7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) : Claire L Shovlin, PhD, FRCP : Lawrence LK Leung, MD : Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is a vascular disorder inherited as an autosomal dominant trait, with a variety of clinical manifestations that vary between relatives who have the same HHT pathogenic gene variant. The most common problems are epistaxis, gastrointestinal bleeding, and iron deficiency anemia, along with characteristic mucocutaneous telangiectasia. In addition, arteriovenous malformations (AVMs) frequently affect the pulmonary, hepatic, and/or cerebral circulations, demanding knowledge of the risks and benefits of screening and treatment of patients with these complications. The pathophysiology, epidemiology, and diagnosis of HHT will be reviewed here. The management of HHT is discussed in detail 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".) Additional discussions of pulmonary AVMs, which affect over one-half of individuals with HHT, are also discussed separately. (See "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults" and "Pulmonary arteriovenous malformations: Clinical https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 1/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate features and diagnostic evaluation in adults" and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) EPIDEMIOLOGY Epidemiologic studies suggest clinical prevalence rates between 1:5000 and 1:8000, with approximately 85,000 individuals affected in Europe [1-6]. Much higher rates are described in certain geographically isolated populations (eg, 1:1330 in Afro-Caribbean residents of Curacao and Bonaire [5]). The rate of diagnosis is lower in lower socioeconomic groups [7]. The majority of patients are unaware of their diagnosis of HHT and have not been diagnosed at the time of hospital admission [8]. As a result, HHT has been subject to under-reporting [7]. PATHOPHYSIOLOGY Genetics HHT is inherited as an autosomal dominant trait with varying penetrance and expression. Pathogenic variants in multiple genes can cause HHT, with three major disease-associated genes [9,10]. As of 2022, 611 different HHT-causal variants are reported on the HHT mutation database hosted by the University of Utah [11]. Of these, pathogenic variants are distributed as follows [11]: ENG (HHT1) 333 of 611 (55 percent). These pathogenic variants cause loss-of-function in ENG (protein product: endoglin, OMIM #187300). ACVRL1 (HHT2) 263 (43 percent). These pathogenic variants cause loss-of-function in ACVRL1 (protein product: activin receptor-like kinase 1, ALK1, OMIM #600376). SMAD4 (JPHT) 15 (3 percent). JPHT is a juvenile polyposis-HHT overlap syndrome in which pathogenic variants cause loss-of-function in SMAD4 (OMIM #175050) [12]. Many additional pathogenic variants in these three HHT genes have been described, with none particularly common in different HHT families across the globe [13]. More recently, homozygosity or heterozygosity for pathogenic variants in GDF2 have been described as a rare cause of HHT [14-16]. GDF2 encodes the ALK1/endoglin ligand bone morphogenetic protein (BMP)-9. It was previously recognized to cause HHT-like features [17,18]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 2/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate These four genes all encode proteins involved in the BMP/transforming growth factor beta (TGF- beta) signaling pathway discussed further below. (See 'Cellular changes' below.) HHT is distinguished clinically and functionally from other vascular malformation syndromes resulting from pathogenic variants in mitogen-associated protein (MAP) kinase pathways. Heritable pathogenic variants in RASA1 and EPHB4 cause separate capillary malformation- arteriovenous malformation (CM-AVM) syndromes CM-AVM1 and CM-AVM2, respectively [19-22]. Somatic variants leading to endothelial overactivation of MAP kinase pathways lead to a number of vascular malformation syndromes discussed separately. (See "Venous malformations".) Genotype-phenotype correlations and variable penetrance All classical features of HHT (nosebleeds; diagnostic mucocutaneous and gastrointestinal telangiectasia; pulmonary, hepatic, cerebral, and rare arteriovenous malformations [AVMs]) (see 'Overview of clinical features' below) can be seen in patients with HHT1, HHT2, and JPHT. (See 'Genetics' above.) Classical features of HHT are strongly predictive of a variant in ENG or ACVRL1 [23]. Nevertheless, for this monogenic condition, there is marked individual variability, with advances in genetic understanding exposing the scale of reduced penetrance, and some of the contributors