Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)∗

3 Hereditary Hemorrhagic Telangiectasia (Osler–Weber– Rendu Syndrome)* Beth L. Roman,1 Douglas A. Marchuk,2 Scott O. Trerotola,3 Reed E. Pyeritz4 1Department

of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States, 2Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States, 3Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States, 4Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

3.1 INTRODUCTION 3.1.1 Historic Perspective The evolution of our recognition and understanding of hereditary hemorrhagic telangiectasia (HHT; OMIM 187300, 600376) begins with the descriptive science of the 19th century and continues through the current era of molecular medicine. Only in the past 2 decades have modern genetic approaches made clear that the previous view of HHT as a single entity was overly simplistic, and that a more accurate concept is of a family of closely related conditions that share similar, but not identical, molecular bases and clinical courses. The history of HHT might be said to start in 1864, when Sutton described a family with apparent autosomal dominant epistaxis, including at least two affected individuals with a history of hemoptysis, one of whom * This article is a revision of the previous edition chapter by Alan E Guttmacher, Douglas A Marchuk, Scott O. Trerotola and Reed E Pyeritz ©2013, Elsevier Ltd.

died at the age of 60 years of what was said to be “ruptured blood vessel of the lungs” [1]. Even with no mention of other symptoms and signs such as telangiectases, this likely represents the first reported case of what we now regard as HHT. Although the following 30 years included a number of reports of families with various signs and symptoms of what may well have been HHT, it was Rendu [2] who first reported the combination of telangiectases and hereditary epistaxis as a discrete entity, and one that he distinguished from the more widely known hemophilia. In the following decade, a number of reports of this condition appeared, most importantly by Osler [3] and Weber [4], whose names soon joined that of Rendu to form the triple eponymic appellation, that in varying order, has been used by many to label the disease ever since. In 1909, Haynes coined the term hereditary hemorrhagic telangiectasia for the condition, in recognition of the three features—its hereditary nature, frequent epistaxis, and multiple telangiectases—that by then were thought to characterize it [5].

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00003-3 Copyright © 2020 Elsevier Inc. All rights reserved.

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The remainder of the first half of the 20th century witnessed numerous case reports, which both reflected and caused somewhat wider medical recognition of HHT; however, the diagnosis was apparently still often not entertained even in the face of “textbook” presentations, and there was relatively little progress in better understanding the condition’s basic underlying biology or in treating it more effectively. In the second half of the twentieth century, several developments began to change this picture—first in terms of therapy, and later in terms of biological understanding. Among major therapeutic advances were the development, starting in the 1950s, of improved methods for managing persistent epistaxis and the development of transcatheter embolotherapy for pulmonary arteriovenous malformations (PAVMs), starting in the late 1970s, by Robert I. White, Jr, Peter Terry, and others [6]. The founding in the 1980s by Bruce Jacobson and others of a patient registry that soon grew into the Hereditary Hemorrhagic Telangiectasia Foundation International (now Cure HHT) provided an impetus for increased patient and provider education, as well for both basic and clinical research. At the end of the twentieth century, new genetic approaches led to dramatic breakthroughs in understanding of the basic biology of HHT. Over 1000 primary research publications have appeared since 1995. In rapid succession in the mid-1990s, Marchuk, Letarte, and others identified two different causative genes, endoglin (ENG) on chromosome 9 and activin A receptor like type 1 (ACVRL1) on chromosome 12 [7,8]. That both genes were involved in the transforming growth factor-beta (TGFβ) and BMP signaling pathways suggested the biology that lay at the core of the HHT phenotype. That two different genes could cause what had previously appeared to be a single clinical condition raised the question of whether HHT was, in fact, a single clinical entity, or a family of related, phenotypically overlapping conditions. The 1990s also saw the establishment of forums for communication among the growing international HHT research community, including regular international meetings that advanced both research and clinical collaborations [9]. The last years of the 20th century and the first decade of the 21st century witnessed other advances, such as the establishment of the first animal (mouse) models for HHT [10–13] and the identification of families segregating features of both juvenile polyposis (JP) and HHT due to mutations in SMAD4 [14]. 

3.1.2 Prevalence Several population-based surveys suggest the prevalence is at least 1 per 5000–8000 [15]. In the County of Fyn, Denmark, the prevalence is 15.6 per 100,000 [16]. In the Netherlands Antilles, the prevalence is much higher, 1 per 1331, at least in part due to founder effect in an island population [17]. As with many other dominant conditions, age dependency of features contributes to incomplete ascertainment in any family- or population-based investigation. No prevalence survey has yet employed molecular diagnosis. 

3.2 PHENOTYPE AND NATURAL HISTORY 3.2.1 Overview Life expectancy in patients with HHT is somewhat reduced, with the occurrence of life-threatening complications more common in young (<50 years) and older (>60 years) patients compared to controls [18–20]. However, one study of patients from a small region of Denmark found no decrease in life expectancy [21]. Quality of life (QOL) is impacted by HHT, with patients more severely affected clinically (especially by epistaxis) having worse QOL scores [22,23]. The fundamental problem in HHT is in the development of blood vessels, especially the connections between arteries and veins. Problems start in the embryo, but they often do not become clinically important until adulthood. If the tiniest connections, the capillaries, are involved, then the lesions are termed telangiectases, or 1- to 2 mm enlargements that appear dark red on the skin, the lips, the tongue, or the nasal or the bowel mucosa. Because the telangiectases are close to the surface and have very thin walls, they bleed easily. This accounts for nosebleeds being an early sign of HHT, and GI hemorrhage being a problem in adulthood. When the abnormal connections are larger, they are termed AVMs. The brain, the lung, and the liver are the primary sites of AVMs, but other organs can be involved. The absence of a capillary connection is established early in life, and the individual lesion may or may not expand slowly over many years. An AVM causes problems because capillaries are bypassed. An AVM anywhere results in increased cardiac output, which places strain on the heart. In the lungs, an AVM provides a direct connection through which bacteria and blood clots in veins can travel directly to the arterial circulation without being filtered by lung capillaries.

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The result can be a stroke or cerebral abscess if the final resting place is the brain, or ischemic damage to an end organ such as the kidney. Also, pulmonary AVMs provide a shunt that prevents venous blood from being oxygenated, so the partial pressure of oxygen in arterial blood is reduced proportional to the number, size, and location of the lung lesions. HHT is often misdiagnosed, both because the features vary considerably among those affected (even within a single family), and features accumulate over the life span of patients. Formal studies of QOL show that the clinical complications of HHT, especially epistaxis, have a significant negative impact [22]. Both marked inter- and intrafamilial variabilities characterize HHT. Interfamilial variability is due, in part, to different mutations in different genes that can affect expression of the HHT mutation. For example, if the unaffected parent has a mutation in PTPN14 (protein tyrosine phosphatase, nonreceptor type), whose protein product interacts with the products of both ENG and ACVRL1, then on average half of the offspring with a mutation in ENG would have enhanced or reduced severity in HHT [24]. Intrafamilial variability is typical of many dominant disorders [25]; the precise biology by which it occurs in HHT is still unknown. Because of the impacts of mutations in ENG and ACVRL1 on angiogenesis, concerns were raised about the occurrence and progression of neoplasia in patients with HHT. For a variety of visceral tumors, survival was enhanced when associated with HHT [26]. In a case-control analysis, the incidence of cancer was reduced in HHT [27]. 

3.2.2 Phenotype

3.2.2.1 Mucocutaneous Telangiectases A telangiectasia can appear as a central core with dilated capillaries extending out from it (spider telangiectases) or as a single macular or slightly elevated, more-or-less circular lesion. Spider telangiectases typically occur because of sun exposure or chronic liver disease. Single, circular lesions are typical of HHT. When slight pressure is applied, telangiectases blanch, then gradually refill when the pressure is released. This distinguishes a telangiectasia from a petechia and an angiokeratoma, which do not blanch, and a cherry angioma, which at best may blanch minimally. In HHT, punctate telangiectases can appear anywhere on the skin or mucus membranes, but are most common on the fingers, palms, face, lips, buccal cheek, and tongue (Fig. 3.1). Microscopy of the nail

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folds often shows dilated loops between capillaries and can be an early diagnostic sign [28]. Telangiectases may be present in children, but they typically appear later and increase with age. Numerous telangiectases in young children, in the absence of brain or lung AVMs or a family history of HHT, should prompt consideration of other diagnoses, such as ataxia–telangiectasia or benign familial telangiectasia. In adults, cutaneous and oral telangiectases occasionally bleed when traumatized, but they generally are of cosmetic concern only. Two areas where telangiectases of the mucus membrane pose substantial clinical risk are the nose and the GI tract. 

