Hereditary Hemorrhagic Telangiectasia

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 most evident on the lips, tongue, buccal mucosa, face, chest, and fingers. The average age of onset is generally later than epistaxis, but may be during childhood. Large AVMs often cause symptoms when they occur in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after 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, visceral AVMs, and/or a family history of HHT. Identification of a heterozygous pathogenic variant in ACVRL1, ENG, GDF2, or SMAD4 establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Nosebleeds are treated with humidification, nasal lubricants, hemostatic products, laser ablation, sclerotherapy, nasal closure, and oral or topical medications. GI bleeding is treated with iron replacement therapy and (if needed) endoscopic ablation, surgical resection of bleeding sites, and/or medical therapy. Pulmonary AVMs with a feeding vessel 1 mm or greater in diameter require consideration of occlusion. Cerebral AVMs are treated, when indicated by location or symptoms, by surgery, embolotherapy, and/or stereotactic radiosurgery. Symptomatic hepatic AVMs are managed medically; liver transplantation is recommended for individuals who do not respond to medical therapy and who develop hepatic failure. Women with HHT considering pregnancy are screened and treated for pulmonary and cerebral AVMs; 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.

Prevention of secondary complications: When pulmonary AVMs are present or suspected, antibiotic prophylaxis for dental and invasive procedures and a filter on intravenous lines to prevent air bubbles from being inadvertently infused is recommended.

Surveillance: Annual evaluations for anemia; supine and sitting pulse-oximetry every one to two years during childhood; evaluation for pulmonary AVMs every five years with contrast echocardiography by age ten years; head MRI in infancy and then rescreening for cerebral AVMs by brain MRI after puberty; periodic screening for gastrointestinal polyps and malignant change in persons with juvenile polyps.

Agents/circumstances to avoid: Vigorous nose blowing; lifting heavy objects; straining during bowel movements; electric or chemical cautery for nosebleeds; anticoagulant and anti-inflammatory agents (including aspirin) in individuals with significant nose or GI bleeding; scuba diving unless contrast echocardiography 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.

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:

• Nosebleeds (epistaxis). Spontaneous and recurrent; night-time nosebleeds heighten the concern for HHT.
• Mucocutaneous telangiectases (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). An arteriovenous malformation lacks capillaries and consists of direct connections between arteries and veins. AVMs may be pulmonary, cerebral, hepatic, spinal, gastrointestinal, or pancreatic.
• Family history. A first-degree relative in whom HHT has been diagnosed

Establishing the Diagnosis

According to published consensus clinical diagnostic criteria, the diagnosis of HHT is considered "confirmed" in an individual with three or more of the above features. The diagnosis of HHT is considered "suspected" in an individual with two of the above features [Shovlin et al 2000]. Identification of a heterozygous pathogenic variant in one of the genes listed in Table 1 establishes the diagnosis if clinical features are inconclusive.

Note: The application of these clinical diagnostic criteria to children at risk for HHT can be misleading. Symptoms and signs of HHT generally develop during childhood and adolescence; epistaxis, telangiectases, and symptoms of visceral AVMs are frequently absent in affected children (see Evaluation of Relatives at Risk).

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

• Serial single-gene testing can be considered. Sequence analysis of ACVRL1 and ENG can be performed first. Deletion/duplication analysis of ACVRL1 and ENG can be done next if no pathogenic variant is found.
  • Sequence analysis of SMAD4 should be considered first in any person with HHT and intestinal polyps. SMAD4 sequence analysis should also be considered in symptomatic individuals in whom no pathogenic variant is identified through sequence analysis and deletion/duplication analysis of ACVRL1 and ENG.
  • Sequence analysis of GDF2 could be considered for symptomatic individuals in whom no pathogenic variant is identified in ACVRL1, ENG, or SMAD4 particularly if dermal telangiectases appear larger than pinhead-pinpoint size and are not limited to the hands, mouth, and face.
• A multigene panel that includes ACVRL1, ENG, GDF2, SMAD4 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes the genes in listed in Table 1) fails to confirm a diagnosis in an individual with features of HHT. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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 arteriovenous malformations 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).

