11/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Very occasionally, PAVMs may bleed; this event is rare unless PAVMs have developed a systemic arterial supply (spontaneously or posttreatment), the individual is pregnant, or the individual has pulmonary hypertension. PAVM hemorrhage may lead to hemoptysis or hemothorax. Hemorrhage may occur from the fragile PAVM vessels into a bronchus or the pleural cavity, causing hemoptysis or hemothorax, respectively. However, this is rare outside of pregnancy [8,95]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.) Patients with PAVMs have an increased prevalence of migraine [96]; migraine may be precipitated by intravenous injections for CT imaging [97]. Migraine symptoms may be reduced after embolization of PAVMs [98]. (See 'Migraines' below.) Cerebral vascular abnormalities Patients with HHT may have cerebral or spinal cord involvement. Cerebrovascular malformations range from benign developmental venous anomalies, through capillary malformations (sometimes inappropriately referred to as micro- AVMs) and cavernous malformations, all with a low hemorrhagic risk, to classical nidal AVMs and high-flow cerebral arteriovenous fistulae (CAVFs; generally found in children) [47]. As detailed in a position statement from the European Reference Network for Rare Vascular Diseases (VASCERN), the clinical presentations and prognosis depend on the type and location of the lesion [47]. Other vascular and nonvascular pathology can occur as in the general population, and these appear to include aneurysms at no greater frequency than in the general population ( image 5) [73,99]. Cerebral vascular malformations affect approximately 10 percent of HHT patients, are often multiple, and are usually silent [59,62,83,100]. They can affect children, when the risks are considerably higher due to the higher prevalence of CAVFs [47]. While full screening across large populations of children in HHT families has not been undertaken, in one cohort of 52 children with HHT referred to neurologic services, neuroimaging at a median age of 5.2 years revealed cerebrovascular malformations in 14 (27 percent), with three developing new lesions over time. Unusually for the broader groups of HHT children, this cohort was highly symptomatic: three had an intracerebral hemorrhage (age of presentation, four to eight years) and another three had ischemic stroke or transient ischemic attack. The most dangerous lesions in HHT are cerebral AVFs, which predominantly affect children. High-flow shunts through AVFs in young infants can present with systemic circulatory overload or hydrovenous dysfunction (eg, macrocephaly, hydrocephalus). Other presentations include seizures, ischemia of the surrounding tissue due to a steal effect, or hemorrhage. Hemorrhage may be less frequent than that seen in non-HHT cerebral AVMs, in part due to the lower https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 12/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate frequency of associated aneurysms. (See "Vascular malformations of the central nervous system", section on 'Capillary telangiectasias'.) Cerebral hemorrhage often has devastating effects. Thus, patients with symptoms suggestive of cerebral AVMs (eg, unexplained headache or neurologic symptoms) deserve further assessment as in the non-HHT population, including noninvasive imaging and ultimately assessment by experienced neurointerventional centers. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'.) For patients without symptoms, the situation is more nuanced and carefully expressed in a recent statement led by European Neurointerventionalists [47]. In the expert European centers, screening discussions are conducted with all families in an informed and personalized way to help all make the appropriate choice [47]. This is important because it is not clear that invasive interventions for incidentally discovered cerebral AVMs are appropriate. Since the 2014 publication of the ARUBA trial, which demonstrated an increased risk of bleeding with treatment of asymptomatic cerebral AVMs, many more countries restrict screening to symptomatic patients or only perform screens after pretest counseling of patients [101]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions' and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Cerebral AVM screening'.) Brain MRI is the most sensitive noninvasive test ( image 6). Safety data have demonstrated that individuals with PAVMs that were embolized using metal-containing materials previously designated MRI-incompatible can actually undergo MRI [93]. Hepatic involvement Hepatic involvement occurs in up to two-thirds of patients with HHT [102-105]. As emphasized in guidance from a 2016 document, this is usually silent [106]; however, symptoms can occur and can be improved by appropriate treatments. The potential varying symptoms relate to development of high-output heart failure, portal hypertension, or biliary disease, reflecting different patterns of vascular involvement [107-109]. Large AVMs between the hepatic artery and hepatic vein can cause a significant left-to-right shunt with increased cardiac output that, particularly when combined with anemia, places patients at risk of angina and heart failure [107,110]. (See "Hepatic hemangioma".) Portal hypertension and hepatic encephalopathy, particularly after episodes of gastrointestinal bleeding, may result both from shunts between the hepatic artery and portal vein, and from increased sinusoidal blood flow, leading to enhanced deposition of fibrous tissue and pseudocirrhosis of the liver [107,111]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 13/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate In our experience, hepatic AVMs affect approximately 50 percent of HHT patients; they are usually silent and not associated with abnormal liver function tests, hepatomegaly or liver bruit. The diagnosis can be established noninvasively by Doppler ultrasonography, CT, or MRI. [112]. Liver biopsy is not recommended as it is not useful in the diagnosis of HHT and may be complicated by bleeding [108]. The natural history of hepatic AVMs was studied in 154 patients with HHT and hepatic vascular malformations who were followed over a median period of 44 months (range: 12 to 181 months) [113]. Eight (5.2 percent) died from vascular malformation-related complications and 39 (25.3 percent) experienced nonfatal complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively, while the rate of complete response to therapy was 63 percent. The Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia (2020) provided new recommendations for the management of hepatic AVMs [56]. Diagnostic testing is recommended in patients with symptoms or signs suggestive of complicated liver AVMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), with high agreement among experts. There was lower agreement (84 percent) for a recommendation to screen all asymptomatic patients, and expert involvement is recommended in these cases [56]. Additionally, estimation of patients prognoses using predictors for liver AVMs is recommended to identify those in need of closer monitoring; management is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.) Iron deficiency Epistaxis commonly causes iron deficiency and sequelae due to generation of hemorrhage-adjusted iron requirements (HAIR) that cannot be met through diet alone [114]. A much smaller proportion of individuals develop iron deficiency anemia due to gastrointestinal bleeding. Screening and management was reviewed in detail in the Second International Guidelines for the Diagnosis and Management of HHT [56]. The approach to managing anemia in this HHT, which is characterized by severe continuing blood losses, differs from the management of anemia in many other settings. It was recommended that all adults with HHT and any children with recurrent bleeding or symptoms of anemia should be tested for anemia and iron deficiency; that initial treatment of iron deficiency and anemia should be with oral iron (which has been shown to increase https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 14/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate hemoglobin in HHT patients, even at modest doses [115]); and that intravenous iron is recommended where oral iron is not effective, not absorbed/tolerated, or where patients are presenting with severe anemia [56]. Management of iron deficiency is presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Iron deficiency and iron deficiency anemia'.) It is important to emphasize that anemia in HHT may be enhanced by other conditions, with the most common exacerbators in our experience being: Menorrhagia [114] Intercurrent infection and/or inflammation preventing iron absorption, along with iron- poor diets [116] Low grade hemolysis [36,117]. Pulmonary hypertension Pulmonary hypertension is not a single disease entity; as in the general population, it can result from multiple causes in people who also have HHT. That said, pulmonary hypertension in HHT is usually due to increased pulmonary flow due to systemic AVMs and/or anemia [118,119]. However, it may be due to a pure pulmonary arterial hypertension (PAH) phenotype indistinguishable from PAH in the general population [119]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".) Venous thromboembolism Patients with HHT are at increased risk of VTE, the management of which can be compounded by other aspects of their HHT, as clinicians often consider (incorrectly) that treatment or prophylaxis with anticoagulants is contraindicated in HHT [56,120,121]. The Second HHT International Guidelines recommended with high agreement among experts that HHT patients receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy where there is an indication, with consideration of their individualized risks, and that bleeding in HHT is not an absolute contraindication for these therapies [56]. Data from the European Reference Network suggest that heparin and warfarin remain the agents of choice [122]. In a study of 609 patients with HHT recruited prospectively in two separate series at a single center, low serum iron levels, attributed to inadequate replacement of hemorrhagic iron losses, were associated with elevated plasma levels of coagulation factor VIII and an increased VTE risk [123]. Management of VTE in individuals with HHT is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals who require anticoagulation (VTE and AF)'.