3.2.2.2 Epistaxis Often the first sign of HHT is recurrent bleeding from the nose (epistaxis). Because epistaxis occurs so frequently in the general population, until the episodes become frequent or severe, the patient or parent may not seek medical attention. Even then, the primary care or emergency physician usually treats or refers to the rhinologist but does not delve into the cause. The family history of a child that reveals severe epistaxis in close relatives can be the most important piece of evidence that a familial disorder should be entertained, and HHT is at the top of a very short list. Bleeding occurs from mucosal telangiectases and eventually affects about 90% of people with HHT. The average age of onset is 12 years and the average frequency is 18 episodes per month. Nocturnal epistaxis is common. Factors that predispose to bleeding include low atmospheric humidity and digital trauma.  3.2.2.3 Gastrointestinal Bleeding from mucosal telangiectases in any portion of the GI tract can lead to chronic anemia. At the most proximal end, lesions on the lips, tongue, and oral mucosa are of cosmetic concern primarily, but bleeding can be annoying and embarrassing. Bleeding from the stomach, small intestine, and colon becomes more common with age; rarely, this is a problem in children or adolescents. Upper and lower endoscopy can reveal the site of blood loss but often shows a myriad of lesions that appear capable of bleeding at any time. Examination of stool for occult blood is of limited use in HHT because swallowed blood from epistaxis yields a positive result.

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(A)

(C)

(B)

(D)

Figure 3.1  Dermal and mucocutaneous features of hereditary hemorrhagic telangiectasia. (A) Digits. (B) Ear. (C) Lips. (D) Tongue.

One uncommon form of HHT is associated with JP and is due to mutations in SMAD4. Juvenile polyps can bleed or obstruct but are most worrisome because of their susceptibility to malignancy. Mutations in ENG can also predispose to juvenile polyps, apparently in the absence of signs of HHT [29]. Involvement of both SMAD4 and ENG in both HHT and polyposis emphasizes the importance of the TGFβ–BMP signaling pathway in the control of a variety of developmental systems. 

3.2.2.4 Central Nervous System Three forms of developmental lesions and one acquired form are common in the brain and spinal column in HHT [30]. Telangiectases, venous malformations, and cerebral arteriovenous malformations (CAVMs) developmental lesions are often clinically silent. Their frequency and natural history are unclear because most patients have not been screened adequately or

repetitively. Screening by magnetic resonance imaging (MRI) found a 23% prevalence of some cerebral vascular malformation in patients with HHT [31]; however, this study also showed that angiography is more sensitive for both detecting and characterizing cerebral lesions. Brain AVMs are more common in patients with a mutation in ENG [32]. The risk of bleeding from any of these lesions is also unclear, but can occur at any age and with any genotype [33]. The overall risk of intracranial hemorrhage from a brain vascular malformation in HHT may not differ from that in an isolated lesion not due to HHT. In HHT, preliminary estimates of risk vary between 0.5% and 1.4%–2.0% per year. If a malformation is large enough or bleeds, the complications include headache, altered mental status, seizure, and stroke. Migraine-like headaches are of increased frequency especially in those who have an intrapulmonary right-to-left shunt [34].

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The most frequent acquired lesions are due to embolization of clots or bacteria through systemic AMVs to the brain. The results are stroke and brain abscess, respectively [35]. Complications due to spinal AVMs are uncommon, but since routine screening is not performed, their prevalence is uncertain [36]. 

3.2.2.5 Lung The single clinical finding that is most likely to prompt consideration of the diagnosis of HHT is the PAVM (Fig. 3.2A). It remains uncertain as to what fraction of people with an apparently isolated PAVM actually has HHT, partly because people thought to have a single PAVM undergo neither detailed screening of the rest of their lungs to detect small lesions nor examination for other features of HHT. PAVMs should be looked for carefully in any person with, or at risk for, HHT, including infants, because considerable morbidity results from these lesions. A PAVM of any size can serve as a conduit for bacteria, air bubbles, or clots from the venous circulation to be transmitted directly to the systemic arterial circulation. The risk of cerebral infarction due to embolization is greater in patients with multiple PAVMs [37]. The PAVM also serves as a right-to-left shunt in terms of oxygenation, and the decrease in arterial PO2 is generally determined by the size, number, and location of PAVMs. The patient may present with progressively worsening dyspnea on exertion, cyanosis, and clubbing. Polycythemia leading to plethora is uncommon because most patients with HHT have chronic blood loss from one source or another. Hemoptysis from rupture of a PAVM or bleeding from bronchial telangiectases is rare but can be life-threatening when massive [38]. Chronic right-to-left shunting can also lead to pulmonary hypertension and right-sided heart failure. Infants and children should be screened for PAVMs since they may have one or more of clinical importance; however, it is presently believed that treatment should be reserved until adulthood unless the PAVMs are symptomatic. Typically, PAVMs emerge in adolescence and young adulthood. It is believed that PAVMs expand over time, albeit very slowly, and it is not clear whether new ones may emerge. Regardless, lifelong assessment for development of treatable PAVMs is considered essential [39]. Some young adults will have no evidence of an intrapulmonary shunt and are unlikely to develop any.

Figure 3.2 Filtration function of pulmonary capillary bed and how a pulmonary arteriovenous malformation (PAVM) bypasses that function to produce paradoxical emboli can be envisioned from these renderings. (A) Normal capillary bed. (B) A simple PAVM. (C) A complex PAVM. (Reprinted with permission from Trerotola, S.O., Pyeritz, R.E., 2010. PAVM embolization: an update. AJR Am J Roentgenol 195, 837–845.)

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A small fraction of patients with HHT have pulmonary hypertension unrelated to their degree of shunting. These patients typically have a mutation in ACVRL1. Some families with primary pulmonary hypertension but without signs of HHT have mutations in ACVRL1 (OMIM 178600). 

3.2.2.7 Other Manifestations Vascular malformations in the kidneys, bladder, retina, and other organs have been reported [45] as has aneurysm of the aorta and coronary arteries [46]. 

3.2.2.6 Liver Four types of hepatic vascular lesions occur in HHT: (1) telangiectases, (2) direct communication of hepatic arteries to hepatic veins, (3) direct communication of hepatic arteries to portal veins, and (4) portal vein-tohepatic vein connections [40,41]. Several recent surveys using ultrasound, computed tomography (CT), or MRI have shown the frequency of hepatic vascular involvement to be much higher than previously thought, in the range of 40%–75% [42]. Discrepancies in prevalence relate to methods of diagnosis, with CT and MRI being more sensitive than ultrasound and auscultation for a bruit. Arteriography is not necessary for routine assessment or screening [41]. Hepatic artery-to-hepatic vein shunts place a strain on the circulation and can lead to congestive heart failure. Direct connections between the systemic arterial and portal circulations can cause portal hypertension, splenomegaly, spider-like telangiectases (which are distinct from the telangiectases typical of HHT), and esophageal and hemorrhoidal varices. Communication between the portal circulation and the systemic venous circulation leads to hepatic encephalopathy, ascites, and an increase in GI hemorrhage. Despite hyperperfusion through the liver, areas of the organ can be relatively ischemic, and areas of fibrosis in a nodular pattern suggest classic cirrhosis [43]or even malignancy. Standard liver function tests are often normal because areas of the liver are relatively spared. Other patients have a pattern suggestive of ischemia in peribiliary regions leading to strictures, bile cysts, increased alkaline phosphatase, and, eventually, hyperbilirubinemia. Neither percutaneous liver biopsy nor retrograde cholangiopancreatography is usually necessary, and both present an increased risk in HHT. An HHT referral center in Italy assessed 502 patients for hepatic involvement and found vascular malformations in 154 [44]. Followed for a mean of 44 months, 5.2% died of hepatic complications and 25.3% suffered complications. Therapies of various types (discussed below) successfully treated two-thirds. 

The familial nature of HHT was recognized from the earliest descriptions of the phenotype. Inheritance is autosomal dominant with high penetrance if careful phenotypic assessment is performed. However, considerable intrafamilial variability occurs.

3.3 GENETICS

3.3.1 HHT1 and Endoglin (ENG) Genetic linkage for HHT families was first established to markers on chromosome 9q33–q34 [47,48]. Mutations in the gene encoding ENG were subsequently identified in HHT1 kindreds [8]. ENG is a homodimeric transmembrane protein expressed at high levels on human vascular endothelial cells of all blood vessels [49]. On endothelial cells, ENG is the most abundant TGFβ-binding protein [50]. The 90 kDa ENG protein is encoded by a gene comprising 15 exons. In addition to the originally identified ENG cDNA, a splice variant was detected called S-endoglin (for short ENG), coding for an 85 kDa protein. The extracellular and transmembrane domains of S-endoglin and the longer ENG version (L-endoglin) are identical, whereas the alternative splicing creates a novel, 14-amino acid residue cytoplasmic domain for S-endoglin. These two isoforms are coexpressed in different cell types although the majority of the transcripts correspond to L-endoglin. With the advent of large-scale diagnostic mutation analysis for HHT in a number of countries, hundreds of distinct mutations have been identified in the ENG gene. At the outset, these mutations appeared to be primarily family specific. This led to difficulty in interpreting novel sequence variants, especially putative missense mutations, because each new family harbored a novel mutation that could not be cross-referenced with a previously described mutation. With the great number of mutations now identified and cataloged in databases, recurrence of the same mutation in apparently unrelated families is slightly more common. Nonetheless, novel sequence variants continue to predominate. In this context, cross-reference to normal sequence polymorphisms identified in large genome or exome sequence databases helps to identify those

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alterations that merely represent normal sequence polymorphisms. Mutations thus far identified in the ENG gene include missense mutations, nonsense mutations, splice-site changes, and small nucleotide insertions and deletions leading to frameshifts and premature stop codons, all found throughout most of the exons of the gene. Additionally, mutations in the 5′ untranslated region can result in HHT. Expression data from a number of frameshift and nonsense mutations show that many of these create unstable messages [51], and therefore, little to no mutant proteins would be produced. Thus, these mutations would create null alleles. Other clear examples of null alleles include large deletions, duplications, and other genomic rearrangements involving multiple exons of the gene. All genetic testing centers for HHT now routinely search for such genomic rearrangements, and one center recommends that the search for DNA sequence variants and genomic rearrangements should occur simultaneously, rather than sequentially, to ensure identification of all possible mutations in the genes [52]. Larger genomic mutations contribute to at least some of the approximately 10%–15% of HHT cases, in which no mutation can be identified in ENG, ACVRL1, or SMAD4. 

