PAVM rupture
8 Geographic variation and founder effects Netherlands Antilles ~1:1300 (ENG founder)
9 Hepatic AVMs cause high-output HF Bevacizumab effective; transplant last resort
10 BMP-VEGF pathway crosstalk mechanism BMP suppresses PI3K/AKT; loss enables VEGF-driven AVMs
11 JP-HHT (SMAD4) dual cancer/vascular risk 25% CRC at median age 33
12 Pomalidomide Phase 3 RCT positive ESS -0.94 (P=0.004); first positive HHT trial
13 Significant sex differences Women: more hepatic/pulmonary AVMs, more invasive treatment
14 Endoglin-cancer biology connection CD105 is a tumor angiogenesis marker and therapeutic target
15 HHT-PAH has poor prognosis 53% 3-year survival, worse than matched IPAH
16 Thrombosis-bleeding paradox 11% arterial TE + 7% VTE despite bleeding disorder; anticoagulation poorly tolerated

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.