DiagnosisClinical DiagnosisThe 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].FindingsNosebleeds (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:PulmonaryCerebralHepaticSpinalGastrointestinalPancreatic [Lacout et al 2010]Family history. A first-degree relative in whom HHT has been diagnosedThe 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 TestingGenes. 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 polyposisThe 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 testingSequence 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]. Table 1. Summary of Molecular Genetic Testing Used in HHTView in own windowGene SymbolProportion of HHT Attributed to Mutations in This Gene ^{1Test MethodMutations DetectedMutation Detection Frequency by Gene and Test Method 2Test AvailabilityENG 39%-59%
(~50% in N America)Sequence analysisSequence variants 3~ 90% Clinical Duplication / deletion analysis 4Exonic and whole-gene deletions~10% ACVRL125%-57%
(~35% in N America)Sequence analysisSequence variants 3~95% Clinical Duplication / deletion analysis 4Exonic and whole-gene deletions~5% SMAD41%-2%Sequence analysisSequence variants 3Unknown ClinicalDuplication / deletion analysis 4Exonic and whole-gene deletionsUnknown; none reported 51. The proportion of ENG and ACVRL1 mutations is roughly similar, with a slight preponderance of ENG mutations in North America 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] and a greater preponderance of ACVRL1 mutations in southern Europe [Lenato et al 2006, Lesca et al 2006, Olivieri et al 2007]. 2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No deletions or duplications involving SMAD4 have been reported to cause SMAD4-related hereditary hemorrhagic telangiectasia. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)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 StrategyTo confirm/establish the diagnosis in a probandSimultaneous 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) DisordersENG. 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 HistoryHereditary 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).Table 2. Age of Onset of Various Signs of HHTView in own windowSign ^{1Age in Years0-910-1920-2930-3940-4950-5960+Nosebleed
n=49237%33%12%7%4%2%Telangiectasesn=40610% 20%20%18%11%5%10% GI bleed
n=1144% 7%11%25%18%21%4% 1. n = number of individuals reporting [Guttmacher, unpublished]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 CorrelationsData 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].

Differential DiagnosisTelangiectases and epistaxis are relatively common 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. Mutations in ATM are causative.CRST (calcinosis, Raynaud phenomenon, sclerodactyly, telangiectasia) syndromeHereditary benign telangiectasia, 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 the history/family history of nosebleed or other bleeding, mucosal telangiectases, AVM, or characteristic pattern of telangiectasia distribution found in HHT.PregnancyChronic liver disease (However, the telangiectases are almost always of the ‘spider’ class and occur on the face and chest and around the umbilicus.)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 mutations in RASA1 [Eerola et al 2003, Revencu et al 2012]. Families have also been reported with autosomal dominant AVMs of the brain and no other features of HHT. 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 symptomsPhysical examination including inspection for telangiectases (particularly on fingers, lips, tongue, oropharynx, cheeks, or conjunctiva) and listening for abdominal bruitsComplete 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 oximetryContrast 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 consultationTreatment of ManifestationsNosebleedsIt 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 bleedingTreatment 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]. AnemiaTreatment 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 AVMsTreatment 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 AVMsTreatment 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 ComplicationsIf 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).SurveillanceThe 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 symptomsPeriodic hematocrit/hemoglobin determination with appropriate treatment for anemiaReevaluation 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 polypsChildhoodBecause 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.PregnancyPregnant 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 AvoidIndividuals 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 RiskIt 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 ManagementPregnant 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 InvestigationNewer 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDACVRL112q13​.13Serine/threonine-protein kinase receptor R3HHT Mutation Database (ACVRL1)
ACVRL1 homepage - Mendelian genesACVRL1ENG9q34​.11EndoglinHHT Mutation Database (ENG)
ENG homepage - Mendelian genesENGSMAD418q21​.2Mothers against decapentaplegic homolog 4SMAD4 Database
SMAD4 homepage - Mendelian genesSMAD4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 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 610655TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 4; HHT4ACVRL1Normal allelic variants. ACVRL1 contains ten exons and spans approximately 14 kb of genomic DNA.Pathologic allelic variants. Current data suggest that approximately one third of pathologic allelic 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 disease-causing mutations have been identified. The frequency of mutations is highest in exons 8, 7, and 3, but these account for only 65% of mutations identified and mutations have been identified in all exons. Missense mutations account for over half (53%) of mutations detected; deletions, insertions, and splice site mutations 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 disease-causing mutations in ACVRL1 result in protein non-expression. HHT is assumed to be the result of haploinsufficiency [Abdalla & Letarte 2006].ENGNormal allelic variants. ENG contains 14 exons and spans approximately 40 kb of genomic DNA.Pathologic allelic variants. Current data suggest that approximately two thirds of mutations 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 disease-causing mutations. The total number of mutations per exon is similar with the exception of exons 1, 9b, 12, and 13, which have fewer mutations. Mutations 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 disease-causing mutations in ENG result in non-expressed proteins. HHT is assumed to be the result of haploinsufficiency [Abdalla & Letarte 2006].SMAD4Normal allelic variants. SMAD4 contains 11 exons and has a cDNA of 2680 bp.Pathologic allelic variants. There are no common pathogenic mutations and all types of mutations have been described. More than two thirds of mutations reported are functionally null alleles (see SMAD4 Mutation Database). Although SMAD4 mutations in individuals with JP-HHT have shown a tendency to cluster in the MH2 domain, mutations in other part of the gene also cause the combined syndrome. Any individual with a SMAD4 mutation should be considered at risk for manifestations of both JP and HHT [Gallione et al 2010, O’Malley et al 2011]. 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 disease-causing mutations in SMAD4 result in non-expressed proteins. HHT is assumed to be the result of haploinsufficiency.