3.3.2 HHT2 and ACVRL1 A second HHT locus (HHT2; OMIM 600376) was identified in the pericentromeric region of chromosome 12 [7]. A potential candidate gene, ACVRL1, encoding the ALK1 protein (activin A receptor like type 1), was shown to map within this interval, and mutations were identified within this gene in HHT2 families. ALK1 protein is expressed primarily on endothelial cells and in highly vascularized tissues. Studies using a reporter gene trap within the mouse Acvrl1 gene suggest that its transcript is expressed most highly, and possibly exclusively, in the arterial endothelium in most organs [53]. By sequence homology, ALK1 had been considered a type I cell surface receptor for the TGFβ superfamily of ligands. Until recently, however, the authentic ligand that activated ALK1 was unknown. The signaling role of ALK1 will be discussed in a later section. Human ACVRL1 contains 10 exons, 9 of which encode the protein sequence [54]. With large-scale mutation screening being performed worldwide in HHT families, hundreds of mutations have been identified in ACVRL1. Mutations in ACVRL1, similar to those

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in ENG, are for the most part family specific, again leading to difficulties of confirmation by cross-referencing with previously described mutations. With the advent of large datasets of exomic sequence variation it is becoming easier to sort out bona fide mutations from population polymorphisms. Mutations are found throughout the gene and fall into classes of nonsense, frameshift, splice-site, and missense mutations. Genomic rearrangements of ACVRL1 are also found, and tests for such genomic mutations are now routinely included in genetic testing for HHT. Overall, missense mutations in ACVRL1 appear to be more common than in ENG. RNA expression data for some of the ACVRL1 nonsense and frameshift mutations show that little or no message can be detected from the mutant allele [54]. These data, in combination with the sum of the mutation data, demonstrate that most mutations create null alleles, which should lead to reduced signaling through the ALK1 receptor. Reduced signaling capacity has been validated now for representative ACVRL1 missense mutations [55]. These authors developed the first functional assay for ALK1 signaling based on the discovery of BMP9 (to be discussed later) as the specific ligand for the receptor. Previously identified missense mutations in ACVRL1 all showed defective BMP9 signaling, whereas known coding polymorphisms did not affect receptor function. Significantly, missense variants of uncertain significance could now be functionally categorized as either mutations or benign polymorphisms, demonstrating the utility of their signaling assay as a tool to inform DNA-based diagnostics. 

3.3.3 HHT3 Evidence for a third locus and gene for HHT (HHT3; OMIM 601101) was provided by a single HHT family [56] that was unlinked to both the HHT1 and HHT2 loci. The locus in this family and in an additional smaller family was mapped to chromosome 5q31–q32 [57]. Higher resolution mapping has further narrowed the candidate interval to a 5.7 Mb interval. The gene has yet to be identified, but no previously known receptor or effector for TGFβ/BMP signaling maps within the revised interval. The eventual identification of this gene is likely to shed new light on HHT pathogenesis. The prevalence of HHT3 also remains uncertain because to date, only two HHT families have shown statistically significant linkage to this region. 

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3.3.4 HHT4 Evidence for a fourth locus and gene for HHT (HHT4; OMIM 61055) was provided by a single, large HHT family that maps to chromosome 7p14 [58]. The HHT4 gene has yet to be identified. As with HHT3, the prevalence of HHT4 remains unknown, but is presumed to be very rare. 

3.3.5 Juvenile Polyposis–HHT A number of case reports suggested an association of JP and HHT or with one or more features of HHT (OMIM 175050), especially, PAVMs [59,60]. One of the two genes mutated in JP is SMAD4, encoding the Smad4 protein, a downstream effector of TGFβ signaling. The other gene mutated in JP is BMPRIA, encoding a type I receptor for another ligand in the TGFβ superfamily [61]. It is now known that most patients with JP harboring a SMAD4 mutation display a combined syndrome of juvenile polyps and HHT [14]. Careful clinical screening for both GI polyps and the various vascular malformations associated with HHT has shown that affected individuals meet diagnostic criterion for both JP and HHT [14]. The combined syndromic phenotype is estimated to occur in 15%–22% of individuals with a SMAD4 mutation, but this may be an underestimate because of a lack of recognition of the HHT phenotype in individuals with clinically silent vascular phenotypes. Mutations in the SMAD4 gene tend to cluster in the carboxyl terminal of the SMAD4 protein, particularly in the MH2 domain. However, the majority of SMAD4 mutations previously described in JP also cluster in the same region, ruling out a clear genotype:phenotype correlation. The molecular analysis of a larger number of JP–HHT cases shows that mutations throughout the SMAD4 gene can cause the syndrome [62]. Therefore, any patient who tests positive for an SMAD4 mutation is at risk for the combined syndrome of JP–HHT, and should be monitored accordingly. Although JP–HHT cases are usually first identified as JP patients, some individuals may first present with the HHT phenotype. Of 30 patients with HHT and no clinical evidence of JP, who were negative for mutations in ENG and ACVRL1, screening for mutations in SMAD4 found 3 positive [63]. These SMAD4-positive patients should be screened intensively for polyps. The determination of the true penetrance of JP–HHT syndrome in SMAD4 mutation carriers requires clinical screening of all JP

patients (harboring any SMAD4 germline mutation) for HHT-associated phenotypes. Because patients with these two disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. In particular, patients with juvenile polyps who harbor a SMAD4 mutation should be screened for the presence of vascular lesions associated with HHT, especially occult AVMs in visceral organs that may otherwise present suddenly with serious medical consequences. 

3.4 GENOTYPE–PHENOTYPE CORRELATIONS IN HHT Large-scale DNA sequencing for diagnostics in multiple countries and populations has provided a few consensus genotype–phenotype correlations in HHT. These correlations can be valuable in genetic counseling and in establishment of guidelines for routine medical care and screening for HHT patients. Although one study found that truncating mutations in the ENG gene are associated with a more severe outcome than missense mutations [64], and another suggested that protein-truncating mutations in ACVRL1 were associated with a higher frequency of epistaxis and telangiectasia [65], in general, mutation-specific genotype–phenotype correlations have not been uniform in all populations. There seems to be limited utility in using the nature of the germline mutation to predict clinical outcomes. This is perhaps not surprising because the variability in clinical presentation among family members harboring the same mutation can be as broad as the variability among different families each with a distinct mutation. The variability among family members with the same germline mutation suggests that yet undiscovered biological (such as hormonal), environmental, genetic and epigenetic factors influence the clinical presentation of HHT. Evidence for the role of other genes in modulating the phenotype comes from genetically engineered mutant mouse strains. The phenotype of mice with an engineered heterozygous mutation in the murine ENG gene is heavily influenced by the genetic background (that is, the particular inbred lineage) of the mice [66]. Similarly, mice lacking the TGFβ1 ligand show profound differences in the resulting phenotype depending on inbred strain background carrying

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the deleted allele. The strain-specific differences for the loss of TGFβ1 have been exploited to map multiple chromosomal loci that modify the resulting phenotype [67–69]. Common sequence variations in the human orthologues of putative modifier genes identified in mice have been examined as modifiers of the phenotype in HHT patient cohorts. These studies have revealed that sequence variation in PTPN14 modulates the PAVM phenotype in HHT patients [24]. Similarly, SNPs in the Adam17 gene (a disintegrin and metalloproteinase) modulate the PAVM phenotype in HHT1 (ENG) but not HHT2 (ACVRL1) patients [70]. There is also evidence that genetic variation in the wild-type copy of ENG in HHT1 patients modulates endoglin expression levels and influences the PAVM phenotype [71]. These studies confirm what has been long surmised, namely, that genetic variation in other genes contributes to the widely variable phenotype among and even within HHT families. However, other than these cases, few authentic genetic modifiers have been identified and validated in human cohorts. These can only be identified using large, well-phenotyped clinical cohorts for each HHT subtype. There is also clear evidence for a correlation between the incidence of various clinical manifestations of HHT and the particular gene mutated. An initial subjective observation was made that the families that were linked to HHT1 (ENG) seemed to have a much higher incidence of PAVMs reported than families for whom this locus was excluded. Further analysis confirmed that this difference was genuine [72]. However, these initial results were interpreted with caution because they relied on incomplete screening for the pulmonary AVMs, such that only patients with symptomatic pulmonary lesions were scored positive for these lesions. Multiple large studies have now confirmed that patients with ENG mutations exhibit anywhere from a twofold to up to a tenfold higher incidence of PAVMs than patients with ACVRL1 mutations [73,74]. Some of the variabilities observed among studies are likely due to differing ascertainment biases for the pulmonary phenotype. Similarly, cerebral AVMs are also more common in patients with ENG mutations than those with ACVRL1 mutations, and in some studies, appear to be almost exclusively found in HHT1 patients. One study found neurological complications secondary to CAVMs and PAVMs only in HHT1 patients [74].

