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Hereditary Hemorrhagic Telangiectasia

Synonyms: HHT, Osler-Weber-Rendu Disease

, MS, CGC and , MD, PhD, FACMG.

Author Information

Initial Posting: ; Last Update: February 2, 2017.

Summary

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 pregnancies at increased risk if the pathogenic variant in the family is known.

Diagnosis

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 multi-gene 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 multi-gene 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 multi-gene panels vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
    For more information on multi-gene panels click 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 multi-gene 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 more information on comprehensive genome sequencing click here.

Table 1.

Molecular Genetic Testing Used in Hereditary Hemorrhagic Telangiectasia

Gene 1Proportion of HHT Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by This Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
ACVRL125%-57% 5, 690% 610% 7
ENG39%-59% 5, 690% 610% 7
GDF23 individuals 8~100%Unknown 9
SMAD41%-2% 6, 10>99% 6Unknown 9
Unknown 11, 12NANA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications

5.

There is a slight preponderance of ENG pathogenic variants in North America (~50%) and in northern Europe [Brusgaard et al 2004, Letteboer et al 2005, Schulte et al 2005, Bossler et al 2006, Prigoda et al 2006, Gedge et al 2007] compared to ACVRL1 pathogenic variants (~35%), and a greater preponderance of ACVRL1 pathogenic variants in southern Europe [Lenato et al 2006, Lesca et al 2006, Olivieri et al 2007].

6.

Sequence analysis of ACVRL1, ENG, and SMAD4 identifies pathogenic variants in approximately 75% of individuals with HHT [Bossler et al 2006, Prigoda et al 2006, Gedge et al 2007, Richards-Yutz et al 2010]. There are no common pathogenic variants, and sequence variants interpreted to be of uncertain significance are particularly common.

7.

The use of deletion/duplication analysis in addition to sequence analysis increases the detection rate by approximately 10% for ACVRL1- and ENG-related HHT [Bossler et al 2006, Prigoda et al 2006, McDonald et al 2011b].

8.

Pathogenic variants in GDF2 were identified in three individuals with features of HHT [Wooderchak-Donahue et al 2013].

9.

No data on detection rate of gene-targeted deletion/duplication analysis are available; however, one large deletion has been associated with juvenile polyposis and HHT [Wain et al 2014].

10.

Approximately 10% of those who test negative for a pathogenic variant in ACVRL1 and ENG [Gallione et al 2006, Lesca et al 2006, Prigoda et al 2006]

11.

One individual with signs of HHT and prominent pulmonary hypertension had a pathogenic variant in BMPR2 [Rigelsky et al 2008].

12.

Linkage analysis in one pedigree suggests a 5.4-cm disease gene interval on chromosome 5 (HHT3) [Cole et al 2005]. Linkage analysis in another pedigree suggests a disease gene in a 7-Mb region on the short arm of chromosome 7 (7p14) (HHT4) [Bayrak-Toydemir et al 2006a]. Rare pedigrees are not linked to any of these loci, suggesting additional heterogeneity.

Clinical Characteristics

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 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.

Differential Diagnosis

Telangiectases and epistaxis can be seen in otherwise healthy individuals.

Recurrent epistaxis can be a sign of various bleeding diatheses, including von Willebrand disease.

Telangiectases occur in a number of conditions:

  • Ataxia-telangiectasia, characterized by progressive cerebellar ataxia beginning between age one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectases of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Diagnosis relies on clinical findings (including slurred speech, truncal ataxia, and oculomotor apraxia), family history, and neuroimaging. Pathogenic variants in ATM are causative; inheritance is autosomal recessive.
  • CRST (calcinosis, Raynaud phenomenon, sclerodactyly, telangiectasia) syndrome (OMIM 181750)
  • Capillary malformation-arteriovenous malformation (CM-AVM) caused in some affected individuals by pathogenic variants in RASA1. RASA1-related disorders are characterized by the presence of multiple, small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain. In persons with RASA1-related disorders cutaneous zones of numerous pinpoint telangiectases – each surrounded by a white pale halo and typically distributed on the limbs or trunk – have also been described [Revencu et al 2013a]. This distribution of telangiectases and the presence of “halos” surrounding each red spot is not typical of HHT. Several individuals with a RASA1 pathogenic variant have the clinical diagnosis of Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft tissue and skeletal growth of an affected limb).
  • Hereditary benign telangiectasia (OMIM 187260), characterized by widespread telangiectases, predominantly on the face, upper limbs, and upper trunk. The telangiectases are venular and associated with upper dermal atrophy. It should be suspected in persons without a history/family history of nosebleed or other bleeding, mucosal telangiectases, AVM, or characteristic pattern of telangiectasia distribution found in HHT.
  • Pregnancy
  • Chronic liver disease (However, the telangiectases are almost always of the 'spider' class and occur on the face and chest and around the umbilicus.)

