Hereditary Hemorrhagic Telangiectasia

Overview and Epidemiology

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular dysplasia affecting approximately 1 in 5,000 to 10,000 individuals worldwide. The condition is caused by mutations in genes encoding components of the TGF-β/BMP signaling pathway, which is critical for normal vascular development and endothelial homeostasis. The disease is named after three physicians who described it across more than a decade: French physician Henri Jules Louis Marie Rendu provided the first clear clinical description in 1896, Canadian-born Sir William Osler characterized the hereditary and familial pattern in 1901 distinguishing it from hemophilia, and British physician Frederick Parkes Weber contributed detailed descriptions of the vascular features in 1907. OMIM entries #187300 (HHT1, ENG mutations) and #600376 (HHT2, ACVRL1 mutations) reflect the two most common genetic subtypes.

HHT affects males and females equally (autosomal dominant inheritance, no sex linkage) and occurs in all ethnic groups across all continents. Despite its relatively high prevalence compared to many rare diseases, HHT remains severely underdiagnosed — the mean diagnostic delay from symptom onset to formal diagnosis is approximately 12 years. This gap persists because nosebleeds in childhood are common in the general population and the specific HHT pattern may not raise alarm until adulthood, because the telangiectases may be subtle in young patients, and because visceral AVMs may be clinically silent until a catastrophic complication (stroke, brain abscess) occurs. Increased awareness campaigns by the HHT Foundation International and the establishment of dedicated HHT Centers of Excellence have begun to narrow this diagnostic gap. When diagnosed, HHT warrants systematic multi-organ screening and lifelong surveillance given the risk of life-threatening visceral arteriovenous malformations.

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Molecular Pathogenesis and TGF-β/BMP Signaling

HHT is a disease of the vascular endothelium caused by haploinsufficiency — loss of one functional allele of key TGF-β/BMP pathway genes is sufficient to cause disease because the remaining single copy cannot maintain normal vascular signaling. Four genes account for the vast majority of cases. ENG (endoglin, chromosome 9q34.11) encodes a TGF-β co-receptor expressed at high levels on vascular endothelial cells; ENG mutations cause HHT Type 1, the most common form, and carry the highest risk of pulmonary AVMs. ACVRL1 (ALK1, chromosome 12q13.13) encodes a type I TGF-β receptor also expressed predominantly in vascular endothelium; ACVRL1 mutations cause HHT Type 2, in which hepatic AVMs predominate. SMAD4 (chromosome 18q21.2) encodes an intracellular TGF-β signal transducer; SMAD4 mutations cause juvenile polyposis-HHT overlap syndrome (JPHT), in which patients develop both juvenile GI polyps (requiring colonoscopic surveillance for colorectal and gastric cancer) and the full HHT phenotype. GDF2/BMP9 (chromosome 10q11.22) mutations cause the rarest form, HHT Type 5.

ENG and ALK1 cooperate in the BMP9/BMP10 signaling axis to maintain vascular quiescence — the resting, non-proliferative state of mature endothelium. When either protein is haploinsufficient, BMP9/BMP10 signaling is impaired, endothelial cells cannot maintain quiescence, and pathological angiogenesis ensues. The result is formation of two types of abnormal arteriovenous connections. Telangiectases are small (0.5–3 mm), dilated capillary-venule connections in the skin and mucous membranes — they appear as bright red or purple spots on the lips, tongue, oral mucosa, fingertips, nasal mucosa, and face; they blanch with pressure (confirming their vascular nature) and are fragile, prone to rupture. Arteriovenous malformations (AVMs) are larger visceral lesions representing direct artery-to-vein connections that entirely bypass the normal capillary bed — this bypass is the key pathological consequence, as the pulmonary capillary bed normally acts as a filter for emboli, bacteria, and air bubbles, and hepatic capillaries mediate normal hepatic perfusion. VEGF is upregulated downstream of impaired BMP9 signaling, providing the rational basis for anti-VEGF therapy (bevacizumab) in HHT.

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Curaçao Diagnostic Criteria

The Curaçao criteria are the internationally accepted clinical diagnostic framework for HHT, established in 2000 at an HHT Foundation consensus meeting held in Curaçao, Dutch Antilles. The criteria define four key clinical features, and diagnosis is based on how many are present in an individual. The four criteria are: (1) Spontaneous recurrent epistaxis — nosebleeds occurring without trauma, the hallmark presenting symptom; (2) Multiple telangiectases at characteristic sites — lips, oral cavity, tongue, fingertips, nose, and face; (3) Visceral lesions — pulmonary arteriovenous malformations (PAVMs), hepatic AVMs, cerebral vascular malformations (AVMs, cavernomas, or fistulas), spinal AVMs, and gastrointestinal telangiectases causing chronic bleeding; (4) Family history — a first-degree relative (parent, sibling, or child) who meets the same criteria for HHT diagnosis.

