Clinical Diagnosis

The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the presence of multiple arteriovenous malformations (AVMs), which may be evident as telangiectases on the skin, mucus membranes, or both, and as larger visceral AVMs [Marchuk et al 1998, Faughnan et al 2011, McDonald et al 2011a, Guttmacher et al 2012].

Findings

• 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
  • Pancreatic [Lacout et al 2010]
• Family history. A first-degree relative in whom HHT has been diagnosed

The clinical diagnosis of HHT [Shovlin et al 2000] is considered:

• Definite when three or more findings are present;
• Possible or suspected when two findings are present;
• Unlikely when fewer than two findings are present.

Note: The application to children of these clinical diagnostic criteria, established mostly for adults, can be misleading. Symptoms and signs of HHT generally develop during childhood and adolescence, such that the absence of epistaxis, telangiectases, or symptoms of solid organ AVM is common in affected children [Morgan et al 2002, Mei-Zahav et al 2006]. Children at risk for HHT by virtue of having an affected parent should undergo molecular genetic testing to confirm or refute the diagnosis if a familial HHT-causing mutation has been identified. In families for which an HHT-causing mutation has not been identified, at-risk children should have repeat clinical evaluation for manifestations of the disorder as they age.

Molecular Genetic Testing

Genes. Three genes are associated with hereditary hemorrhagic telangiectasia:

• ENG. Hereditary hemorrhagic telangiectasia type 1 (HHT1)
• ACVRL1 (ALK1). Hereditary hemorrhagic telangiectasia type 2 (HHT2)
• SMAD4. Hereditary hemorrhagic telangiectasia variably associated with juvenile polyposis

The percentage of mutations in ENG and ACVRL1 are virtually equal (53% and 47% respectively) after founder effects are excluded [Bayrak-Toydemir et al 2004].

Other loci (HHT3 and HHT4). At least two kindreds appear to have mutations in two as-yet-unknown genes [Cole et al 2005, Bayrak-Toydemir et al 2006a]. Cole et al [2005] reported a 5.4-cm disease gene interval on chromosome 5 (HHT3) based on linkage analysis in one pedigree. Bayrak-Toydemir et al [2006a] reported a 7-Mb region on the short arm of chromosome 7 (7p14) based on linkage analysis in one pedigree. One individual with signs of HHT and prominent pulmonary hypertension had a mutation in BMPR2 [Rigelsky et al 2008]. Rare pedigrees are unlinked to any of these loci, suggesting additional heterogeneity.

Clinical testing

• Sequence analysis/mutation scanning. Sequence analysis of ENG, ACVRL1, and SMAD4 identifies mutations 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 mutations, and sequence variants interpreted to be of uncertain significance are particularly common.
  
  Recent reports suggest that approximately 1%-2% of persons clinically diagnosed with HHT will have a mutation detected in SMAD4, or approximately 10% of those who test negative for a mutation in ENG and ACVRL1 [Gallione et al 2006, Lesca et al 2006, Prigoda et al 2006]. Mutations 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 only [Howe et al 2004, Gallione et al 2010] or HHT only [Gallione et al 2006, Prigoda et al 2006]. One study found SMAD4 mutations in three of 30 persons referred for DNA-based testing for HHT who were found to be negative for mutations in ENG and ACVRL1 [Gallione et al 2006]. Another study showed that 2% of 194 persons referred for DNA-based testing for HHT had SMAD4 mutations [Prigoda et al 2006].
• Duplication/deletion analysis. Several techniques including quantitative PCR and multiplex ligation-dependent probe amplification (MLPA) are used to identify deletions not detectable by sequence analysis. The use of one of these methods 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].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

• Simultaneous testing of ENG and ACVRL1 by both sequence analysis and duplication/deletion analysis is recommended given the relatively high percentage of mutation-negative results and uncertain variants by sequence analysis alone.
• SMAD4 testing (sequence analysis) is recommended for symptomatic individuals in whom no mutation is identified in ENG or ACVRL1 and in any person with HHT and intestinal polyps.
• It is important to differentiate those with SMAD4-related HHT from those with ENG- or ACVRL1-related HHT, as medical management differs significantly for affected individuals based on this distinction.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

ENG. No other phenotypes are known to be associated with mutations in ENG. There have been four individuals with juvenile polyposis syndrome (JPS) reported to have missense mutations in ENG [Sweet et al 2005, Howe et al 2007], but it is not clear that the mutations are pathogenic. Of hundreds of individuals with HHT reported with known ENG mutations, none has been reported to have JPS.

ACVRL1. Mutations in ACVRL1 are a rare cause of pulmonary arterial hypertension [Austin et al 2012].

SMAD4. Mutations in SMAD4 have been reported in families with a combined syndrome of JPS and HHT [Gallione et al 2004], as well as in families who presented with JPS or HHT only. Although the proportion of individuals with a mutation in SMAD4 who manifest HHT only is unknown, it is suspected that all mutations in SMAD4 put individuals and families at risk for manifestations of both JPS and HHT [Gallione et al 2010]. Reports to date which suggest that the majority of individuals with SMAD4 mutations have only JPS are likely attributable to variable expressivity, age-related penetrance of HHT, and the focus of the clinical evaluation [O’Malley et al 2011].