to phenotypic variability: In keeping with other monogenic diseases, null alleles that define HHT do not imply that individual will necessarily develop particular clinical features of HHT [24]. In a 2022 study of 152 unrelated adults in the United Kingdom with genetically confirmed HHT due to pathogenic variants in ACVRL1, ENG, or SMAD4, only 104 (68 percent) met a clinical diagnosis of HHT [25]. This group included 83 unrelated probands with one or more pulmonary AVMs and genetically-confirmed HHT; of these 83, 20 (24 percent) had few if any features of HHT [25]. It has been recognized for more than two decades that pulmonary and cerebral AVMs are more common in HHT1 patients, while hepatic AVMs, hepatic AVM-associated pulmonary hypertension, and pulmonary arterial hypertension (PAH) are more common in children and adults with HHT2 [26-31]. Variants in genes that increase the likelihood of developing pulmonary AVMs (in HHT1) and hepatic AVMs (in HHT2) are recognized [32-34]. These include hypomorphic variants in the remaining disease allele from the unaffected parent [33]. Variants in other genes have been implicated, potentially inherited from either parent, particularly protein tyrosine phosphatase non-receptor type 14 PTPN14 and a disintegrin and metalloprotease 17 (ADAM17) for pulmonary AVMs in HHT1 [32,35]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 3/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate There have been no clear data that HHT bleeding differs between molecular HHT subtypes. Instead, new data suggest that HHT bleeding is more severe if there is chance coinheritance of a deleterious DNA variant in one of 35 coagulation and platelet genes that cause bleeding disorders in the general population [36]. These variants affecting hemostasis are very common in the general population. In 104 patients with HHT undergoing whole genome sequencing, predicted loss of function variants in platelet genes were found in 10 percent of patients (1 in 10), and loss of function variants in coagulation genes were found in 12.5 percent (1 in 8) [36]. Further, in blinded analyses, HHT patients with more severe hemorrhage were more likely to have a deleterious variant in a platelet gene or coagulation gene [36]. 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 [37-41]. It is believed that most, if not all, cases of HHT result from haploinsufficiency (lack of sufficient protein for normal function) for endoglin (encoded by ENG) or ALK1 (encoded by ACVRL1); the most consistent mechanism is via generation of a premature termination codon resulting in nonsense-mediated decay of the abnormal messenger RNA (mRNA) transcript [42]. There is ongoing debate regarding whether vascular malformations result from local loss of endoglin/ALK1 expression, with newer evidence pointing to somatic loss of the second allele in lesions [43]. The University of Utah hosts the HHT mutation database [11]. Cellular changes The HHT genes (ENG, ACVRL1, SMAD4 and GDF2) all encode proteins involved in the bone morphogenetic protein (BMP) signaling pathway, which is required for the development and maintenance of arteriovenous identity. Disruption of their function perturbs vascular remodeling and disrupts blood vessel wall integrity. Endoglin, ALK1 and Smad4 proteins modulate signaling by the BMP/transforming growth factor beta (TGF ) superfamily, ligands for which include BMP2, TGF-betas, activins, and inhibins. Endoglin and ALK1 are transmembrane glycoproteins expressed abundantly on vascular endothelial cells. ALK1 is a type I receptor for the superfamily; endoglin associates with different superfamily receptor complexes (and with ALK1, a receptor complex for BMP9 [44]). Smad4 acts downstream of these receptors in signal transduction cascades. In most cell types, TGF-beta 1 signaling via the type II receptor (TbetaRII) is propagated through ALK5 (TbetaRI), although in endothelial cells, TbetaRII signaling can also be propagated through ALK1 [45]. Endoglin can modify TGF-beta-1 signaling, but with the discovery of specific ligands https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 4/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate for ALK1, attention has also focused on BMP ligands BMP9 and BMP10 [46]. BMP9 is of particular interest, where the endoglin-BMP9 interaction has been defined and clinical evidence has emerged [14,17,44]. The pure pulmonary artery hypertension (PAH) phenotype seen in patients with HHT is indistinguishable from primary PAH in the general population, caused by pathogenic DNA sequence variants in BMPR2, which encodes the BMPRII protein that also associates with ALK1, and where