Additionally, adults can develop one or a couple of cutaneous telangiectases with age. These often raise concern, especially when the person also has multiple cherry angiomata, which are quite frequent in older individuals and are unrelated to HHT.

Pulmonary AVMs. Most individuals with a pulmonary AVM have HHT; an unknown percentage of individuals who have an isolated pulmonary AVM do not have HHT.

Cerebral AVMs occur most frequently as an isolated finding, but may be a manifestation of HHT or another dominantly inherited vascular dysplasia such as capillary malformation-arteriovenous malformation (CM-AVM) caused by pathogenic variants in RASA1 [Eerola et al 2003, Revencu et al 2013b]. Families have also been reported with autosomal dominant AVMs of the brain and no other features of HHT. However, the presence of multiple cerebral AVMs is highly suggestive of HHT [Bharatha et al 2012]. The absence of a family history of recurrent nosebleed and presence of telangiectases specifically on the lips, face, and hands best distinguish other vascular dysplasias from HHT.

Management

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

Nosebleeds

It is appropriate to consider intervention for nosebleeds in the case of anemia attributable to the nosebleeds or if an individual feels that the frequency or duration interferes significantly with normal activities.

Humidification and the daily application of nasal lubricants may be helpful.

Hemostatic products (gauze, sponge or powder products) available over the counter help individuals self-manage significant nosebleeds.

Laser ablation typically done under general anesthesia may be the most effective intervention for control of mild to moderate nosebleeds. Office-based sclerotherapy was shown to be a potentially safe and useful alternative in an uncontrolled Spanish study [Morais et al 2012] and a small retrospective US pilot study [Boyer et al 2011].

Young's nasal closure is a consideration for severe epistaxis which has proven unresponsive to the above methods [Richer et al 2012]. Surgical treatment for severe epistaxis in persons with HHT should be performed by surgeons who treat people with HHT regularly.

Oral drug therapy. A meta-analysis of studies of hormonal and anti-hormonal treatment concluded that estrogen-progesterone at doses used for oral contraception may eliminate bleeding in symptomatic HHT and is a reasonable initial option to consider for fertile women [Jameson & Cave 2004]. An anti-estrogen, tamoxifen, was reported to decrease nosebleeds in one series [Yaniv et al 2009]. Antifibrinolytic drugs such as tranexamic acid (Cyklokapron®) have been used with some success in selected individuals; the associated risks are not well established [Fernandez-L et al 2007]. Thalidomide, an angiogenesis inhibitor, reduced the severity and frequency of nosebleeds in six of seven affected individuals in a small series [Lebrin et al 2010]. Oral propranolol has also been suggested as a potential treatment [Albiñana et al 2012].

Topical drug therapy. Current evidence and experience suggest that the simple humidification and moisturizing effects of medicated sprays and ointments are more helpful than the particular medication. A multi-HHT center randomized, cross-over, placebo controlled trial (NOSE Trial) to study the efficacy of several medicated nose sprays (bevacizumab, estriol, and tranexamic acid) in the treatment of epistaxis concluded that all groups, including the placebo group using saline spray, had a significant improvement in epistaxis. None of the three topical therapies was any better at decreasing epistaxis frequency than twice-daily saline spray [Whitehead et al 2016]. Another randomized, multicenter, placebo-controlled clinical trial of three doses of bevacizumab nasal spray was published simultaneously with the NOSE Trial. Here again, topical bevacizumab had no effect on epistaxis [Dupuis-Girod et al 2016]. Case reports or small series suggest that these and other topically administered agents (e.g., timolol 0.5% ophthalmic solution) may help reduce the duration or frequency of nosebleeds in those with HHT [Flanagan et al 2012, Guldmann et al 2012, Olitsky 2012, Reh et al 2013].

Case reports and a small series [Bose et al 2009, Brinkerhoff et al 2011, Suppressa et al 2011, Dupuis-Girod et al 2012, Thompson et al 2014] suggest that IV administration of the anti-angiogenic drug bevacizumab may be efficacious in those with severe, intractable nosebleeds.

Gastrointestinal Bleeding

Treatment is unnecessary unless aggressive iron therapy has been ineffective in maintaining hemoglobin concentration in the normal range.

Endoscopy, capsule endoscopy, mesenteric and celiac angiography, and radionuclide studies may be used to localize the source of bleeding and its type [Grève et al 2010].

Endoscopic application of a heater probe, bicap, or laser is the mainstay of local treatment.

Small bowel bleeding sites and larger vascular malformations can be removed surgically after they are identified by nuclear medicine studies.