Interpretation is scored by how many of these four features are present. A score of 3 or 4 indicates definite HHT. A score of exactly 2 indicates suspected HHT, and molecular genetic testing is strongly recommended to confirm or exclude the diagnosis. A score of 0 or 1 makes HHT unlikely. Molecular genetic testing — panel sequencing of ENG, ACVRL1, and SMAD4 — identifies a pathogenic mutation in approximately 85% of individuals who meet clinical criteria for definite HHT. Genetic testing is important not only for diagnostic confirmation but for cascade family testing: once a mutation is identified in a proband, at-risk relatives can be tested definitively, enabling early surveillance and prevention of complications (particularly PAVM-related stroke) in those who test positive.

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Epistaxis: The Cardinal Symptom

Spontaneous recurrent epistaxis (nosebleeds) is the most prevalent manifestation of HHT, occurring in 90–95% of affected individuals. It is typically the first symptom to appear, with average onset around age 12, though it may begin in early childhood or not until adulthood. The frequency and severity of nosebleeds increase with age and can range from occasional mild bleeds to multiple severe hemorrhages daily. In many patients, the blood loss is severe enough to cause iron-deficiency anemia requiring intravenous iron infusions or repeated blood transfusions. The mechanism is straightforward but unamenable to simple compression: nasal mucosal telangiectases on the septum and inferior turbinates lack the normal supporting connective tissue of healthy capillaries, making them fragile and prone to spontaneous rupture. Because the lesions are arteriovenous connections rather than simple capillaries, compressing the nose does not produce the tourniquet effect that stops ordinary epistaxis.

Management follows a stepwise treatment ladder. First-line conservative measures include nasal humidification (saline nasal spray, petroleum jelly application, bedroom humidifiers) to reduce desiccation of fragile mucosa; these reduce friction and bleeding frequency with no risk. Topical tranexamic acid spray provides antifibrinolytic support locally. Laser or bipolar cautery can ablate visible telangiectases, though repeated treatments risk worsening mucosal atrophy and are not curative. Systemic oral tranexamic acid provides moderate epistaxis reduction. Intranasal bevacizumab — injected directly into the nasal mucosa — has RCT evidence of 50–60% reduction in epistaxis duration and frequency by targeting VEGF-driven telangiectasia formation. Intravenous systemic bevacizumab is reserved for severe or refractory epistaxis, with response rates of 70–80% or greater. Pomalidomide (an oral immunomodulator) received FDA Breakthrough Therapy Designation in 2021 and Phase 2 trial results show significant epistaxis reduction with a more favorable side-effect profile than thalidomide. Surgical septodermoplasty (Young's procedure) — which replaces telangiectasia-bearing nasal mucosa with skin grafts — and complete nasal closure are reserved for the most severe, intractable cases. All patients with significant blood loss require active iron replacement, preferably intravenous in high-output bleeding states.

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Pulmonary Arteriovenous Malformations (PAVMs)

Pulmonary AVMs are present in 40–60% of patients with HHT Type 1 (ENG mutations) and in 15–25% of those with HHT Type 2 (ACVRL1 mutations). Many PAVMs are clinically silent for years, discovered only on screening. Symptomatic patients may experience dyspnea on exertion, cyanosis, hypoxemia (low oxygen saturation due to right-to-left shunting of blood bypassing alveolar gas exchange), orthodoxia (decreased oxygen saturation specifically in the upright position, as lower-lobe PAVMs are gravity-dependent), and platypnea (dyspnea worsening in the upright position). Hemoptysis is rare but alarming when it occurs.

The most feared consequences of untreated PAVMs arise from loss of the pulmonary capillary filter function. Normally, the pulmonary capillaries trap thrombi, bacteria, air bubbles, and other emboli before they can reach the systemic circulation. PAVMs create a direct conduit bypassing this filter, enabling paradoxical embolism. The two principal life-threatening complications are ischemic stroke — occurring in up to 25% of HHT patients with untreated PAVMs, typically from paradoxical thromboembolism or paradoxical air embolism during IV access — and brain abscess, with an annual incidence of approximately 1% in patients with untreated PAVMs. Brain abscesses arise from bacteremia with oral organisms (Streptococcus, Staphylococcus) bypassing the pulmonary filter and seeding the brain; the risk is increased after dental procedures, and prophylactic antibiotics are standard before dental or invasive procedures in patients with known untreated PAVMs. Air-eliminating filters should always be used during intravenous access.