GDF2 (encoding BMP9) has also been identified as disease causal. (See 'Genotype- phenotype correlations and variable penetrance' above and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.) Vascular lesions Individuals with HHT can have vascular lesions in a variety of vascular beds, and the lesions can include arteriovenous shunts (eg, AVMs/arteriovenous fistulae [AVFs]) and telangiectasia. Arteriovenous shunts An arteriovenous shunt is a direct communication between arteries and veins. In anatomic shunts, abnormal vessels replace the normal capillary bed. These may be sacs (eg, for pulmonary AVMs), small collections of intervening vessels (nidal AVMs), or direct high-flow connection between the arterial and venous side (AVFs). Telangiectasia A telangiectasia is a small, dilated blood vessel (arteriole, venule, or capillary) that is apparent near the surface of skin or mucous membranes. These lesions can also be seen in other disorders besides HHT, or in otherwise healthy individuals, as part of a syndrome or in isolation. Additional vascular lesions are increasingly recognized, some seen more commonly in patients with HHT, and others, such as aneurysms, present at rates similar to the general population [47]. Differing disease patterns in members of the same family, as well as in mouse models, suggest that other genetic and environmental influences modify the HHT phenotype, and modifier genes are now described as above [32-34,36]. (See 'Genotype-phenotype correlations and variable penetrance' above.) Why AVMs develop in particular vascular beds and not others remains unclear and is the subject of ongoing research. One possibility that has supporting evidence in some examined lesions suggests that somatic loss of the second allele occurs in some lesions, noting that in the limited AVM data, there is evidence of persistent expression of the second allele [43,48]. Several animal models of HHT have been described. Null mice for ENG and ACVRL1 die between embryonic day 10.5 to 11.5 because of gross vascular and cardiac defects [49]. Heterozygous mice develop variable but more HHT-specific features including nosebleeds, telangiectasia, https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 5/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate dilated vessels, and AVMs [50,51]. Conditional LoxP knockout alleles for all three HHT genes and for ALK1 have been created; in animal models, they cause HHT-like vascular malformations to occur in a consistent and predictable manner [52]. There is substantial interest in roles of vascular endothelial growth factor (VEGF) in HHT. Increased plasma levels of VEGF and TGF-beta-1 have been seen in HHT patients [53,54]. Furthermore, treatment with angiogenesis inhibitors has some efficacy in treating HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Bevacizumab and other systemic antiangiogenic therapies'.) It is unclear whether VEGF is involved directly in the pathogenesis of what has been recognized as a BMP/TGF-beta superfamily disease, or whether these observations reflect the role of angiogenesis as a "second hit" phenomenon in HHT [33,55]. CLINICAL FEATURES Overview of clinical features The combination of epistaxis, gastrointestinal bleeding, and iron deficiency anemia associated with characteristic telangiectasia on the lips, oral mucosa, and fingertips ( picture 1) has become firmly established as a medical entity. All three areas were addressed within the Second International Guidelines [56]; they are prominent in new tools to evaluate quality of life in HHT [57,58]. The classical constellation of findings underestimates potentially life-threatening aspects of HHT. In major series to date, at least one-half of HHT patients have pulmonary arteriovenous malformations (PAVMs), placing them at risk of early onset, preventable strokes; cerebral abscess; and other complications [59-61]. Similarly hepatic AVMs affect approximately one-half of HHT patients and there is increasing concern about their implications, leading to a focus for the Second International Guidelines [56]. Approximately 10 percent have cerebral involvement [59,62,63] with varying vascular abnormalities [47]. Separate sets of considerations apply in pregnancy and pediatrics; these areas are also addressed. Individuals with HHT present to a wide range of clinicians spanning medical, surgical, general practice disciplines, and emergency departments, most of whom lack appreciation of the full range of consequences of the diagnosis of HHT for patients and their families [64]. Separate Consensus Frameworks have been generated by the European Reference Network, VASCERN, to assist general