For severe GI bleeding associated with intractable iron deficiency anemia, various pharmacologic agents have shown promise based on case reports or small uncontrolled series. Treatment with oral estrogen-progesterone or tranexamic acid has decreased transfusion needs [Proctor et al 2008]. A number of single cases of dramatic reduction in GI bleeding after IV administration of the anti-angiogenic drug bevacizumab have been reported [Flieger et al 2006, Fodstad et al 2011].

Anemia

Treatment of anemia with iron replacement and red blood cell transfusion, if necessary, is appropriate.

Persons with iron deficiency who are intolerant of or do not respond to oral iron benefit from parenteral administration of iron.

Pulmonary AVMs

Treatment of pulmonary AVMs is indicated for dyspnea, exercise intolerance, and hypoxemia, but is most important for prevention of lung hemorrhage and the neurologic complications of brain abscess and stroke, even in those who are asymptomatic with respect to pulmonary function and oxygen saturation. Any pulmonary AVM with a feeding vessel that exceeds 1.0 mm in diameter requires consideration of occlusion [Trerotola & Pyeritz 2010]. Transcatheter embolotherapy (TCE) with coils, occluder devices (Amplatzer®), or both is the treatment of choice. Occasionally, a small lesion cannot be reached because of its location or the size of the feeding vessel. Multiple coils may be needed to occlude AVMs with large or multiple feeding arteries.

Long-term follow up by chest CT and/or contrast echocardiography is indicated after transcatheter occlusion of pulmonary AVMs because of reported recanalization and development or growth of untreated pulmonary AVMs [Cottin et al 2007]. Usually a follow-up CT is done six to 12 months post-occlusion, and if no recanalized or new PAVMs are noted, follow-up CT is done at five-year intervals thereafter [Trerotola & Pyeritz 2010, Faughnan et al 2011].

Hepatic AVMs

Treatment of cardiac failure or liver failure secondary to hepatic AVMs is currently problematic. Embolization of hepatic AVMs, which is successful for treatment of pulmonary AVMs, has led to lethal hepatic infarctions. Most individuals with symptomatic hepatic AVMs can be satisfactorily managed with intensive medical therapy [Buscarini et al 2011].

Liver transplantation has been the standard treatment for those (usually older) individuals whose symptoms of hepatic failure do not respond to medical management [Buscarini et al 2006, Lerut et al 2006, Dupuis-Girod et al 2010, Lee et al 2010, Chavan et al 2013].

Bevacizumab administered intravenously has been reported to decrease cardiac output and symptoms of heart failure in affected individuals with severe symptoms secondary to hepatic AVMs in case reports and one series [Mitchell et al 2008, Dupuis-Girod et al 2012].

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

Cerebral AVMs

Cerebral AVMs greater than 1.0 cm in diameter are usually treated using neurovascular surgery, embolotherapy, and/or stereotactic radiosurgery.

Note: Before proceeding with treatment for any visceral AVM, individuals and their doctors are encouraged to contact the nearest multidisciplinary HHT clinic, which can be located through the support group, Cure HHT, to assure that appropriate diagnostic and treatment plans are in place.

Intestinal Polyps

Any individual diagnosed with juvenile polyposis (JP) should be screened for manifestations of HHT, and the family should be screened for polyps. Any person with HHT who has gastrointestinal polyps, especially at an early age, should be evaluated for JP and managed accordingly (see Juvenile Polyposis Syndrome).

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 of air embolism. Women with treated pulmonary AVMs appear to be at no higher risk during pregnancy than those without pulmonary AVMs.

Therapies Under Investigation

Newer therapies designed to interfere with the development of abnormal vascular connections include thalidomide and bevacizumab; while numerous case reports and small uncontrolled series tout promise, 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 for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

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/has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be lower. It should be noted, however, that although highly penetrant, the disease may not present until after age 40 years. Observable symptoms and manifestations can be subtle, even well into adulthood.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

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 a pathogenic variant in an HHT-related gene, 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 four HHT-related genes need long-term follow up and evaluations. Although identifying affected relatives when the familial pathogenic variant is known results in considerable savings of healthcare costs over the life of the at-risk relative, for a variety of reasons, individuals at 50% risk for inheriting HHT often decline molecular genetic testing when the familial pathogenic variant is known [Bernhardt et al 2012].