Screening and treatment follow HHT Foundation International guidelines. Contrast (bubble) echocardiography — in which agitated saline creates microbubbles that appear in the left heart within 3–5 cardiac cycles if a right-to-left shunt is present — is the first-line screening test; it is highly sensitive and widely available. If positive, CT pulmonary angiography (CTPA) characterizes PAVM anatomy and identifies feeding artery diameters, which determines treatment eligibility. PAVMs with feeding artery diameters of 2–3 mm or greater are treated by transcatheter embolization — a minimally invasive catheter-based procedure in which coils or vascular plugs occlude the PAVM feeding artery, immediately restoring the capillary filter function. Surgical resection is reserved for PAVMs not amenable to embolization. Treated PAVMs require follow-up CTPA at 6–12 months (to confirm occlusion and detect recanalization) and then every 3–5 years, as new PAVMs can develop over time. All patients with HHT should be screened beginning at diagnosis (age 16 in children of HHT-affected parents) and every 5 years thereafter.

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Hepatic AVMs and Cerebral Vascular Malformations

Hepatic AVMs are found in 32–78% of HHT patients, with higher prevalence in HHT Type 2 (ACVRL1 mutations). Three anatomical types of intrahepatic shunts occur: hepatic artery to hepatic vein, hepatic artery to portal vein, and portal vein to hepatic vein. The majority of hepatic AVMs are asymptomatic and discovered incidentally on imaging. When symptomatic, the most important complication is high-output cardiac failure — large hepatic arteriovenous shunts dramatically increase cardiac output (sometimes doubling or tripling normal values) as the heart compensates for the effective arteriovenous steal. This occurs in approximately 5–8% of patients with hepatic AVMs and is the leading indication for liver transplantation in HHT. Systemic intravenous bevacizumab has demonstrated striking efficacy in this setting, reducing cardiac output substantially in multiple case series and controlled studies (Dupuis-Girod 2012) and averting liver transplantation in many patients who had no other option. Additional complications include portal hypertension (causing varices, ascites, and splenomegaly) and biliary ischemia (ischemic cholangiopathy from arterial steal away from the bile ducts). A critical management rule: hepatic AVMs in HHT must never be treated with transcatheter embolization — unlike PAVMs, hepatic AVMs are diffuse throughout the organ and embolization carries a high risk of hepatic infarction and biliary necrosis. Doppler ultrasound is the initial screening modality for hepatic AVMs; CT angiography provides definitive anatomical characterization when clinical suspicion is high or symptoms arise.

Cerebral vascular malformations are present in 10–15% of HHT patients and include arteriovenous malformations (AVMs), cavernous malformations (cavernomas), and developmental venous anomalies. Cerebral AVMs carry a risk of spontaneous hemorrhagic stroke estimated at approximately 2–4% per year, which can cause intracerebral hemorrhage with potentially devastating neurological deficits. Seizures, focal deficits, and headache are other presenting features. MRI brain with gadolinium at the time of HHT diagnosis is recommended for all patients to identify cerebral vascular malformations. Treatment decisions for cerebral AVMs — neurosurgical resection, stereotactic radiosurgery (Gamma Knife), or endovascular embolization, often in combination — depend on AVM size, location relative to eloquent cortex, and patient-specific risk factors. Gastrointestinal telangiectases occur throughout the GI tract in HHT and can cause chronic occult blood loss leading to iron deficiency anemia; they are evaluated with capsule endoscopy or push enteroscopy and treated with argon plasma coagulation, systemic bevacizumab, or thalidomide analogues when bleeding is significant.

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Diagnosis, Genetic Testing, and Surveillance Protocol

Clinical diagnosis rests on the Curaçao criteria (3 or more features = definite HHT). Molecular diagnosis by panel genetic testing — sequencing of ENG, ACVRL1, and SMAD4 — identifies a pathogenic mutation in approximately 85% of clinically definite cases. A negative gene panel does not exclude HHT in a patient with a strong clinical picture, as additional causative genes (GDF2/BMP9, RASA1, others) may be identified by expanded panels or remain unknown. Once a familial mutation is identified, cascade testing of first-degree relatives is efficient and accurate, enabling early surveillance of mutation-positive family members.