Natural History

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. Telangiectases are most evident on the lips, tongue, buccal mucosa, face, chest, and fingers, and are common in adulthood throughout the gastrointestinal mucosa. They may appear as pinhead-size lesions or as larger, even raised lesions with multiple draining venules. All telangiectases are distinguished from petechiae and angiomata by their ability to blanch with gentle pressure, and then immediately 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.

The term AVM usually refers to the "large" telangiectases, greater than a few millimeters in diameter and sometimes up to several centimeters in diameter. AVMs occur most commonly in the brain, lung, or liver. In the brain, they are typically present at birth, whereas they typically develop over time in the lung and liver. In contrast to the complications of smaller telangiectases, the complications of AVMs often result from the shunting of blood, leading to increased cardiac output and, in the lung, desaturation of arterial blood. Lung AVMs also provide a ready right-to-left shunt for venous emboli (clots or bacteria) to reach the arterial circulation. Occasionally, a pulmonary AVM can rupture, leading to hemoptysis.

The most common features that bring young individuals with HHT to medical attention are epistaxis (nosebleeds) and telangiectases. 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. 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.

While similar proportions of affected individuals eventually develop telangiectases of the face, oral cavity, or hands, the average age of onset is generally later, but may be during childhood. Thirty percent of affected individuals report telangiectases first appearing before age 20 years and two thirds before age 40 years [Berg et al 2003].

Telangiectases can also be found anywhere in the gastrointestinal (GI) system. Most commonly, the stomach and the proximal small intestine (duodenum) are involved. Approximately one quarter of all individuals with HHT eventually have gastrointestinal bleeding [Kjeldsen et al 2000, Longacre et al 2003, Ingrosso et al 2004, Proctor et al 2005]. Bleeding from GI telangiectases most commonly begins after age 50 years, is usually slow but persistent, and often becomes increasingly severe with age. No particular foods, activities, or medications have been identified as contributors to GI bleeding in individuals with HHT.

Epistaxis and/or GI bleeding can cause mild to severe anemia, often requiring iron replacement therapy or rarely, blood transfusion.

Pulmonary AVMs occur in approximately 30%-50% of affected individuals and cerebral AVMs in at least 10% [Kjeldsen & Kjeldsen 2000, Bayrak-Toydemir et al 2004]. Spinal AVMs appear to be significantly less common, but may present with paralysis. 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. Vascular lesions in the pancreas are common but rarely a clinical issue [Lacout et al 2010]. Although data suggest that the incidence of visceral AVMs may depend on the gene mutated, with pulmonary and possibly cerebral AVMs being more common with mutations in ENG (HHT1) than in ACVRL1 (HHT2) and hepatic AVMs more common in HHT2 [Kjeldsen et al 2005, Bayrak-Toydemir et al 2006b, Letteboer et al 2006], all of these lesions have been seen in individuals with both HHT types.

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. 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. Migraine headache, polycythemia, and hypoxemia with cyanosis and clubbing of the nails are other complications of pulmonary AVMs [Shovlin & LeTarte 1999, Kjeldsen et al 2000, Cottin et al 2007]. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease [Garcia-Tsao et al 2000]. Hepatic focal nodular hyperplasia occurs in HHT at a prevalence greater than the general population [Buscarini et al 2004b, Brenard et al 2010].

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].

Pulmonary hypertension is another pulmonary vascular manifestation of HHT. Although much less common than pulmonary AVMs, it either can 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 2012] (see Pulmonary Arterial Hypertension).

Pregnancy. 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.

Genotype-Phenotype Correlations

Data suggest that while no absolute genotype-phenotype correlations exist between clinical phenotypes and specific mutations or mutational types [Shovlin et al 1997], certain clinical manifestations may be more common in particular types – for example, pulmonary AVMs in HHT1 and hepatic AVMs in HHT2. However, both types are clearly multisystem vascular dysplasias with most manifestations having been 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, occurs almost exclusively in individuals with mutations in ACVRL1 [Trembath et al 2001, Harrison et al 2003].

Mutations 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 a SMAD4 mutation who had presented as JP only were found to have features of HHT when specifically reexamined for such manifestations [O’Malley et al 2011].

Penetrance

HHT displays age-related penetrance with increased manifestations developing over a lifetime (see Table 2).

• 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].
• Intracranial hemorrhage secondary to AVM has been reported as 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.

