Clinical characteristics.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.

Diagnosis/testing.

The diagnosis of HHT is established in a proband with three or more of the following clinical features:

• Epistaxis
• Mucocutaneous telangiectases in characteristic locations
• Visceral AVMs
• A first-degree relative diagnosed with HHT on the basis of the preceding criteria

Identification of a heterozygous pathogenic variant in ACVRL1, ENG, or SMAD4 establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Nosebleeds are treated with humidification, topical moisturizing therapy, hemostatic products, antifibrinolytic therapy, ablation therapy, systemic antiangiogenic agents, septodermoplasty, and nasal closure as needed. GI bleeding and anemia is treated with iron replacement therapy and (if needed) blood transfusions and antiangiogenic agents. Pulmonary AVMs with a feeding vessel 1-2 mm or greater in diameter typically require occlusion for stroke prevention. When pulmonary shunting is present, use antibiotic prophylaxis for dental and non-sterile invasive procedures, taking care to prevent air bubbles from being introduced in intravenous lines. This may include an air filter when available and compatible with the medication being administered. Treatment of pulmonary artery hypertension as per cardiologist, pulmonologist, and other relevant specialists. Symptomatic hepatic AVMs are managed medically; liver transplantation is recommended for individuals who do not respond to medical therapy and who develop high-output heart failure. Cerebral AVMs are treated as indicated by size, location, or symptoms: by surgery, embolotherapy, and/or stereotactic radiosurgery. Gastrointestinal polyps are treated according to guidelines for juvenile polyposis syndrome.

Surveillance: Annual evaluation by a health care provider familiar with HHT for signs and symptoms of complications; annual hematocrit, hemoglobin, and ferritin; evaluation for pulmonary AVMs every five years with transthoracic contrast echocardiography (TCE) in adults, TCE or chest radiograph with pulse oximetry in children; brain MRI with and without contrast using sequences that detect blood products in infancy and again after puberty for cerebral AVMs; colonoscopy at age 15 years and repeated every three years if no polyps are found, or annually with esophagogastroduodenoscopy if colonic polyps are identified in those with SMAD4-HHT.

Agents/circumstances to avoid: Vigorous nose blowing; lifting heavy objects; straining during bowel movements; finger manipulation in the nose; anticoagulant and anti-inflammatory agents (including aspirin) in individuals with significant nose or GI bleeding; scuba diving unless TCE within the last five years was negative for evidence of a right-to-left shunt; liver biopsy.

Evaluation of relatives at risk: Molecular genetic testing is offered to at-risk family members if the germline pathogenic variant has been identified in the family. If the pathogenic variant in the family is not known, at-risk family members should be evaluated for signs and symptoms of HHT, and screening should be offered to at-risk family members if the diagnosis cannot be ruled out.

Pregnancy management: Women with HHT considering pregnancy are screened and treated for pulmonary and cerebral AVMs; sizable pulmonary AVMs discovered during pregnancy are treated during the second trimester. Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia despite aggressive iron replacement therapy.

Genetic counseling.

HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability. Most individuals have an affected parent. Each child of a proband and the sibs of most probands are at a 50% risk of inheriting the pathogenic variant. Prenatal testing is possible for a pregnancy at increased risk if the pathogenic variant in the family is known.

Suggestive Findings

Hereditary hemorrhagic telangiectasia (HHT) should be considered in an individual with any of the following features:

• Spontaneous and recurrent nosebleeds (epistaxis). Night-time nosebleeds heighten the concern for HHT.
• Multiple telangiectases at characteristic sites. Small blanchable red spots that are focal dilatations of post-capillary venules or delicate, lacy red vessels composed of markedly dilated and convoluted venules; multiple, at characteristic sites, including lips, oral cavity, fingers, and nose. Transillumination of the digits is helpful for detecting vascular lesions not evident on the skin [Mohler et al 2009].
• Visceral arteriovenous malformation (AVM). Typically pulmonary, cerebral, hepatic, spinal, gastrointestinal, or pancreatic. AVMs outside these locations are uncommon and not suggestive of HHT.
• Family history. A first-degree relative in whom HHT has been diagnosed according to these criteria. Note: Any family history of the above clinical features is suggestive of HHT, but only a first-degree relative with a diagnosis of HHT based on Curaçao criteria fulfills this diagnostic criterion.

Establishing the Diagnosis

The clinical diagnosis of HHT can be established in a proband using criteria referred to as the Curaçao criteria, which require three or more of the above suggestive findings [Shovlin et al 2000, Faughnan et al 2020], or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in one of the genes listed in Table 1 identified by molecular genetic testing.

Note: (1) The application of clinical diagnostic criteria to children at risk for HHT can fail to identify affected children. Signs and symptoms of HHT generally develop during childhood and adolescence; epistaxis, telangiectases, and symptoms of visceral AVMs are frequently absent in affected children [Gonzalez et al 2018, Gonzalez et al 2019] (see Evaluation of Relatives at Risk). (2) The vascular malformations of HHT occur in characteristic locations. Telangiectases and AVMs in locations other than those listed above as characteristic should not be considered suggestive of HHT.