clinicians as they encounter people with HHT during a standard consultation, and separately, HHT specialists [65]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 6/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Most patients with HHT experience only epistaxis, mucocutaneous telangiectasia, and a tendency to develop iron deficiency anemia secondary to blood loss [6,13,66,67]. However, some patients can have substantial symptoms, particularly attributable to severe recurrent nosebleeds and/or gastrointestinal bleeding, resulting in transfusion dependence, augmented when visceral arteriovenous malformations (AVMs) are present with resultant higher cardiac outputs. Visceral AVMs are usually silent, but they can cause major pathology (see 'Sites of large arteriovenous malformations' below): PAVMs allow systemic venous blood to bypass the normal pulmonary circulation, resulting in paradoxical embolic stroke, brain abscess, migraines, and other complications; hemorrhage is rare except in pregnancy when it occurs at a rate of approximately 1 percent ( image 1 and table 1) (see 'Pulmonary AVMs' below). Although PAVMs differ in size and complexity of vascular supply, all present the risk of continuous right-to-left shunting, determined by the proportion of the cardiac output flowing through the AVMs. Cerebral vascular malformations in HHT are more diverse and span a range of vascular abnormalities with varying risks of hemorrhage, from minimal risk (eg, benign developmental venous anomalies, capillary malformations [sometimes inappropriately referred to as micro-AVMs], and cavernous malformations), to greater risk of hemorrhage (nidal AVMs) and significant risk of hemorrhage (AV fistulae [AVFs]) [47]. (See 'Cerebral vascular abnormalities' below.) Hepatic AVMs can result in high-output cardiac failure or other pathologies, and are increasingly recognized as causing significant morbidity, requiring careful management and timely interventions. (See 'Hepatic involvement' below.) The majority of children in HHT families are troubled only by epistaxis, but there are children who become symptomatic due to AVMs, and issues are discussed further within the Second International Guidelines and European consensus statement [47,68]. As noted above, most, if not all, AVMs may be present in childhood. In a series of 44 children screened in a multidisciplinary HHT center, 52 percent had hepatic AVMs, 45 percent had PAVMs, and 16 percent had cerebral AVMs [69]. (See 'Onset of disease manifestations' below.) Despite the evident morbidity and mortality associated with HHT, life expectancy is surprisingly good, particularly in older individuals and in more recent series. Possible explanations are provided by relative protection from certain cancers, as might be predicted from the anticancer efficacy of antibodies that mimic the molecular basis of HHT (see 'Cancer frequency' below) and reduced rates of myocardial infarction [70]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 7/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Onset of disease manifestations HHT telangiectasia are not generally present at birth; they develop with increasing age. Screening programs that use imaging rather than clinical assessment identify AVMs earlier than the classical age-related prevalence studies, which were based on clinical signs; in the imaging-based studies, approximately 70 percent of individuals developed some clinical sign of HHT by the age of 16 years, rising to over 90 percent by the age of 40 years. The following describe the findings from these more intensive screening programs: Epistaxis is usually the earliest sign of disease, often occurring in childhood. Mucocutaneous and gastrointestinal telangiectasia develop progressively with age [67,71]. PAVMs generally become apparent after puberty, although they may be present during childhood, and a computed tomography (CT)-based screening program indicated similar incidences in 74 children and 476 adults with HHT [72]. Age of development of cerebral vascular malformations appears to depend on type, with most thought to have developed during childhood [73]. There are specific circumstances in which HHT pathologies become more hazardous, the most important of which is pregnancy, which results in a 1 percent risk of maternal death per pregnancy (due to PAVM hemorrhage, cerebral hemorrhage, and thrombotic complications), with all published maternal deaths occurring in women previously considered well. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.) There is also significant morbidity and mortality in younger patients, predominantly attributed to the consequences of visceral AVMs, especially pulmonary, cerebral, and hepatic AVMs; pulmonary hypertension; and venous thromboembolism (VTE). (See 'Pulmonary hypertension' below and 'Venous thromboembolism' below.) Many of these risks were quantified by a prospective 30-year follow-up series in Denmark [3] and a retrospective study of the parents of 74 Italian patients with HHT [74]. Even in these long retrospective series, for patients who did not present spontaneously to a clinician before the age of 60 years, there was no excess mortality [3]. A subsequent 20-year follow-up series from Denmark indicated that life expectancy can be normalized for patients whose epistaxis, anemia, and PAVMs are expertly managed [75]. This finding was confirmed by a second study in Europe [76]. Epistaxis The most common clinical manifestation of HHT is spontaneous, recurrent epistaxis from telangiectasia of the nasal mucosa. Some patients experience no or minimal occasional episodes, but for the majority, recurrent and frequent epistaxis is a feature, with many patients https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 8/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate experiencing daily bleeds. In an online survey of 666 patients with HHT, 649 (97 percent) reported nosebleeds, and 326 (49 percent) reported the use of specialist invasive treatments for epistaxis, most requiring multiple different modalities [77]. In another study of 220 patients with HHT, nearly one-half reported nosebleeds occurring daily, and three-quarters reported nosebleeds at least once a week [78]. A summary of additional studies is provided within the Second HHT International Guidelines [56]. Epistaxis may be provoked by a variety of factors, such as changes in external temperature, humidity, activity, and posture. Additional data also highlight the possibility of dietary aggravation of nosebleeds in patients with HHT (eg, from alcohol, spices, high-salicylate dietary items, and migraine-precipitating foods) [77,78]. Patients can present with hemodynamic disturbance secondary to acute blood loss, particularly for patients describing arterial bleeds (ie, gushing nosebleeds in the epistaxis severity score) [79,80]. Management and prevention of epistaxis can range from mild interventions, such as nasal humidification, to tranexamic acid (which is effective but carries potential side effects), to more aggressive measures, depending on the severity of bleeding. Ablative therapies are recommended before considering systemic antiangiogenic therapy, with septodermoplasty and Young's procedure to close the nostrils also recommended for the most severe cases, as discussed in the Second HHT International Guidelines [56]. Iron supplementation is commonly needed, and blood transfusions may be required. These subjects are discussed in detail separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Epistaxis' and "Approach to the adult with epistaxis" and "Management of epistaxis in children".) Gastrointestinal bleeding Recurrent gastrointestinal bleeding occurs in up to one-third of patients with HHT, often presenting as iron deficiency anemia or an acute gastrointestinal bleeding episode, most commonly in patients over the age of 40 years [71,81]. Gastrointestinal bleeding probably contributes less frequently to iron deficiency than under-recognized epistaxis. In many patients, improvement in nasal hemorrhage is able to significantly reduce iron and transfusion requirements. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Iron status'.) Telangiectasia can occur throughout the gastrointestinal tract and are more common in the stomach or duodenum than in the colon ( picture 2A-B). They are visualized by endoscopy, are similar in size and appearance to mucocutaneous telangiectasia, and may be surrounded by an anemic halo. Less commonly, AVMs and aneurysms occur; these lesions may be visualized on https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 9/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate angiographic studies of the gastrointestinal tract ( image 2). (See "Angiodysplasia of the gastrointestinal tract".) Recommendations for management from the HHT International Guidelines are presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Therapy for specific vascular lesions and iron deficiency'.) Mucocutaneous telangiectasia Telangiectasia of the skin and buccal mucosa are present in most individuals in later life but may be absent or subtle when younger [71]. They mostly occur on the lips, tongue, buccal mucosa, and fingertips, but can occur elsewhere, where they are less HHT specific and therefore not used for diagnostic purposes ( picture 1 and picture 3) [82]. Bleeding can occur but is rarely clinically important. Sites of large arteriovenous malformations Clinically important AVMs can occur in a number of organs, such as the lung, brain, and liver. While single AVMs can occur sporadically in the normal population as well as in patients with HHT, the presence of multiple AVMs in an organ such as the lung or brain make a sporadic etiology less likely [8,83]. However, single AVMs are still strongly associated with HHT in both organs. Additionally, CT-based research screening programs of asymptomatic individuals have identified pancreatic AVMs at surprisingly high frequency [84]. Pulmonary AVMs Pulmonary arteriovenous malformations (PAVMs) are abnormal vessels that replace normal capillaries between the pulmonary arterial and venous circulations, often resulting in bulbous sac-like structures ( image 3 and image 4). They provide a direct capillary-free communication between the pulmonary and systemic circulations. Patients with PAVMs are at risk for complications, most commonly neurologic sequelae due to paradoxical embolism, with embolic material evading the filtering function of the pulmonary capillaries and reaching the central nervous system. The clinical features, diagnosis, and epidemiology of PAVMs are discussed in detail separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults" and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".) Management of PAVMs is also presented in detail separately, including screening, embolization, and the use of prophylactic antibiotics to reduce the role of brain abscess. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pulmonary AVMs' and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 10/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Hypoxia and respiratory symptoms Pulmonary arterial blood passing through these right-to-left shunts cannot be oxygenated, leading to hypoxemia. Hypoxemia results in an erythrocytotic stimulus, which can lead to clinically significant levels of secondary polycythemia. However, the majority of patients with PAVMs have no respiratory symptoms, and most are unaware that they have HHT or PAVMs [8,85]. In one review, fewer than one-third of affected individuals exhibited physical signs indicating a substantial right-to-left shunt, such as cyanosis, clubbing, and/or polycythemia ( table 2) [86]. These proportions are likely to fall still further as more patients are diagnosed with more sensitive screening programs. When symptoms such as reduced exercise capacity occur, this generally reflects low hemoglobin and/or airflow limitation rather than hypoxemia [87,88]. Cerebral embolic events (ischemic stroke and brain abscess) and bleeding Catastrophic embolic cerebral events (embolic stroke, transient ischemic attack, and brain abscess) occur in patients with clinically silent PAVMs and carry significant morbidity and mortality, indicating the need for early diagnosis and intervention, including embolization of PAVMs and antibiotic prophylaxis for interventional procedures, especially dental [8,89]. Ischemic stroke The burden of ischemic stroke due to paradoxical embolism is summarized in a 2022 review [90]. A study of 497 consecutive patients with CT-proven PAVMs found that 61 (12 percent) had acute, noniatrogenic ischemic stroke at a median age of 52 years [91]. Additionally, the first nationwide analysis of 4,271,010 patients with ischemic stroke found that 822 had a PAVM diagnosis, with strokes occurring a decade earlier than stroke in patients without PAVMs [92]. Other studies have documented that ischemic stroke precedes the diagnosis of HHT [8]. As recently reviewed, the burden of silent cerebral infarction in patients with PAVMs is considerably higher than that of clinical stroke, with evidence of silent cerebral infarction by magnetic resonance imaging (MRI) in nearly 50 percent of individuals with PAVMs by 50 years of age [63,90,93]. Brain abscess In a 2017 study of 445 consecutive adults with HHT and CT-confirmed PAVMs, 37 (8.3 percent) had brain abscesses [94]. By multivariate logistic regression, brain abscess was associated with low oxygen saturation (indicated greater right-to-left shunt), higher transferrin saturation, intravenous use of iron for anemia, male sex, and venous thromboemboli. There were no relationships between the anatomic attributes of PAVMs and the likelihood of brain abscess. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Natural history' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pulmonary AVMs'.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 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