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, it is likely that this is an underestimate [Guttmacher et al 2012]. 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 founder effect.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 seems 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.
• Measurement of oxygen saturation via pulse oximetry
• Contrast echocardiography for detection of pulmonary shunting/AVM [Gossage 2010, van Gent et al 2010] and measurement of the pulmonary artery systolic pressure as a screen for pulmonary artery hypertension [Olivieri et al 2006]. 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 of lesions(s) is the next step [Cottin et al 2004, Nawaz et al 2008].
• Head MRI (with and without gadolinium) to detect cerebral AVMs, performed as early as possible, preferably in the first year of life [Morgan et al 2002]. If no cerebral AVMs are detected, MRI does not need to be repeated later in life unless new symptoms or signs emerge. Adults 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 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 HAVM are less satisfactory than those for PAVM or CAVM.
• Genetics consultation

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 patients self-manage significant nosebleeds.
• Laser ablation may be the most effective intervention for control of mild to moderate nosebleeds [Mahoney & Shapshay 2006].
• Severe epistaxis, which has proven unresponsive to the above methods, is treated by septal dermoplasty [Fiorella et al 2005], Young’s nasal closure [Hitchings et al 2005], or use of a nasal obturator [Woolford et al 2002, Bruschini et al 2011]. Surgical treatment for severe epistaxis in persons with HHT should be performed by surgeons who treat people with HHT regularly.
• A recent 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].

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.
• In some trials, hormonal treatment with estrogen-progesterone or tranexamic acid has decreased transfusion needs [Proctor et al 2008].

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 PAVMs 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 [Moussouttas et al 2000]. Any PAVM with a feeding vessel that exceeds 1.0 mm in diameter requires consideration of occlusion [Lee et al 1997, 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 is indicated after transcatheter occlusion of PAVMs because of reported recanalization and development or growth of untreated PAVMs [Cottin et al 2007]. Usually a follow-up CT is done 6-12 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].

Cerebral AVMs greater than 1.0 cm in diameter are usually treated using neurovascular surgery, embolotherapy, and/or stereotactic radiosurgery [Fulbright et al 1998].

Hepatic AVMs

• Treatment of cardiac failure or liver failure secondary to HAVMs is currently problematic. Embolization of HAVMs, which is successful for treatment of PAVMs, has led to lethal hepatic infarctions. Most patients with symptomatic HAVM can be satisfactorily managed with intensive medical therapy [Odorico et al 1998, Buscarini et al 2006, Buscarini et al 2011].
• Liver transplantation is currently considered the treatment of choice for those (usually older) individuals whose symptoms do not respond to medical management [Buscarini et al 2006, Lerut et al 2006, Dupuis-Girod et al 2010, Lee et al 2010].
• Liver biopsy should be avoided in individuals with HHT [Buscarini et al 2006].

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 HHT Foundation International 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 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 [Christensen 1998, 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 determination with appropriate treatment for 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 rather than pulmonary angiography is used if the previous contrast echocardiogram revealed evidence of a right to left shunt.
• 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 [Morgan et al 2002, 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 mutations [Al-Saleh et al 2009].
• Head MRI with and without gadolinium is recommended as early as the first few months of life.
• 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.

Pregnancy

• Pregnant women with HHT and untreated pulmonary AVMs are at high risk for lung hemorrhage. Therefore, screening for and treatment of pulmonary AVMs should be performed before pregnancy.
• A pregnant woman who has not had a recent pulmonary evaluation should be evaluated as soon as pregnancy is recognized [Shovlin et al 1995, Shovlin et al 2008]. Chest CT, with abdominal shielding, should be delayed until the second trimester.
• Women not discovered to have pulmonary AVMs until they are already pregnant should undergo occlusion during the second trimester.

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 such as 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.

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

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the disease-causing mutation in the family is known, as early diagnosis and treatment can reduce morbidity and mortality. However, relatives who are at risk often resist advice to undergo molecular screening [Bernhardt et al 2011].

If the disease-causing mutation in the family is not known, it is appropriate to offer clinical diagnostic evaluations to identify those family members who will benefit from early treatment.

Individuals at risk for HHT should follow the protocol described in Surveillance.

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 tout promise, controlled trials are needed [Mitchell et al 2008, Bose et al 2009, Davidson et al 2010, Lebrin et al 2010, Brinkerhoff et al 2011, Patrizia et al 2011].

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.

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 a de novo constitutional or somatic gene mutation [Best et al 2011].
• Recommendations for the evaluation of parents of a child who represents an apparent simplex case (i.e., a single occurrence in a family) include physical examination, documentation of medical history targeted at symptoms and manifestations of HHT, and molecular genetic testing if a mutation has been identified in the 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, the risk to the sibs 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.
• No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband. Each child of an individual with HHT has a 50% chance of inheriting the disease-causing mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Surveillance for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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 during adulthood and childhood. Testing of at-risk asymptomatic individuals for HHT is possible using the techniques described in Molecular Genetic Testing. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for HHT, an affected family member should be tested first to confirm (and identify) the molecular diagnosis in the family. 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 about possible problems that they may encounter with regard 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 with a positive test result need arrangements for long-term follow up and evaluations.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like hereditary hemorrhagic telangiectasia) do not affect intellect and have some treatment available are not common. 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 decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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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. Lux A, Marchuk DA. Hereditary hemorrhagic telangiectasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 212. Available online. Accessed 12-3-12.

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

• 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