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, genotype-phenotype correlations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant in ACVRL1, ENG, GDF2, or SMAD4 has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hereditary Hemorrhagic Telangiectasia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Hereditary Hemorrhagic Telangiectasia (View All in OMIM)

131195ENDOGLIN; ENG
175050JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME; JPHT
187300TELANGIECTASIA, HEREDITARY HEMORRHAGIC, OF RENDU, OSLER, AND WEBER; HHT
600376TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2; HHT2
600993MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; SMAD4
601101TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 3; HHT3
601284ACTIVIN A RECEPTOR, TYPE II-LIKE 1; ACVRL1
605120GROWTH/DIFFERENTIATION FACTOR 2; GDF2
610655TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 4; HHT4
615506TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 5; HHT5

Molecular Genetic 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

Gene structure. ACVRL1 contains ten exons and spans approximately 14 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Current data suggest that most of pathogenic variants in ACVRL1 are functionally null alleles [Berg et al 1997, Pece et al 1997, Gallione et al 1998, Richards-Yutz et al 2010]. No common pathogenic variants have been identified. The frequency of pathogenic variants is highest in exons 8, 7, and 3, but these account for only 65% of pathogenic variants identified and variants have been identified in all exons. Missense variants account for more than half (53%) of pathogenic variants detected; deletions, insertions, and splice site variants have also been reported [Abdalla & Letarte 2006, Richards-Yutz et al 2010]. (For more information, see Table A.)

Normal gene product. Serine/threonine-protein kinase receptor R3 is a type I cell-surface receptor for the TGF-superfamily of ligands. It is expressed predominantly on endothelial cells [Abdalla & Letarte 2006].

Abnormal gene product. Current data suggest that most pathogenic variants in ACVRL1 result in loss of protein expression. HHT is assumed to be the result of haploinsufficiency [Abdalla & Letarte 2006].

ENG

Gene structure. ENG contains 14 exons and spans approximately 40 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Current data suggest that approximately two thirds of variants in ENG are functionally null alleles [Berg et al 1997, Pece et al 1997, Gallione et al 1998, Richards-Yutz et al 2010]. There are no common pathogenic variants. The total number of variants per exon is similar with the exception of exons 1, 9b, 12, and 13, which have fewer variants. Pathogenic variants of all types have been reported [Abdalla & Letarte 2006]. (For more information, see Table A.)

Normal gene product. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex. It is expressed predominantly on endothelial cells.

Abnormal gene product. Current data suggest that most pathogenic variants in ENG result in loss of protein expression. HHT is assumed to be the result of haploinsufficiency [Abdalla & Letarte 2006].

GDF2

Gene structure. GDF2 (also known as BMP9) is a small gene comprising two exons and a transcript of 1955 bp (NM_016204.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Missense variants in GDF2 were identified in three individuals with features of HHT including epistaxis [Wooderchak-Donahue et al 2013].

Normal gene product. GDF2 encodes growth/differentiation factor 2 (also known as BMP9 or bone morphogenetic protein 9), a protein of 429 amino acids (NP_057288.1). After post-translational cleavage of the signal peptide and the propeptide, the mature peptide is 110 amino acid residues. It is a member of the bone morphogenetic protein family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues.

Abnormal gene product. Cell culture studies suggested that these variants resulted in loss of mature protein and/or function. A bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis [Wooderchak-Donahue et al 2013].

SMAD4

Gene structure. SMAD4 contains 11 exons and has a cDNA of 2680 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. There are no common pathogenic variants and all types of variants have been described. More than two thirds of pathogenic variants reported are functionally null alleles (see SMAD4 Database). Although SMAD4 pathogenic variants in individuals with JP-HHT have shown a tendency to cluster in the MH2 domain, pathogenic variants in other parts of the gene also cause the combined syndrome. Any individual with an SMAD4 pathogenic variant should be considered at risk for manifestations of both JP and HHT [Gallione et al 2010, O'Malley et al 2012].

Normal gene product. SMAD4 encodes a 552-amino acid protein that functions as an intracellular signaling molecule in the TGF-beta/BMP pathway.

Abnormal gene product. Most pathogenic variants in SMAD4 result in non-expressed proteins. HHT is assumed to be the result of haploinsufficiency.

References

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Suggested Reading

  1. Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, Back W, Kaufmann A, Keller KM, Blaas SH, Siebert R, Vogt S, Spranger S, Holinski-Feder E, Sunde L, Propping P, Friedl W. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44:702–9. [PMC free article: PMC2752176] [PubMed: 17873119]
  2. Marchuk DA, Lux A. Hereditary hemorrhagic telangiectasia. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 212. New York, NY: McGraw-Hill. Available online.

Chapter Notes

Acknowledgments

Robert I White, MD
School of Medicine, Yale University

Alan Guttmacher, MD
National Human Genome Research Institute, National Institutes of Health

Author History

Alan Guttmacher, MD; National Institutes of Health (2000-2009)
Jamie McDonald, MS, CGC (2000-present)
Reed E Pyeritz, MD, PhD, FACMG (2009-present)

Revision History

  • 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 to live Web site
  • 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 to live Web site
  • 26 June 2000 (me) Review posted to live Web site
  • January 2000 (jm) Original submission
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