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In comparison to HHT1, HHT2 patients (ACVRL1 mutation) more commonly exhibit GI bleeding and show a higher frequency of hepatic AVMs [65], with two studies observing severe or symptomatic hepatic disease only in HHT2. HHT2 is also associated with an increased risk to develop pulmonary hypertension [75– 77]. Pulmonary hypertension has also been observed in HHT1 cases [78]. Despite the wealth of genotype:phenotype data that has emerged, the establishment of correlations such as these continues to be fraught with difficulties due to ascertainment bias. Unless each family member is carefully and consistently screened using the same modality and for the entire spectrum of clinical manifestations regardless of current clinical presentation, these correlations will continue to be incomplete. The best data have come from the more recently published studies from large HHT centers of excellence, where comprehensive clinical screening was coordinated with molecular diagnostics. But even these more robust estimates of the incidence of clinical phenotypes should be used cautiously because these different incidence rates merely represent averages over large numbers of patients. Numerous individual cases are known that would violate the averages, and negligence in screening for any of the visceral manifestations associated with HHT could result later in serious medical consequences for the patient. 

3.5 ALK1 SIGNALING AND HHT PATHOGENESIS The TGF beta superfamily of growth factors transmit their signal via a complex of cell membrane bound receptors. Downstream intracellular effectors of the signal are the SMAD proteins, which once phosphorylated can form a complex with a common SMAD protein (SMAD4) to translocate to the nucleus to modulate the expression of a number of responsive genes. As discussed earlier, ALK1 is a type 1 serine-threonine kinase receptor, and ENG is a type III accessory protein, without direct kinase activity but capable of modulating the activity of a signaling receptor. SMAD4 is the aforementioned common SMAD that complexes with other family members to modulate gene expression. These genes encoding these three components of the signaling pathway are mutated in HHT and have been recognized for some time. However, the authentic ligand(s)

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for this pathway was more recently discovered. BMP9 and BMP10 are closely related members of the TGF beta superfamily of growth factors. Both are present in human plasma [79] and both can bind to ALK1 to activate its signaling pathway [80,81]. Further evidence for a role of BMP9 as an important ligand in HHT pathogenesis is that certain missense mutations found in HHT1 (ENG) patients block BMP9 binding to the ENG receptor [82]. Recently, three rare sequence variants in the GDF2 gene, encoding the BMP9 ligand, have been reported in patients with a vascular phenotype resembling HHT [83]. The similarity of the vascular phenotype between these individuals/families and HHT individuals/families further supports the role of BMP9 as an important ligand in HHT pathogenesis. Early studies on the functional consequences of ALK1 provided conflicting data on whether this pathway is pro- or antiangiogenic [84–88]. These different interpretations of the role of this pathway are likely due to the use of different cell lines and experimental systems. However, the consensus from static cell culture–based studies using relevant ligand is that BMP9/ ALK1 signaling supports vascular quiescence; that is, it has an antiangiogenic role. More recent dynamic cell culture studies suggest a role for blood flow–associated mechanical forces, which remodel the primitive vasculature into the mature circulatory system, in ALK1 signaling. Fluid shear stress promotes the association of ENG with the ALK1 receptor, thereby increasing the affinity of the complex for the BMP9 ligand. With low concentrations of BMP9, flow will therefore potentiate the signaling through the ALK1 receptor [89]. An important relationship between ALK1 signaling and blood flow has also been demonstrated in animal models (see below). Another signaling pathway suggested in HHT pathogenesis is oxidative stress [90,91]. Both the ENG and ALK1 protein have been shown to associate with endothelial nitric oxide synthase. Reduction or loss of either protein leads to endothelial nitric oxide synthase uncoupling and, rather than nitric oxide, generation of reactive oxygen species. Mice heterozygous for Acvrl1 or Eng mutations show increased reactive oxygen species in several organs, including those affected in HHT patients. Thus antioxidant therapy might provide some benefit to HHT patients. 

3.6 ANIMAL MODELS OF HHT Although the consequences of disrupted ALK1 signaling in humans have been appreciated for more than 20 years, the molecular and cellular missteps that lead to AVMs are only now beginning to be understood. Much of this new information comes from mouse and zebrafish Acvrl1, Eng, Bmp9, and Bmp10 loss-of-function models.

3.6.1 Mouse Models of HHT

3.6.1.1 Acvrl1/HHT2 Mouse Models Because HHT2 is an autosomal dominant condition, Acvrl1 heterozygotes should theoretically represent the best disease model. Heterozygous Acvrl1 mice develop dilated vessels and hemorrhage, but with generally mild phenotype and age-dependent but incomplete penetrance [92], which somewhat limits their use as a disease model. In contrast, global or endothelial-specific homozygous deletion during the embryonic, neonatal, or adult period results in fully penetrant AVMs, vascular leakage, and death [13,93–97]. In the embryonic model, remodeling of the extraembryonic yolk sac vasculature is impaired, intraembryonic vessels are severely dilated, and AVMs develop between the dorsal aorta and cardinal vein [13,93]. In the neonatal model, retinal AVMs and lung hemorrhage have been reported [89,96]. And in the adult model, Acvrl1 deletion results in AVMs and hemorrhage in the lung, uterus, and GI tract; however, brain and skin AVMs develop in these mice only in response to an angiogenic stimulus [94,95,97–102]. Taken together, these observations confirm that endothelial ALK1 signaling is required throughout life to prevent AVMs. The endothelial-specific requirement for ALK1 is supported by its predominant expression in arterial endothelial cells [53].  3.6.1.2 Eng/HHT1 Mouse Models Similar to Acvrl1 heterozygous mice, Eng heterozygous mice have been of limited utility in studying the pathogenesis of HHT. These mice develop dilated vessels, hemorrhage, and AVMs with low expressivity and incomplete penetrance [11,103], and only on a background that is predisposed to vascular defects [104]. Therefore, Eng homozygous nulls have been used in the majority of functional studies. Eng-deleted embryonic mice exhibit no, or very small, AVMs [10–12,105]. Although global deletion is embryonic lethal, lethality is

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likely caused by cardiac defects, and consequent effects on blood flow may lead to failed plexus remodeling and vessel dilation [10,11,106]. Similar to Acvrl1 deletion, endothelial-specific Eng deletion in neonates causes retinal AVMs [107,108]. However, in contrast to Acvrl1, global or endothelial-specific Eng deletion in adults does not cause spontaneous AVMs in any tissue; instead, AVMs arise in skin and brain only in response to an angiogenic cue such as VEGF stimulation or wounding [97,109]. Notably, global but not endothelial-specific Eng deletion in adults is rapidly lethal [97], suggesting that, in addition to a role for endothelial Eng in AVM prevention, Eng is important in other cell types. The expression pattern of Eng supports this assertion. Although Eng is expressed predominantly in the endothelium and endocardium in embryonic mice [110], expression extends also to hematopoietic stem cells, mesenchymal stem cells, macrophages, and vascular smooth muscle cells [111–115]. 

3.6.1.3 Bmp9 and Bmp10 Mouse Models Investigations into ALK1 ligand requirements during mouse embryonic development identify BMP10 as the critical player at the earliest developmental stages, but suggest later redundancy of BMP9 and BMP10 [116– 118]. Mouse Bmp9 nulls are viable and exhibit little overt phenotype, although patent ductus arteriosus and enlarged lymphatics have been reported [119–121]. In contrast, mouse Bmp10 null mutations are embryonic lethal due to cardiac trabeculation defects and AVMs connecting the dorsal aorta and cardinal vein, similar to AVMs observed in Acvrl1 nulls [116,122]. The embryonic requirement for Bmp10 but not Bmp9 might be due to temporal differences in expression, with the onset of cardiac Bmp10 expression preceding the onset of liver Bmp9 expression [116]. Supporting the concept of BMP9 and BMP10 functional redundancy, knock-in of Bmp9 into the Bmp10 locus prevents embryonic AVMs [116], and neonatal depletion of both BMP9 and BMP10 causes retinal vascular dysplasia and AVMs [116,118,123,124]. However, the degree of ligand redundancy at later times or in other vascular beds is not known. 

3.6.2 Zebrafish Models of HHT

3.6.2.1 acvrl1/HHT2 Zebrafish Models In zebrafish embryos, acvrl1 is expressed in a subset of arterial endothelial cells, with highest expression in

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cranial vessels closest to the heart [125,126]. Zebrafish acvrl1 mutants were first identified in large-scale forward genetic screens, and four independent mutant alleles exhibit indistinguishable phenotypes with 100% penetrance [125–127]. In these mutants, vascular patterning is normal, but acvrl1-expressing cranial arteries enlarge and lethal shunts that connect the arterial and venous vasculature develop beneath the hindbrain, just downstream of these enlarged arteries. Although shunt location differs between mice and zebrafish, the Acvrl1 null phenotype is remarkably similar in these distant species. 