The HHT Foundation International surveillance protocol specifies the following at initial diagnosis and on follow-up: Pulmonary AVMs — bubble echocardiogram (all patients at diagnosis); if positive, proceed to CT pulmonary angiography; screen again at age 16 in children of affected parents, and every 5 years lifelong regardless of prior negative results, as PAVMs can develop or enlarge over time. Cerebral vascular malformations — MRI brain with gadolinium at diagnosis for all patients; one-time screening is generally sufficient in the absence of new neurological symptoms. Hepatic AVMs — not routinely screened in asymptomatic patients; Doppler ultrasound or CT angiography is indicated when symptoms of heart failure, portal hypertension, or biliary disease arise. Pregnancy represents a high-risk period in HHT: estrogen and progesterone upregulate VEGF, causing PAVMs to enlarge significantly during gestation; all PAVMs should be identified and treated before planned pregnancy; HHT specialists should co-manage pregnancy. The risk of new PAVMs forming during pregnancy makes surveillance important even in previously negative patients entering pregnancy.

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Systemic Therapies: Bevacizumab, Pomalidomide, mTOR

Bevacizumab (Avastin, anti-VEGF monoclonal antibody) is the most important systemic disease-modifying therapy currently available for HHT. Its use is mechanistically justified by the VEGF upregulation downstream of impaired BMP9 signaling. Systemic intravenous bevacizumab is used for: (1) high-output cardiac failure from hepatic AVMs — multiple studies and the landmark RCT by Dupuis-Girod et al. (JAMA 2012, PMID 22392165) demonstrated significant reductions in cardiac output (mean reduction ~1 L/min), liver blood flow, and improvement in functional status, with a 70% response rate; (2) severe or refractory epistaxis not controlled by local measures — robust evidence of 50–70% reduction in epistaxis duration and hemoglobin stabilization; (3) management of multiple or diffuse PAVMs not amenable to embolization. Intranasal bevacizumab injected directly into the nasal mucosa has been validated in multiple RCTs for epistaxis reduction. Common side effects of systemic bevacizumab include hypertension, impaired wound healing, thromboembolic events, and (with prolonged use) proteinuria and osteonecrosis of the jaw. Treatment is typically given as induction courses repeated at 6–12 month intervals.

Pomalidomide (Pomalyst), an immunomodulatory drug (IMiD) related to thalidomide, received FDA Breakthrough Therapy Designation in 2021 for HHT-associated severe epistaxis. Its mechanism in HHT involves modulation of endothelial cell behavior, reduction of VEGF expression, promotion of vascular maturation, and reduction of telangiectasia density. Phase 2 trial data (Invernizzi et al., J Intern Med 2020, PMID 32237070) demonstrated significant reduction in epistaxis severity score and frequency with oral pomalidomide, with a more tolerable side-effect profile than thalidomide. Pomalidomide avoids the severe peripheral neuropathy that limits thalidomide use with longer-term exposure. Thalidomide itself was historically the first systemic antiangiogenic agent shown to reduce HHT epistaxis substantially, but peripheral neuropathy, teratogenicity (strict REMS program required), and constipation limit its long-term use; pomalidomide is now preferred when an oral IMiD is chosen. Pazopanib (a multi-target tyrosine kinase inhibitor blocking VEGFR, PDGFR, and FGFR signaling) has shown promise in case series for refractory epistaxis and hepatic AVM complications and is under investigation. The emergence of multiple targeted anti-angiogenic agents reflects the central role of dysregulated VEGF/BMP9 signaling in HHT pathobiology and offers patients with refractory disease a growing pharmacological toolkit.

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Key Research Papers

  1. Faughnan ME, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73-87. PMID: 19553198
  2. McDonald J, et al. Hereditary Hemorrhagic Telangiectasia. GeneReviews [Internet]. 2021. PMID: 20301525
  3. Dupuis-Girod S, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307(9):948-955. PMID: 22392165
  4. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 2010;24(6):203-219. PMID: 20870325
  5. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet. 2009;17(7):860-871. PMID: 19337313
  6. Kjeldsen AD, et al. Clinical symptoms and quality of life in patients with hereditary haemorrhagic telangiectasia (HHT). QJM. 2000;93(11):707-714. PMID: 11077028
  7. Woodall MN, et al. Pulmonary AVM embolotherapy. J Vasc Interv Radiol. 2011;22(3):283-290. PMID: 21281934
  8. Letteboer TG, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet. 2006;43(4):371-377. PMID: 16155191
  9. Maher CO, et al. Surgical treatment of intracranial arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. Neurosurgery. 2001;49(3):595-602. PMID: 11523671
  10. Invernizzi R, et al. Pomalidomide treatment for epistaxis in hereditary hemorrhagic telangiectasia. J Intern Med. 2020;288(2):256-260. PMID: 32237070
  11. Ricard N, et al. BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood. 2012;119(25):6162-6171. PMID: 22565989
  12. Buscarini E, et al. Hereditary haemorrhagic telangiectasia diagnosis and management from the European Reference Network for Rare Vascular Diseases (VASCERN). Eur J Med Genet. 2019;62(7):103508. PMID: 30503947

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