Molecular genetic testing approaches can include a combination of concurrent gene or serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HHT has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs are called telangiectases. The term AVM usually refers to the "large" telangiectases, greater than a few millimeters in diameter and sometimes up to several centimeters in diameter. The most common feature that brings individuals with HHT to medical attention are epistaxis (nosebleeds).

Phenotype Correlations by Gene

Pulmonary and cerebral AVMs are more common in individuals with ENG pathogenic variants, and hepatic AVMs are more common in individuals with ACVRL1 pathogenic variants. However, pathogenic variants in both ENG and ACVRL1 cause multisystem vascular dysplasias, with most manifestations associated with both [Kjeldsen et al 2005, Bayrak-Toydemir et al 2006b, Letteboer et al 2006, Lesca et al 2007].

Pulmonary hypertension in the absence of severe vascular shunting, a rare HHT manifestation, has occurred most commonly in individuals with pathogenic variants in ACVRL1, but has also been reported in individuals with pathogenic variants in ENG [Soubrier et al 2013].

Pathogenic variants in SMAD4 have been reported in families with a combined syndrome of juvenile polyposis syndrome (JPS) and HHT [Gallione et al 2004], as well as in families reported to have JPS or HHT only. A recent study found that the majority of families with an SMAD4 pathogenic variant who presented with JPS only were found to have features of HHT when specifically reexamined for such manifestations [O'Malley et al 2012].

Genotype-Phenotype Correlations

Data suggest that no absolute genotype-phenotype correlations exist between clinical phenotypes and specific pathogenic variants [McDonald et al 2015].

Penetrance

Penetrance is approximately 95% by late adulthood.

Nomenclature

The original description of the syndrome was made by Sutton in 1864. However, Osler in the US, Parkes Weber in the UK, and Rendu in France are typically given credit; hence the eponymous Osler-Weber-Rendu syndrome (or Rendu-Osler-Weber in articles in the French literature). The designation "hereditary hemorrhagic telangiectasia" was suggested in 1912 by one of Osler's residents.

The gene now identified as ACVRL1 is referred to in many publications as ALK1. Note: Other genes were also previously named ALK1.

Prevalence

The incidence of HHT in North America is estimated at 1:10,000 [Marchuk et al 1998]; however, this is likely an underestimate [Guttmacher et al 2013]. For example, when a proband is diagnosed, it is not unusual to identify multiple relatives in the family who have not been diagnosed with HHT but have experienced epistaxis, embolic stroke, and/or other manifestation(s) of HHT.

HHT occurs with wide ethnic and geographic distribution. The condition is especially prevalent in the Netherland Antilles because of a founder effect.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HHT, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended [Faughnan et al 2011, Hosman et al 2017, Faughnan et al 2020].

Treatment of Manifestations

Surveillance

The following surveillance is recommended for all individuals with an established diagnosis of HHT and for all individuals at risk for HHT based on family history in whom HHT has not been ruled out by molecular diagnosis [Faughnan et al 2020].

Agents/Circumstances to Avoid

Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol.

Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. However, HHT is not an absolute contraindication for anticoagulation (prophylactic or therapeutic) or antiplatelet therapy. It is recommended that individuals with HHT receive these therapies when there is an indication, with consideration of their individualized bleeding risks [Faughnan et al 2020]. Two case series demonstrated that anticoagulation or antiplatelet therapy is well tolerated by most individuals with HHT [Edwards et al 2012, Devlin et al 2013].

When anticoagulation is pursued, unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are preferred over direct-acting oral anticoagulants, which are less well tolerated in individuals with HHT [Shovlin et al 2019]. In individuals with atrial fibrillation, if anticoagulation is not tolerated, alternate approaches can be considered, such as left atrial appendage closure [Vorselaars et al 2015]. Avoiding the use of dual antiplatelet therapy and/or combination of antiplatelet and anticoagulation is recommended when possible.

Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt.

Liver biopsy should be avoided in individuals with HHT [Buscarini et al 2006].

Evaluation of Relatives at Risk

It is recommended to evaluate at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and prompt initiation of treatment to reduce morbidity and mortality.

If the pathogenic variant in the family is known, evaluate with molecular genetic testing.

If the familial pathogenic variant is not known and the diagnosis of HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is established (see Surveillance).

• Individuals older than age 40 years should have a targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring.
• In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT in addition to an evaluation for brain and pulmonary AVMs should be done initially, as features of HHT may not be identified by medical history and clinical examination in younger individuals.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with HHT and untreated pulmonary AVMs are at increased risk for complications related to hemorrhage or embolic events. Women with treated pulmonary AVMs appear to be at no higher risk during pregnancy than those without pulmonary AVMs. For this reason, published management guidelines recommend that pregnant women with HHT who have not been recently screened and/or treated for pulmonary AVM should be managed as follows:

• In asymptomatic women, initial screening for pulmonary AVMs should be performed using either transthoracic contrast echocardiography with agitated saline contrast or low-dose noncontrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.
• In women with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose noncontrast chest CT. This testing can be performed at any gestational age, as clinically indicated.
• Pulmonary AVMs should be treated starting in the second trimester unless otherwise clinically indicated.