3.6.2.2 eng/HHT1 Zebrafish Models As in mice, zebrafish eng is expressed in arterial and venous endothelial cells during embryogenesis [128]. However, in contrast to mice, zebrafish eng mutants are homozygous viable and exhibit only minor vascular defects including transient increases in embryonic axial vessel diameter, enlarged vessels in adult brain, and wound-induced AVMs in adult tail fin vessels [128]. These observations suggest that the function of Eng may be more limited in zebrafish than in mice, with some role in endothelial cells but no apparent requirement in the endocardium or other cell types.  3.6.2.3 bmp9 and bmp10 Zebrafish Models As in mouse, the physiologically relevant embryonic Alk1 ligand in zebrafish is Bmp10. Morpholino-mediated transient knockdown of bmp9 causes only minor defects in venous remodeling and no AVMs [83,129]. In contrast, simultaneous knockdown of paralogs bmp10 and bmp10-like, both of which are expressed in the heart, perfectly phenocopies acvrl1 mutants [129]. Whether Bmp9 and Bmp10/Bmp10-like are redundant later in zebrafish development, as has been suggested in mice, is currently unknown. 

3.7 MECHANISTIC BASIS OF AVM PATHOGENESIS Based on animal and cell culture models, several hypotheses have been put forth regarding the molecular and cellular defects that give rise to HHT-associated AVMs. These hypotheses include (1) disruption of arterial identity; (2) failed smooth muscle cell recruitment; (3) enhanced angiogenesis; and (4) aberrant endothelial cell migration.

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3.7.1 Arterial Identity in HHT Pathogenesis A long-standing hypothesis regarding the origin of HHT-associated AVMs is that abrogation of ALK1 signaling impairs the acquisition or maintenance of arterial endothelial cell molecular identity, eliminating a repulsive force necessary to properly segregate arteries and veins. This theory is based in part on evidence that manipulation of Notch signaling to eliminate distinctions between arteries and veins results in AVMs [130–133]. Indeed, select arterial markers are induced in cultured endothelial cells by BMP9/ALK1 and downregulated in Acvrl1 null mice [13,96,105,117,118,134], and ALK1 cooperates with Notch in cultured endothelial cells to induce expression of some arterial-specific Notch target genes [117,135,136]. However, zebrafish acvrl1 mutants and mouse Eng mutants develop AVMs without compromised arterial–venous identity [107,127], weakening support for the arterial identity hypothesis. Because embryonic AVMs steal blood flow from the majority of embryonic vessels, and because arterial-like magnitudes of mechanical force are required to maintain expression of arterial-specific genes [137,138], altered arterial identity in Acvrl1 mutants may be a secondary consequence of AVM development. 

3.7.2 Impaired Pericyte/Vascular Smooth Muscle Cell Coverage in HHT Pathogenesis

The vascular phenotype of Acvrl1 and Eng mouse mutants is characterized by impaired investment of vascular mural cells, including pericytes and smooth muscle cells [12,13,93,105], leading to the hypothesis that defective mural cell recruitment may contribute to AVM development and/or susceptibility to hemorrhage. Supporting a primary role for impaired mural cell recruitment in HHT pathogenesis, thalidomide treatment enhances smooth muscle cell investment and normalizes hyperbranching of retinal arteries in Eng heterozygous mice [139]. However, in the absence of hemorrhage or AVMs in this model, effects on these clinically relevant endpoints cannot be assessed. Because zebrafish acvrl1 and eng embryonic mutants develop lethal or transient shunts, respectively, prior to vessel acquisition of a pericyte or smooth muscle coat [125,126,128,140], it seems unlikely that HHT-associated AVMs could be caused by decreased mural cell recruitment and/or differentiation. Furthermore, in contrast to embryonic AVMs, neonatal retinal AVMs and downstream veins have increased smooth muscle cell coverage in Acvrl1- or Eng-deleted

mice [107,123], demonstrating that decreased mural cell coverage is not a conserved hallmark of HHT-associated AVMs. 

3.7.3 Enhanced Angiogenesis in HHT Pathogenesis

During the activation phase of angiogenesis, highly migratory tip cells lead trailing stalk cells, and tip cell migration and stalk cell proliferation are controlled by VEGFA [141]. In endothelial cells grown in two-dimensional culture, ALK1 activation inhibits migration and proliferation, whereas ACVRL1 or ENG depletion has opposite effects [84,86,88,142–144], suggesting a role for ALK1 in limiting VEGF response, quieting angiogenesis, and promoting the resolution (or stabilization) phase of angiogenesis. In concordance with this hypothesis, in three-dimensional endothelial cell culture systems, ALK1 activation promotes a stalk cell fate and inhibits sprouting, and ACVRL1 knockdown has opposite effects [117,134]. Furthermore, in mice, abrogation of ALK1 signaling neonatally causes retinal hypervascularization and enhanced endothelial cell proliferation [107,117,124]. However, additional data from animal models fail to support the hypothesis that hypersprouting and excessive angiogenesis underlies AVM development. First, hypersprouting is not apparent in embryonic Acvrl1- or Eng-deficient mice and zebrafish, which exhibit AVMs with simple, dilated morphology [13,93,125]. Second, endothelial cell proliferation is not affected in zebrafish acvrl1 mutants [145]. And third, retinal vascular hypersprouting in neonatally deleted Eng mice was recently shown to arise secondarily to hypoxia caused by upstream AVMs [108]. 

3.7.4 Aberrant Endothelial Cell Migration in HHT Pathogenesis

Imaging vascular development in zebrafish acvrl1 mutant embryos first implicated aberrant endothelial cell migration in HHT pathogenesis [145]. In wild-type embryos, arterial endothelial cells within the intimal layer of perfused arteries closest to the heart migrate in a retrograde fashion, against the direction of blood flow [145]. Loss of acvrl1 impairs this migration, thereby increasing distal arterial endothelial cell number and distal arterial caliber [126,145]. This phenomenon also contributes to AVM development in the Eng-deleted neonatal mouse retina [108]. Additional lines of evidence also support a role for ALK1 in transducing a response to blood flow. In

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mice and zebrafish, arterial Acvrl1 expression depends on blood flow [53,125,126,146], and in zebrafish, a subset of molecular changes triggered by loss of blood flow can be reversed by restoring endothelial Bmp10/Alk1 signaling [126,129,145]. Because BMP9 and BMP10 are present in blood, one mechanism by which blood flow affects ALK1 signaling is distribution of ligands to arterial endothelial cells [79,129]. However, additional data suggest that ALK1 is necessary for transduction of flow-induced mechanical force into a biochemical signal. For example, shear stress enhances the ALK1 and ENG interaction and potentiates BMP9-induced ALK1 signaling [89], and several ALK1-regulated genes, including CX40, CXCR4, DLL4, EDN1, SMAD6, and SMAD7 are mechanoresponsive [147–151]. The mechanism by which blood flow–dependent ALK1 signaling controls retrograde endothelial cell migration remains unknown. 

3.7.5 HHT-Associated AVMs as a Secondary Consequence of Altered Hemodynamic Environment

Aberrant migration per se does not explain HHT-associated AVM development. In zebrafish acvrl1 mutants, AVMs develop downstream of arterial segments that have enlarged due to aberrant migration [126,145]. These AVMs represent retention of normally transient arteriovenous segments that most often are located immediately downstream of the enlarged arteries. Because vessel segments that develop into AVMs experience high flow rate, and because AVM development can be uncoupled from aberrant migration by stopping blood flow [126,127], HHT-associated AVMs may represent an adaptive response to high-magnitude shear stress [152,153]. Retinal AVM location in neonatal mouse HHT models similarly supports a role for hemodynamic force in shunt site selection [89,108]. In the developing retinal vasculature, the proximal arterial segments and first-order branches experience the highest shear stress magnitude [154], and in Acvrl1-deleted mice, enlarged arterioles in these proximal first-order branches give rise to AVMs [89]. In sum, both zebrafish and mouse models strongly support a two-step model of HHT-associated AVM development [108,125,126,145]. In step 1, Alk1 loss impairs flow-dependent retrograde arterial endothelial cell migration within the wall of perfused arteries, thereby increasing distal arterial endothelial

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cell number and distal arterial caliber. In step 2, an Alk1-independent flow response is activated to normalize shear stress downstream of these enlarged arteries, resulting in maintenance of primitive artery–vein connections or selection of capillary segments for enlargement. 