Epistaxis (nosebleeds). The nasal mucosa is fragile and minor insults from drying air and repeated minor abrasions result in recurrent bleeding. Epistaxis has an average age of onset of approximately 12 years [Aassar et al 1991]. As many as 95% of affected individuals eventually experience recurrent epistaxis, with one third having onset by age ten years, approximately 80% by age 20 years, and 90% before age 30 years [Berg et al 2003]. However, many do not have nosebleeds that are frequent or severe enough to cause anemia or to result in medical treatment or consultation. Epistaxis was a common cause of death in HHT before the development of blood transfusion.

Telangiectases associated with HHT are found primarily on the lips, tongue, buccal mucosa, face, chest, and fingers. The average age of onset is generally later than epistaxis, but may be during childhood; 30% of affected individuals report telangiectases first appearing before age 20 years and two thirds before age 40 years [Berg et al 2003]. They may appear as pinhead-size lesions or as larger, even raised lesions with multiple draining venules. Telangiectases are distinguished from petechiae and angiomata by their ability to blanch with gentle pressure, and then immediately but often slowly refill. Because of their thin walls, narrow tortuous paths, and proximity to the surface of the skin or to a mucous membrane, telangiectases can rupture and bleed after only slight trauma. Since the contractile elements in the vessel wall are lacking, given the abnormal arterial connection, bleeding from telangiectases is frequently brisk and difficult to stop. Telangiectases of the skin are significantly less likely to bleed than those of the nasal mucosa.

Telangiectases are common in adulthood throughout the gastrointestinal (GI) mucosa, but most commonly, the stomach and the proximal small intestine (duodenum) are involved. Approximately one quarter of all individuals with HHT eventually have bleeding from GI telangiectases. It most commonly begins after age 50 years, and is slow but persistent; but can become increasingly severe with age [Plauchu et al 1989, Kjeldsen & Kjeldsen 2000]. It presents more often as iron deficiency anemia than acute GI hemorrhage; but GI bleeding is a less common cause of iron deficiency in individuals with HHT than under-recognized epistaxis. No particular foods, activities, or medications have been identified as contributors to GI bleeding in individuals with HHT.

AVMs. AVMs occur most commonly in the lungs, liver, and brain. Although hemorrhage is often the presenting symptom of cerebral AVMs, most visceral AVMs present as a consequence of blood shunting through the abnormal vessel and bypassing the capillary bed.

Pulmonary AVMs occur in approximately 30%-50% of affected individuals [McDonald et al 2011a] and can develop over time but rarely after age 30. Shunting of air, thrombi, and bacteria through pulmonary AVMs (thus bypassing the filtering capabilities of the lungs) may cause transient ischemic attacks (TIAs), embolic stroke, and cerebral and other abscesses. In one series, serious neurologic events including TIA, stroke, and brain abscess occurred in 30%-40% of individuals with pulmonary AVMs with feeding arteries 3.0 mm or greater in diameter [White 1996]. These neurologic complications may occur in individuals with isolated pulmonary AVMs and near-normal arterial oxygen tension. Pulmonary AVMs frequently enlarge with time [White 1996]. One study of 42 children with pulmonary AVMs demonstrated that children can have life-threatening complications from these lesions. More than half presented with exercise intolerance, cyanosis, or clubbing, and although the neurologic complications were less frequent than in adults, they had occurred in 19% prior to detection and treatment [Faughnan et al 2004]. Migraine headache and polycythemia are additional complications of pulmonary AVMs. Occasionally, a pulmonary AVM can rupture, leading to hemoptysis.