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 15/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate In each series, there was an inverse association between factor VIII levels and serum iron that persisted after adjustment for age, inflammation, and/or von Willebrand factor. Low serum iron levels were also associated with VTE: the age-adjusted odds ratio (OR) of 0.91 (95% CI 0.86-0.97) per 1 micromol/L increase in serum iron implied a 2.5-fold increase in VTE risk for a serum iron of 6 micromol/L compared with the mid-normal range (17 micromol/L). The association appeared to depend upon factor VIII levels, as once adjusted for factor VIII levels, the association between VTE and iron was no longer evident. Arterial thromboses and platelets Iron deficiency is also emerging as a strong risk factor for ischemic stroke in HHT patients with PAVMs. In a series of 497 consecutive patients with HHT and CT-proven PAVMs, the risk of stroke decreased as serum iron increased (adjusted OR 0.96 per mg/mL increase in serum iron; 95% CI 0.92-1.00) [91]. The actual platelet count did not differ in patients with and without strokes. This finding means that for the same PAVMs, the stroke risk would approximately double with serum iron 6 micromol/L compared with mid-normal range (eg, 7 to 27 micromol/L) [91]. This study in HHT patients confirmed data from the 1970s in non- HHT patients that iron deficiency is also associated with enhanced platelet aggregation in response to 5-hydroxytryptamine (5HT) [124]. Importantly, the Second International Guidelines for HHT recommend avoiding the use of dual antiplatelet therapy and anticoagulation where possible in HHT [56]. Migraines Migraines are more common in HHT patients than in patients without HHT [125- 127]. Migraine features and precipitants appear indistinguishable from migraines in the general population [78]. Multiple studies demonstrate that the risk of migraine in HHT patients is approximately doubled by the presence of PAVMs, and there is evidence that migraines improve following PAVM treatment [78,96,98,127-129]. (See 'Pulmonary AVMs' above.) Cancer frequency The frequency of various cancer types in patients with HHT versus controls has been studied. A survey of cancer frequency in patients with HHT over 60 years and age- matched controls showed that despite the predisposition to gastrointestinal cancers conferred by SMAD4 mutation in some patients, age-adjusted rates of cancer were similar in individuals with HHT versus controls (OR 1.04, 95% CI 0.90-1.21) [130]. Evaluation of common cancer types revealed a lower incidence of lung cancer (OR 0.48, 95% CI 0.30-0.70); an increase in early-onset but fewer late-onset colorectal cancers; no difference in prostate cancer; and a higher incidence of breast cancer (OR 1.52, 95% CI 1.07-2.14). The increase in breast cancer was speculatively attributed to thoracic radiation exposure. A subsequent study of 246 PAVM patients demonstrated that protocols for diagnosis, treatment, and follow-up result in levels of radiation exposure that would be classified as harmful, particularly in patients with underlying HHT; the https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 16/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate mean cumulative effective dose (CED) of radiation over an 11-year period was 51.7mSv, and in 26 patients, CED exceeded 100mSv [131]. CT scans accounted for 46 percent of the CED, and interventional procedures accounted for 51 percent. Laboratory findings Routine coagulation and platelet counts are usually normal in HHT. Iron deficiency is the most common finding, especially in those with insufficient iron supplementation. Iron deficiency may be found in people with or without anemia, depending on whether there is a concurrent polycythemic drive due to PAVM-induced hypoxemia. A comparison of red cell indices in HHT patients compared with controls (healthy blood donors) noted a dramatic increase in anemia in the HHT patients [9]. In people with HHT, iron deficiency is associated with marginal increases in platelet counts, as seen in the general population, though the platelet count exceeded 400,000/microL in only 35 of 465 individuals (7.5 percent) and exceeded 500,000/microL in only 7 individuals (1.5 percent), and there was no association with ischemic stroke. Iron deficiency is also associated with elevated factor VIII levels and a shortened activated partial thromboplastin time (aPTT) [91,132]; these findings are associated with an increased prevalence of VTE [123]. DIAGNOSIS HHT may be diagnosed clinically (using three or more Cura ao Criteria (see 'Consensus criteria' below)), or by documentation of a pathogenic or likely pathogenic variant in an HHT gene. (See 'Genetic testing' below.) The Second International Guidelines on HHT recommend making (or excluding) the diagnosis using the Cura ao criteria and/or identifying pathogenic variant in one of the HHT genes [56]. HHT can be diagnosed clinically with confidence, particularly if there is a first-degree relative with HHT, even when an HHT gene variant has not been identified in the family. (See 'Clinical features' above.) HHT can be excluded with relative confidence if a known familial pathogenic variant is not present in the individual, taking into account the exact variant subtype. Absence of HHT clinical features does not preclude a diagnosis of HHT as shown by genetic studies [25]. Absence of an HHT causal variant does not preclude a diagnosis of HHT unless the causal gene in that family has already been identified in a preceding generation. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 17/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate When the individual is the first affected ("founder") member of the family, mosaicism may be present [37-39]; this can pose challenges for molecular testing [40,41]. A child of a parent with HHT should be considered to have possible HHT unless the disorder is excluded by genetic testing for the known familial variant. Consensus criteria International consensus diagnostic criteria (the Cura ao diagnostic criteria) are based upon the following four findings [133,134]: Spontaneous and recurrent epistaxis Multiple mucocutaneous telangiectasia at characteristic sites Visceral involvement (eg, gastrointestinal telangiectasia; pulmonary, cerebral, or hepatic arteriovenous malformations [AVMs]) A first-degree relative with HHT These criteria define "definite" (three or four criteria), "suspected" (two criteria), and "unlikely" (zero or one criterion). These have been validated by molecular studies; in probands who met the strictly applied criteria in an HHT Center of Excellence, 137 of 141 (97.2 percent) were found to have a pathogenic variant in either ENG (66 of 141 [46.8 percent]), ACVRL1 (69 of 141 [48.9 percent]), or SMAD4 (2 of 141 [2.8 percent]) [135]. Genetic testing The diagnosis may be established or confirmed by identification of a pathogenic sequence variant in ENG, ACVRL1, SMAD4, or GDF2. Although this is not required to make a diagnosis of HHT, the Second International Guidelines suggest genetic testing for all individuals with HHT, as it may facilitate family testing and additional evaluations (eg, screening colonoscopies for individuals with pathogenic variants in the SMAD4 gene) [56]. Genetic testing can also be used to establish the diagnosis in individuals with suspected HHT who do not meet clinical criteria. (See 'Consensus criteria' above.) Genetic testing does not detect all variants that might be present, and care is required not to over-interpret sequence variants that are not disease-causing. Detailed discussions for HHT are provided within the context of the American College of Medical Genetics and Genomics (ACMG) guidance and current databases [9]. Multiple centers for genetic testing are available in different countries. Previously reported variants (including pathogenic, likely pathogenic, benign, likely benign, and variants of unknown significance [VUSs]/pending classification) are registered on the HHT mutation database, available at http://arup.utah.edu/database/HHT/ [136] and on ClinVar [137]. A more general discussion of variant classification and determination of significance is presented separately. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 18/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.) RESOURCES Educational materials for patients with HHT and the location of specialized centers for diagnosing and managing HHT and pulmonary arteriovenous malformations (PAVMs) are available from Cure HHT, VASCERN HHT, and other patient groups. Additional information is available online: Introduction to HHT from VASCERN HHT https://www.youtube.com/watch? v=0YjWf7Agn40&feature=youtu.be Overview of HHT https://www.youtube.com/watch?v=z2gALD8xSNE&feature=youtu.be SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) SUMMARY AND RECOMMENDATIONS Prevalence Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with a clinical prevalence of 1:5000 to 1:8000. The true prevalence is likely to be higher in view of the paucity of clinical symptoms present in genetically-confirmed individuals diagnosed based on other presentations. Many individuals with HHT are unaware of their disease. (See 'Epidemiology' above.) Pathophysiology All HHT genes encode proteins involved in bone morphogenetic protein (BMP) signalling, most commonly ENG (encodes endoglin) and ACVRL1 (encodes ALK1). Rarer causes are SMAD4, which is important to identify because haploinsufficiency also results in juvenile polyposis syndrome requiring additional screening, and GDF2, which is rare and has an increased association with pulmonary hypertension. Pathogenic variants in these genes perturb vascular remodeling and disrupt blood vessel wall integrity. (See 'Pathophysiology' above.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 19/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Clinical features Patients with HHT may be asymptomatic or have a wide spectrum of clinical manifestations. Overall life expectancy is normal with appropriate management, but there can be life-limiting complications, and these subgroups are the ones most familiar to hospital clinicians. As summarized in the Consensus Orphanet statement from the European Reference Network, the most common signs include epistaxis, cutaneous or mucosal telangiectasia, anemia, and complications of visceral arteriovenous malformations (AVMs). The age of onset of AVM complications varies from childhood to older adulthood. (See 'Clinical features' above.) Pulmonary Pulmonary AVMs (PAVMs) may manifest with brain abscess, stroke, transient ischemic attack, chronic hypoxemia, or rarely, hemorrhagic rupture. CNS Central nervous system (CNS) AVMs can bleed, or rarely cause symptoms of compression. Hepatic Hepatic AVMs can remain latent; in a limited number of individuals, they can lead to high output cardiac failure, portal hypertension, pulmonary hypertension, or ischemic cholangitis. Gastrointestinal Gastrointestinal telangiectasia increase with age and can worsen anemia due to chronic blood loss. Diagnosis HHT may be diagnosed clinically (using three or more Cura ao Criteria) or by genetic testing showing a pathogenic or likely pathogenic variant in an HHT gene. (See 'Genetic testing' above.) The following four international consensus criteria define "definite HHT" (three to four criteria present), "suspected HHT" (two criteria), and "unlikely HHT" (zero or one criterion). (see 'Consensus criteria' above): Spontaneous and recurrent nosebleeds Multiple mucocutaneous telangiectasia at characteristic sites Visceral involvement (gastrointestinal, pulmonary, cerebral, or hepatic AVMs) A first-degree relative with HHT Management Management of HHT is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 20/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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