3.8 DIAGNOSIS Until very recently, the diagnosis of HHT could only be made on clinical grounds. However, with the clinical availability of DNA-based genetic testing, this has changed. In some situations, when signs, symptoms, and/ or family history raise the possibility of HHT, genetic testing can now provide a definitive answer. However, because of technical challenges, including that HHT can be due to a mutation in any one of several genes, and that most families tested to date have had unique mutations, genetic testing is not always simple or definitive. Genetic testing is particularly helpful when the “familial” mutation has been identified; in such cases, presence or absence of the mutation, and thus of affected status, in other family members can usually be readily determined. In other situations, clinical grounds remain the mainstay for making the diagnosis. Investigators in Canada compared the use of molecular diagnosis for identifying which relatives in an HHT family were affected and then performing clinical screening only in those who test positive, with the current protocol of performing clinical screening of every relative at risk [155]. From a cost perspective, based on expenses incurred for both molecular and clinical testing in Canada, traditional clinical screening was 50% more expensive. A similar study was conducted in the United States, where many health economic issues are quite different from Canada [156]. However, the conclusion that molecular genetic screening of at-risk relatives is highly cost effective was affirmed. These results may not be generalized to countries with substantially different cost structures for the various tests. The classic findings in HHT are the quadrad of recurrent epistaxis, multiple telangiectases, visceral AVMs, and a positive family history. However, clinical diagnosis can be challenging, especially because many patients with HHT do not show evidence of all features and recurrent epistaxis (as an isolated finding or an indication of an underlining bleeding diathesis, such as von Willebrand disease) and, to a lesser extent, multiple

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telangiectases (as an isolated finding, or due to CREST syndrome, ataxia–telangiectasia, hereditary benign telangiectasia, chronic liver disease, or pregnancy) are each common findings in the general population. However, when the full triad of recurrent epistaxis, multiple telangiectases, and family history is present, the diagnosis of HHT is both straightforward and rarely incorrect. Family history may be inadequate since its utility depends on who obtains it and how much time is devoted to it, how much the proband knows and whether he or she is willing or able to search for additional information, and how the pedigree is updated and stored in an accessible form. The presence of such characteristic visceral lesions as AVMs can also be a key to clinical diagnosis, particularly PAVMs, because a majority of those with a PAVM prove to have HHT (this is especially true if there are multiple PAVMs). Similarly, GI telangiectases are often, but not always, a sign of HHT. Indeed, any individual with pulmonary, cerebral, hepatic, or spinal AVMs or GI telangiectases should be evaluated for the possibility of having HHT. Perhaps the most useful framework for making the diagnosis of HHT on clinical grounds is the so-called Curaçao criteria, devised by a number of clinicians from around the world experienced in the disorder [9]. The four criteria in this construct are as follows: • Epistaxis • Multiple telangiectases at characteristic sites (lips, oral cavity, fingers, nose) • Visceral lesions (such as GI telangiectases or pulmonary, cerebral, hepatic, or spinal AVMs) • Family history of a first-degree relative with HHT according to these criteria. The diagnosis of HHT is believed to be definite if three or four of these criteria are present, possible if two are present, and unlikely if fewer than two criteria are present. The authors of the CuraÇao criteria also noted that “Within HHT families, a firm diagnosis can be made on the basis of two separate visceral manifestations, though this is not applicable to the general population” [9]. 

3.9 MANAGEMENT The key to effective management and improvement in morbidity and mortality is regular screening for the various manifestations discussed subsequently. Unfortunately, for a variety of reasons including the knowledge of physicians, patients are inadequately screened [157].

The most effective therapies, which potentially address all of the clinical manifestations, will deal with the underlying mutations in ENG and ACVRL1. Because all mutations in these genes responsible for HHT cause loss of function of the mutant allele, therapies that enhance production of the normal protein seem attractive [158].

3.9.1 Mucocutaneous Telangiectases Lesions on the tongue, lips, and fingers may bleed when traumatized. Photocoagulation with a laser can be effective in stopping acute bleeding [159]. Smaller lesions can be eliminated, and this is of some cosmetic utility on and around the face. 

3.9.2 Epistaxis Often the most frustrating and debilitating feature of HHT is recurrent bleeding from the nose. Bleeding often starts spontaneously, even during sleep, and can be profuse. The unpredictability of epistaxis and the difficulty in stemming the acute hemorrhage may severely affect a patient’s occupation, social interactions, and activities. Local pressure by pinching the bridge of the nose is obviously the first maneuver, but the actual telangiectasia that is bleeding may be so proximal as to not be compressible externally. Various devices have been used for internal compression of nares. Some have been designed by patients, whereas others (such as Foley catheters, with the balloon providing tamponade) have gained currency in emergency departments. None is routinely efficacious, and some carry risks. Typically, the clot will be dislodged when the gauze or device is removed. Prolonged pressure on the mucosal surface can cause ischemia or infarction. A variety of medical and surgical approaches have been employed over the past decades, but only recently subjected to clinical trials [160]. Cauterizing agents, such as silver nitrate, may be useful for an initial, small bleed, but are useless for large ones, and may permanently damage the mucosa. Angiographic procedures to localize the feeding artery and embolize it are fraught with hazards, especially necrosis of nasal tissue or ischemia of the vascular supply to the eye. The combined sphenopalatine and ethmoid arteries supply about twothirds of the blood to the septum; occluding one or both leads to collateral formation within a few months. Once the acute event ends, endoscopic examination of the nares typically reveals many telangiectases,

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and the ones most likely to bleed can be treated with laser phototherapy. A variety of wavelengths have been studied, and rhinologists often have their favorite instruments. Some patients achieve long-term improvement from periodic photocoagulation. However, those who continue to bleed enough to require transfusion of packed erythrocytes on a regular basis need to be considered for a major surgical procedure. In the past, septal dermoplasty, in which the inferior turbinate is resected and a skin autograft is placed by suturing to the septum superiorly and then packing the nose [161], was recommended. After several weeks, the graft adheres to the nasal mucosa and often provides relief for several years. Unfortunately, telangiectases eventually can appear on the surface of the graft and lead to renewed epistaxis. Additionally, the grafted skin must be kept moist and can be a site of bacterial overgrowth. More recently, Young’s procedure, in which the most severely affected side of the nose is sutured shut, has gained favor [162,163]. Prevention of epistaxis, although imperfect, is important to practice. The goals in severe cases should be to reduce or eliminate the need for visits to emergency rooms, reduce or eliminate the need for transfusions, and improve the QOL. The ambient humidity should be kept as high as feasible. Allergies should be controlled to the extent possible and airborne irritants, such as cigarette smoke, should be excluded. Spraying the nares with dilute saline or carefully applying an emollient such as petroleum jelly reduces crusting. Various medications, including hormones and antifibrinolytics, have also been useful in selected patients, but all have important risks and contraindications [164–166]. Local or systemic agents that produce vasoconstriction can be beneficial in the short term, but they cause a rebound inflammation in the nasal mucosa that is counterproductive. Several agents have been reported to be effective in reducing severe epistaxis in individual patients or small, nonrandomized series. The β-blocker propranolol, used for its antiangiogenic effect, was modestly effective in one small trial [167]. The anti-VEGF drug, bevacizumab, given topically or systemically, held promise as did tranexamic acid. A placebo controlled, randomized trial of bevacizumab, estriol, and tranexamic acid failed to detect differences in epistaxis frequency among the groups [168]. In another trial, increasing doses of bevacizumab administered as a nasal spray compared to placebo showed no benefit [169].

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Thalidomide and its derivatives such as pomalidomide are also being studied [170]. Drugs that alter platelet function, such as aspirin and nonsteroidal anti-inflammatory agents, should be avoided. However, if a patient with HHT develops a clinical problem that requires systemic anticoagulation, such as atrial fibrillation or deep venous thrombosis, then warfarin can be used with attention to keeping the INR in the low end of the therapeutic range. There is as yet no experience in HHT with the newer oral anticoagulants such as inhibitors of thrombin or Factor Xa. 

3.9.3 Central Nervous System AVMs in the brain occur in about 10% of patients [171]. They can occur in HHT due to mutation in any gene, but are more common in ENG mutations. Vascular malformations present at birth are usually asymptomatic, but large venous malformations and CAVMs, in the absence of bleeding, may cause problems because of their size or location. Whether any particular lesion needs to be treated by radiation, surgery, or vascular occlusion needs to be considered on the basis of the patient’s symptoms and age [172]. The occurrence of silent brain infarcts in patients over 30 years old did not differ significantly from the general population, but increased with age and were more common in patients with PAVMs [171]. Brain abscess, due to paradoxical embolization of bacteria through a PAVM, needs to be treated in several ways. First, based on the neurologic and general health status, a decision about drainage and antibiotics must be made. Second, further central nervous system (CNS) embolization must be minimized by treating all sources of right-to-left shunts. Just because PAVMs are the most likely culprit in HHT, the presence of a patent foramen ovale or atrial septal defect should not be overlooked. Because of the risk of CNS embolization in HHT, particular care must be paid to any instance when bacteria or air might enter the bloodstream. All people with HHT should adhere to routine prophylaxis against endocarditis. Additionally, all intravenous lines, except for the infusion of blood or radiographic contrast, should have special filters to prevent air bubbles from entering the vein. 