The frequency of hepatic vascular abnormalities was 74% in one study that systematically imaged the liver of affected individuals using CT [Ianora et al 2004] and 41% in another study using ultrasound examination [Buscarini et al 2004a]. However, only a small minority (8% in the study using CT) were symptomatic. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease [Garcia-Tsao et al 2000]. Hepatic focal nodular hyperplasia is also associated with the shunting effects of blood through these high-flow vascular lesions [Buscarini et al 2004b, Brenard et al 2010].

In the brain, AVMs are typically present at birth. Cerebral AVMs occur in approximately 10% of individuals with HHT [McDonald et al 2011a].

Spinal AVMs appear to be significantly less common, but may present with paralysis.

Vascular lesions in the pancreas are common but rarely a clinical issue [Lacout et al 2010].

Anemia. Epistaxis, or less commonly GI bleeding, can cause mild to severe anemia, often requiring iron replacement therapy or rarely, blood transfusion. In middle age adults, GI bleeding becomes a more important contributor to anemia and iron deficiency.

Pulmonary hypertension is another pulmonary vascular manifestation of HHT. Although much less common than pulmonary AVMs, it can either result from systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension [Cottin et al 2007, Girerd et al 2010, Austin et al 2013] (see Pulmonary Arterial Hypertension).

Phenotype Correlations by Gene

Pulmonary AVMs are more common in individuals with ENG pathogenic variants, and hepatic AVMs are more common in individuals with ACVRL1 pathogenic variants. However, both types are clearly multisystem vascular dysplasias with most manifestations described in 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 had presented as JP 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

HHT displays age-related penetrance with increased manifestations developing over a lifetime.

• Approximately 50% of diagnosed individuals report having nosebleeds by age ten years and 80%-90% by age 21 years. As many as 95% eventually develop recurrent epistaxis.
• The percentage of individuals with telangiectases of the hands, face, and oral cavity is similar to the percentage with epistaxis, but the age of onset of telangiectases is generally five to 30 years later than for epistaxis [Plauchu et al 1989, Porteous et al 1992].
• Cerebral AVMs are almost always congenital [Faughnan et al 2011]. Intracranial hemorrhage secondary to AVM can be the presenting symptom of HHT in infants and children with HHT [Morgan et al 2002].

Anticipation

While intrafamilial variability is considerable, there has been no systematic generational progression to suggest anticipation.

Nomenclature

The original description of the syndrome was made by Sutton in 1864. However, Osler in the USA, 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

A number of studies indicate that HHT is significantly more frequent than formerly thought, at least in the populations investigated. The overall 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, or GI bleeding.

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 hereditary hemorrhagic telangiectasia (HHT), the following evaluations are recommended [Faughnan et al 2011, McDonald et al 2011a]:

• Medical history, with particular attention to epistaxis and other bleeding, anemia or polycythemia, diseases of the heart, lung and liver, and neurologic symptoms
• Physical examination including inspection for telangiectases (particularly on fingers, lips, tongue, oropharynx, cheeks, or conjunctiva) and listening for abdominal bruits
• Complete blood count, with particular attention to anemia or polycythemia. If anemia is present, it is important to consider other causes of anemia, particularly when the anemia appears to be disproportionate to the amount of epistaxis. People with HHT may develop medical problems unrelated to HHT (e.g., ulcers or colon cancer) that can cause GI blood loss. Polycythemia raises suspicion for pulmonary arteriovenous malformations.
• Contrast echocardiography for detection of pulmonary shunting/AVM and measurement of the pulmonary artery systolic pressure as a screen for pulmonary artery hypertension. When pulmonary shunting is suggested (or if dependable contrast echocardiography is not available), CT angiography with cuts of 3 mm or less to define size and location of lesions(s) is the next step.
• Head MRI (with and without gadolinium) to detect cerebral AVMs, performed as early as possible, preferably in the first year of life. Adults, including those screened with MRI in infancy, should all have a screening head MRI to detect unsuspected vascular lesions and occult cerebral abscesses.
• Consideration of ultrasound or CT examination for evidence of hepatic AVM if the individual has symptoms such as high-output failure associated with hepatic vascular abnormalities or otherwise unexplained elevations in liver function tests, or if presence of a visceral AVM would confirm a diagnosis of HHT
  Note: Screening for hepatic AVMs in asymptomatic individuals is not common practice because:
  • Hepatic AVMs are not usually symptomatic and, when they do become symptomatic, it is not sudden and catastrophic, as is seen with pulmonary AVMs and cerebral AVMs; and
  • Treatment options for hepatic AVMs are less satisfactory than those for pulmonary or cerebral AVMs.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prevention of Primary Manifestations