An unenhanced brain MRI is recommended in pregnant women with symptoms suggestive of cerebral AVM. Women who are asymptomatic do not require routine screening for cerebral AVMs during pregnancy.

Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia refractory to aggressive iron replacement therapy.

Expert consensus is to not withhold an epidural because of a diagnosis of HHT, and that screening for spinal vascular malformations is not required. Two case series showed no evidence of hemorrhagic complications from epidural or spinal anesthesia [Shovlin et al 2008, de Gussem et al 2014, Faughnan et al 2020].

Therapies Under Investigation

Newer therapies designed to interfere with the development of abnormal vascular connections are being investigated; while numerous case reports and small uncontrolled series indicate promise, results from controlled trials are needed [Flieger et al 2006, Mitchell et al 2008, Bose et al 2009, Davidson et al 2010, Lebrin et al 2010, Brinkerhoff et al 2011, Fodstad et al 2011, Suppressa et al 2011, Dupuis-Girod et al 2012].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Hereditary hemorrhagic telangiectasia (HHT) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with HHT have an affected parent.
• A proband with HHT may rarely have the disorder as the result of de novo pathogenic variant or mosaicism [McDonald et al 2015].
• If the proband appears to be the only affected family member (i.e., a simplex case), and:
  • The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
  • The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
    Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see Surveillance).
• If the proband has a known ACVRL1, ENG, or SMAD4 pathogenic variant that cannot be detected in leukocyte DNA of either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with HHT may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the HHT-causing pathogenic variant has been identified in the proband and molecular genetic testing has established that neither parent is heterozygous for the familial pathogenic variant.

Sibs of a proband. The risk to the sibs depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the HHT-causing pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known HHT-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, sibs should be considered at risk for HHT and, if the familial pathogenic variant is known, offered molecular genetic testing. If the familial pathogenic variant is not known, sibs should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see Surveillance). Although HHT is highly penetrant, a heterozygous parent may not have manifestations of the disorder until after age 40 years and observable symptoms and manifestations can be subtle, even well into adulthood.

Offspring of a proband. Each child of an individual with HHT has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has an HHT-causing pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management: Surveillance and Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic individuals. Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Surveillance). Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members when a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in an HHT-related gene.

Testing of asymptomatic at-risk family members usually involves pre-test consultation to discuss the possible impact of positive and negative test results. Those seeking testing should be counseled regarding possible problems that they may encounter with respect to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Informed consent should be procured, and records kept confidential. Individuals identified to have a pathogenic variant in one of the three HHT-related genes need long-term follow up and evaluations.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the HHT-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Currently, all known genetic defects that cause HHT are in genes that encode proteins within the transforming growth factor beta (TGF-β) signaling pathway.

• ACVRL1 encodes serine/threonine-protein kinase receptor R3, a type I cell-surface receptor for the TGF-superfamily of ligands. It is expressed predominantly on endothelial cells [Abdalla & Letarte 2006].
• ENG encodes endoglin, a component of the transforming growth factor beta (TGF-beta) receptor complex. It is expressed predominantly on endothelial cells.
• SMAD4 encodes a 552-amino acid protein that functions as an intracellular signaling molecule in the TGF-beta/BMP pathway.

Mechanism of disease causation. Loss of function

Author Notes

David Stevenson, MD is a practicing medical geneticist at Stanford University and helps direct the Stanford HHT Center of Excellence.
www.stanfordchildrens.org/en/service/genetics/vascular-anomaly-genetic-clinic.

Jamie McDonald MS, CGC, Associate Professor, Emeritus, Department of Pathology at the University of Utah was the Co-Director of the University of Utah HHT Center of Excellence from 2009-2021; and its co-founder and genetic counselor since 1996.

Jamie has many publications related to HHT, including invited review articles and original research focused particularly on the clinical and molecular diagnosis of HHT. She has served on the Cure HHT Global Research and Medical Advisory Board for many years. She co-chaired the Clinical and Molecular Diagnosis Group at the International HHT Guidelines Conference, which led to publication of the initial consensus guidelines for diagnosis and management in 2011. She was an invited member of the international conference which led to the publication in 2021 of the second consensus guidelines for the diagnosis and management of HHT.
ude.hatu.csh@dlanoDcM.eimaJ

Acknowledgments

Pinar Bayrak-Toydemir, MD, PhD, Department of Pathology, University of Utah

Author History

Alan Guttmacher, MD; National Institutes of Health (2000-2009)
Jamie McDonald, MS, CGC (2000-present)
Reed E Pyeritz, MD, PhD, FACMG; Perelman School of Medicine, University of Pennsylvania (2009-2021)
David Stevenson, MD (2021-present)

Revision History

• 24 November 2021 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 5 January 2012 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 22 November 2005 (me) Comprehensive update posted live
• 16 March 2004 (cd) Revision: sequence analysis
• 26 February 2004 (cd) Revision: quantitative PCR added as a test method
• 4 August 2003 (cd) Revisions
• 17 June 2003 (ca) Comprehensive update posted live
• 26 June 2000 (me) Review posted live
• January 2000 (jm) Original submission

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