3.9.4 Lung Plain chest radiography, pulse oximetry, arterial blood gases, or a combination thereof are insensitive for

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detecting all but major right-to-left shunts in the lung. The contrast echocardiogram, in which agitated saline is injected into an antecubital vein as the four-chambered view of the heart is observed, is a useful screening tool for PAVMs [173]. In the normal situation, the microbubbles are absorbed in the lung capillaries and do not appear in the left atrium. Appearance of contrast (“bubbles” in common parlance, but not of a size to endanger the CNS) in the left atrium immediately (i.e., one to three heart beats) after it enters the right side of the heart strongly suggests a septal defect, typically a patent foramen ovale. If this occurs, then a pulmonary shunt cannot be diagnosed, and the patient must have a chest CT scan. When contrast appears after four heartbeats, then there is likely a shunt in the pulmonary circulation. However, an up to 28% of normal volunteers will have delayed passage of a few bubbles [174]. Graded transthoracic echocardiography (TTCE) has been introduced in an attempt to quantify right-to-left shunting in PAVM screening and has the potential to revolutionize PAVM screening and follow-up. Velthuis and colleagues [175] correlated the results of graded TTCE and CT in 772 patients and found that in addition to Grade 0 (no shunting), Grade 1 also yielded no treatable PAVMs. Even a grade of 2 yielded only 28% treatable PAVMs. Vorselaars [176] suggested utility of graded TTCE to follow-up of untreated PAVMs. Graded TTCE notwithstanding, current standard protocol per 2011 HHT guidelines to address the size, number, and location of PAVMs is a high-resolution pulmonary CT scan [39], preferably a CT arteriogram. The ability to reformat the images is especially useful to distinguish potential PAVMs from lung nodules of various types and to define the number and size of the feeding arteries and the draining veins (Fig. 3.3). Embolotherapy has become the standard for treatment of nearly all PAVMs (Fig. 3.4), with the possible exception of diffuse-type PAVMs. Embolization is accomplished on an outpatient basis, and it is common to be able to treat all of the PAVMs in a single procedure, minimizing the impact of treatment on the patient and their family [177]. Ideally, embolization is performed by interventional radiologists and ideally at HHT centers of excellence, or at least by an interventional radiologist with extensive experience in embolotherapy and PAVM embolization in particular. In the past, PAVMs with feeding arteries of < 3 mm diameter were left untreated. However, current guidelines [39] acknowledge that

treating PAVMs with feeding arteries as small as 2 mm in diameter is appropriate, and we and others treat any PAVM that can be reached by a catheter. After treatment of all accessible PAVMs, repeat CT scan in 6 months is essential to document that all remain occluded (i.e., that there is no persistence) [178]. Current guidelines recommend a follow-up CT scan every 3–5 years; we screen with CT every 5 years. Current and future research into graded TTCE may well change these recommendations in the future. Major complications related to PAVMs can occur during pregnancy and in the postpartum period due to pulmonary hemorrhage, increased right-to-left shunting, or cerebrovascular events; however, these are mostly due to large PAVMs. Evaluation with low-dose noncontrast CT scanning can screen for large PAVMs in need of embolotherapy before delivery. Embolotherapy of treatable PAVMs can be safely performed in the second and third trimesters and is essential to avoid these devastating complications [179].Children with HHT and normal pulse oximetry are unlikely to have a PAVM needing treatment. However, children with even mild hypoxemia may have treatable PAVMs even though asymptomatic and should be screened regardless of symptomatology [180]. 

3.9.5 Liver Vascular lesions in the liver are much less amenable to treatment than are PAVMs. Occlusion of the feeding vessel or vessels, although technically feasible, carries an unacceptable risk of infarction of substantial regions of liver parenchyma. There also is an increased risk of infection associated with endoscopic retrograde cannulation of the pancreas, so ERCP is contraindicated in HHT. A recent and very preliminary report of surgical flow reduction in the major hepatic arteries suggests this approach may be viable if corroborated [181]. It is also possible to achieve flow reduction using less invasive percutaneous interventional techniques, but these are as yet unvalidated. While embolization has been reported [182], it is widely believed in the HHT community based on experience with poor outcomes that embolotherapy in the liver is contraindicated in HHT with rare exception. Patients who have hepatic encephalopathy can be treated with nitrogen restriction and lactulose. Those with high-output cardiac failure respond initially to diuretics.

(A)

(B)

(C)

(D)

(E)

(F)

(G)

(H)

Figure 3.3  Fifty-two-year-old woman with known right upper lobe pulmonary arteriovenous malformation (PAVM). Patient was followed for 14 years at another institution and told treatment was not needed. She has obvious hereditary hemorrhagic telangiectasia (HHT) with a strong family history, epistaxis, and telangiectases and was known by her primary care physician to have HHT. She was asymptomatic. (A) Color-enhanced coronal reconstruction from CT shows simple PAVM in the right upper lobe; feeding artery and draining vein are labeled. Feeding artery measured 12 mm in diameter. (B) Representative image showing feeding artery (arrow), sac (asterisk), and draining vein (arrowhead). (C) Image from selective right upper lobe pulmonary angiography confirms simple angioarchitecture; the feeding artery is indicated. (D) Image obtained during contrast injection with 16 mm Amplatzer vascular occluder deployed at the mouth of PAVM sac. Arrow shows occluder still attached to delivery cable. (E) Diagrammatic representation of panel D. (F and G) Subtracted (F) and unsubtracted (G) postembolization pulmonary arteriograms after placement of coils in addition to Amplatzer vascular occluder show occlusion of PAVM. (H) Representative image from coronal CT reconstruction 6 months after embolization. Sac has completely disappeared. Characteristic appearance of Amplatzer device (arrow). Patient reported marked improvement in her exercise tolerance. (Reprinted with permission from Trerotola, S.O., Pyeritz, R.E., 2010. PAVM embolization: an update. AJR Am J Roentgenol 195, 837–845.)

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Figure 3.4 Multiple treated (some persistent) and untreated pulmonary arteriovenous malformations (PAVMs) in one lung. In future, transthoracic echocardiography may help guide which PAVMs need treatment, especially those persisting after initial treatment. (Reprinted with permission from Trerotola, S.O., Pyeritz, R.E., 2010. PAVM embolization: an update. AJR Am J Roentgenol 195, 837–845.)

The therapy of last resort is liver transplantation [183]. Unfortunately, because tests of liver function often remain relatively normal despite severe vascular disease in the liver, patients have difficulty gaining access to the transplant list. One report found vascular dilatation in the allografts of two patients at 8 and 10 years following transplant; whether these findings were in some way related to the underlying HHT, and if so, how common and important this issue is will remain to be studied [166]. 

3.9.6 Gastrointestinal Hemorrhage from the GI tract can be one of the most debilitating and frustrating problems of HHT, especially in older people. There is no good way to monitor chronic bleeding. Testing the stool for occult blood is useless because most patients swallow blood from bouts of epistaxis, which turns the test positive. Patients should monitor their bowel movements for signs of moderate

GI bleeding (e.g., tarry stools). However, most patients who become anemic have mild, chronic bleeding that escapes their attention. Upper and lower endoscopy typically shows multiple mucosal telangiectases from the oral cavity to the duodenum and from the rectum to the ileocecal valve. The number of telangiectases roughly correlates with the anemia and transfusion requirement [184]. Any lesion that appears to be bleeding can be cauterized. However, there is no point in attempting to treat all telangiectases, especially if repeated endoscopies are contemplated. Capsule endoscopy confirms that telangiectases exist throughout the jejunum and ileum; but push enterostomy or major surgery are rarely required [185]. As with refractory epistaxis, hormonal (estrogen/progesterone in women without contraindications, and danazol in men) and antifibrinolytic therapy may have a role in chronic GI bleeding [184]. Similarly, experimental agents such as thalidomide [186,187] and bevacizumab are worth studying [139,188]. Selective mesenteric arteriography can reveal intestinal AVMs that can be embolized, but the site or sites of chronic blood loss usually remain obscure. 

3.9.7 Anemia Unless a contraindication exists, virtually all adults with HHT should take supplemental iron. The amount and form of iron depend on the severity of the anemia [189]. Oral iron can produce adverse effects including constipation and nausea. Patients who do not tolerate oral iron supplements or do not absorb iron from the intestine (e.g., celiac disease) need intravenous iron. All preparations can produce allergic reactions. Those with lower iron content can be infused faster with less risk of adverse effects; however, multiple infusions are necessary. Those with higher iron content must be infused slower, but if successful, may replete stores with one dose. Additional cofactors, folate, and B12 should be considered. Inability to replete iron stores due to severe blood loss despite iron supplementation requires episodic or even regular transfusions of packed erythrocytes. Any person being treated for anemia should have periodic assessment of blood counts and iron stores. 

3.9.8 Circulation Visceral AVMs necessitate increased cardiac output to maintain systemic blood pressure. Pulmonary hypertension can be one result and is more common

CHAPTER 3 

Hereditary Hemorrhagic Telangiectasia

in patients with a mutation in ACVRL1 [190]. Additionally, anemia necessitates increased cardiac output, which when combined with hypoxia from pulmonary AVMs, can increase stroke volume and heart rate chronically and strain the heart [191]. Any patient with a combination of these factors should have periodic TTCE to assess ventricular function and pulmonary arterial pressure. 

3.9.9 Pregnancy Most pregnant women with HHT experience few complications but should be considered high-risk because of the risk of complications, especially in latter stages when cardiac output is maximal [192]. 