See Treatment of Manifestations. Prevention is currently focused at ablating, occluding, resecting or shrinking telangiectases and AVMs to prevent associated morbidity and mortality.

Prevention of Secondary Complications

If contrast echocardiography is positive for pulmonary shunting, even if no pulmonary AVM is demonstrated by chest CT, a lifetime recommendation for prophylactic antibiotics in accordance with the American Heart Association protocol for dental cleaning and other "dirty" procedures is advised because of the risk of abscess, particularly brain abscess, associated with right to left shunting [Dupuis-Girod et al 2007]. For the same reason, an air filter or extreme caution not to introduce air bubbles is recommended with IV lines.

Note: The risk associated with these lesions is not for subacute bacterial endocarditis (SBE).

Surveillance

The following protocol is recommended for follow up of all individuals for whom the diagnosis of HHT is definite 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 2011]:

• Annual evaluation by a health care provider familiar with HHT, including interval history for epistaxis or other bleeding, shortness of breath or decreased exercise tolerance, and headache or other neurologic symptoms
• Periodic hematocrit/hemoglobin and ferritin determination with appropriate treatment for iron deficiency anemia
• Reevaluation for pulmonary AVM at approximately five-year intervals [Nawaz et al 2008]:
  • Contrast echocardiogram is used (if available) if the previous contrast echocardiogram did not reveal evidence of a pulmonary or intracardiac right to left shunt.
  • Chest CT with contrast rather than pulmonary angiography is used if the previous contrast echocardiogram revealed evidence of a right to left shunt.
• Reevaluation for cerebral AVM. While cerebral AVMs are nearly always congenital, development or evolution of cerebral AVMs in the first two decades of life has been reported [Hetts et al 2014]. Accordingly, many HHT experts recommend rescreening the brain once more after puberty if the initial brain MRI was done in childhood.
• Periodic screening for gastrointestinal polyps and malignant change in persons with juvenile polyps

Childhood

• Because serious complications of pulmonary and cerebral AVM can occur at any age [Mei-Zahav et al 2006, Curie et al 2007], screening for pulmonary and cerebral AVMs is recommended in children from families with HHT, especially those with ENG pathogenic variants [Al-Saleh et al 2009].
• Head MRI with and without gadolinium is recommended as early as the first few months of life [Faughnan et al 2011].
• Pulse oximetry in the supine and sitting positions every one to two years during childhood is recommended as a minimum to screen for pulmonary AVMs. It may be of concern if the sitting value is even a few percentage points below that of the supine value. (Since most pulmonary AVMs are in the lower lobes, many individuals with pulmonary AVMs have higher oxygen saturation when lying than when sitting because of the effect of gravity.) Oxygen saturations below 97% should be followed up with contrast echocardiography. Many, but not all, serious complications of pulmonary AVM during childhood have occurred in hypoxemic children.
• By at least age ten years, additional evaluation should be performed by contrast echocardiography, with a follow-up CT if positive.

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.

Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds in most situations.

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. In one study, lower dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use [Devlin et al 2013].

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 appropriate to evaluate at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from preventive measures (see Prevention of Primary Manifestations) 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, consequently, HHT cannot been ruled out by molecular diagnosis, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (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 also at high risk for lung hemorrhage and cerebral complications