3.9.10 Counseling The same issues that arise in most serious autosomal dominant disorders occur in HHT. The recent availability of molecular diagnosis offers promise of presymptomatic and prenatal diagnosis. However, complexities often arise because of intergenic heterogeneity, “negative” results, and DNA sequence variants of uncertain pathogenic importance. The Hereditary Hemorrhagic Telangiectasia Foundation International (www.curehht.org) plays an important role in several areas. The organization facilitates the establishment of centers at academic hospitals that provide comprehensive medical and counseling services for patients and families with HHT. There are now 48 centers worldwide, including 25 in North America. The Foundation also sponsors national conferences for patient education and support, and biennial international research symposia. 

3.9.11 Life Expectancy Infants and children with HHT and unusually severe vascular malformations in the CNS or lung can die. Many adults with HHT live into their eighth and ninth decade despite severe anemia from epistaxis and GI bleeding. In 1999, a mortality analysis of patients in one county in Denmark showed that patients younger than age 60 years died at twice the rate of the population average [16]. A more recent study from an HHT center in Italy confirmed an increased peak in mortality rate in patients under the age of 50 years, and somewhat higher mortality in those ages 60–79 years [20]. Life expectancy was not related to gender or to genotype.

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ACKNOWLEDGMENTS This revision was accomplished during a time of support for REP by the National Heart, lung and Blood Institute (GenTAC) and the National Human Genome Research Center (Center of Excellence in ELSI Research P50-HG-004487), both of the US National Institutes of Health (NIH), and while in residence at the Brocher Foundation, Hermance, Switzerland. BLR was supported by NIH R01HL133009, R01HL136566, and Department of Defense W81XWH-17-0429. We also thank all of our colleagues who shared their published and unpublished work and commented on sections of this chapter.

REFERENCES [1]  Sutton H. Epistaxis as an indication of impaired nutrition, and of degeneration of the vascular system. Med Mirror 1864:769–81. [2] Rendu J. Èpistaxis répétées chez un sujet porteur de petits angiomes cutanes et muqueux. Gaz Hop 1896:1322–33. [3] Osler W. On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Bull Johns Hopkins Hosp 1901;12:333–7. [4] Weber FP. Multiple hereditary developmental angiomata (telangiectases) of the skin and mucous membranes associated with recurring haemorrhages. Lancet 1907;2:160–2. [5] Hanes FM. Multiple hereditary telangiectases causing hemorrhage (Hereditary Hemorrhagic Telangiectasia). Bull Johns Hopkins Hosp 1909;20:63–73. [6] Terry PB, Barth KH, Kaufman SL, et al. Balloon embolization for treatment of pulmonary arteriovenous fistulas. N Engl J Med 1980;302:1189–90. [7] Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189–95. [8] McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-b binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994;8:345–51. [9] Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66–7.

134

SECTION 1 

Cardiovascular Disorders

[10] Arthur HM, Ure J, Smith AJ, et al. Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 2000;217:42–53. [11] Bourdeau A, Dumont DJ, Letarte M. A murine model of hereditary hemorrhagic telangiectasia. J Clin Investig 1999;104:1343–51. [12] Li DY, Sorensen LK, Brooke BS, et al. Defective angiogenesis in mice lacking endoglin. Science 1999;284:1534–7. [13] Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 2000;26:328–31. [14] Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363:852–9. [15] Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med 2003;79:18–24. [16] Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med 1999;245:31–9. [17] Westermann CJ, Rosina AF, De Vries V, et al. The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of The Netherlands Antilles: a family screening. Am J Med Genet 2003;116A:324–8. [18] de Gussem EM, Edwards CP, Hosman AE, et al. Life expectancy of parents with hereditary haemorrhagic telangiectasia. Orphanet J Rare Dis 2016;11:46. [19] Donaldson JW, McKeever TM, Hall IP, et al. Complications and mortality in hereditary hemorrhagic telangiectasia: a population-based study. Neurology 2015;84:1886–93. [20] Sabba C, Pasculli G, Suppressa P, et al. Life expectancy in patients with hereditary haemorrhagic telangiectasia. QJM 2006;99:327–34. [21] Kjeldsen A, Aagaard KS, Torring PM, et al. 20-year follow-up study of Danish HHT patients-survival and causes of death. Orphanet J Rare Dis 2016;11:157. [22] Pasculli G, Resta F, Guastamacchia E, et al. Health-related quality of life in a rare disease: hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease. Qual Life Res 2004;13:1715–23. [23] Zarrabeitia R, Farinas-Alvarez C, Santibanez M, et al. Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT). Health Qual Life Outcomes 2017;15:19. [24] Benzinou M, Clermont FF, Letteboer TG, et al. Mouse and human strategies identify PTPN14 as a modifier of















angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 2012;3:616. [25] McDonald JE, Miller FJ, Hallam SE, et al. Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet 2000;93:320–7. [26] Duarte CW, Murray K, Lucas FL, et al. Improved survival outcomes in cancer patients with hereditary hemorrhagic telangiectasia. Cancer Epidemiol Biomark Prev 2014;23:117–25. [27] Duarte CW, Black AW, Lucas FL, et al. Cancer incidence in patients with hereditary hemorrhagic telangiectasia. J Cancer Res Clin Oncol 2017;143:209–14. [28] Mager JJ, Westermann CJ. Value of capillary microscopy in the diagnosis of hereditary hemorrhagic telangiectasia. Arch Dermatol 2000;136:732–4. [29] Sweet K, Willis J, Zhou XP, et al. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. J Am Med Assoc 2005;294:2465–73. [30] Krings T, Ozanne A, Chng SM, et al. Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day-60 years. Neuroradiology 2005;47:711–20. [31] Fulbright RK, Chaloupka JC, Putman CM, et al. MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 1998;19:477–84. [32] Komiyama M, Ishiguro T, Yamada O, et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet 2014;59:37–41. [33] Akers AL, Ball KL, Clancy M, et al. Brain vascular malformation consortium: overview, progress and future directions. J Rare Disord 2013;1:5. [34] Thenganatt J, Schneiderman J, Hyland RH, et al. Migraines linked to intrapulmonary right-to-left shunt. Headache 2006;46:439–43. [35] Gallitelli M, Guastamacchia E, Resta F, et al. Pulmonary arteriovenous malformations, hereditary hemorrhagic telangiectasia, and brain abscess. Respiration 2006;73:553–7. [36] Brinjikji W, Nasr DM, Cloft HJ, et al. Spinal arteriovenous fistulae in patients with hereditary hemorrhagic telangiectasia: a case report and systematic review of the literature. Interv Neuroradiol 2016;22:354–61. [37] Faughnan ME, Lui YW, Wirth JA, et al. Diffuse pulmonary arteriovenous malformations: characteristics and prognosis. Chest 2000;117:31–8. [38] Ference BA, Shannon TM, White Jr RI, et al. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 1994;106:1387–90.

CHAPTER 3 

Hereditary Hemorrhagic Telangiectasia

[39] Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011;48:73–87. [40] Garcia-Tsao G. Liver involvement in hereditary hemorrhagic telangiectasia (HHT). J Hepatol 2007;46:499–507. [41] Hashimoto M, Tate E, Nishii T, et al. Angiography of hepatic vascular malformations associated with hereditary hemorrhagic telangiectasia. Cardiovasc Interv Radiol 2003;26:177–80. [42] Ianora AA, Memeo M, Sabba C, et al. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement. Radiology 2004;230:250–9. [43] Saluja S, White RI. Hereditary hemorrhagic telangiectasia of the liver: hyperperfusion with relative ischemia–poverty amidst plenty. Radiology 2004;230:25–7. [44] Buscarini E, Leandro G, Conte D, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic telangiectasia. Dig Dis Sci 2011;56:2166–78. [45] Plauchu H, de Chadarevian JP, Bideau A, et al. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989;32:291–7. [46] Hsi DH, Ryan GF, Hellems SO, et al. Large aneurysms of the ascending aorta and major coronary arteries in a patient with hereditary hemorrhagic telangiectasia. Mayo Clin Proc 2003;78:774–6. [47] McDonald MT, Papenberg KA, Ghosh S, et al. A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34. Nat Genet 1994;6:197–204. [48] Shovlin CL, Hughes JM, Tuddenham EG, et al. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet 1994;6:205–9. [49] Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 1990;265:8361–4. [50] Cheifetz S, Bellon T, Cales C, et al. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 1992;267:19027–30. [51] Pece N, Vera S, Cymerman U, et al. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Investig 1997;100:2568–79. [52] McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med 2011;13:607–16. [53] Seki T, Yun J, Oh SP. Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its























135

role in arterialization and vascular remodeling. Circ Res 2003;93:682–9. [54] Berg JN, Gallione CJ, Stenzel TT, et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet 1997;61:60–7. [55] Ricard N, Bidart M, Mallet C, et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood 2010;116:1604–12. [56] Wallace GM, Shovlin CL. A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1. Thorax 2000;55:685–90. [57] Cole SG, Begbie ME, Wallace GM, et al. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 2005;42:577–82. [58] Bayrak-Toydemir P, McDonald J, Akarsu N, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet 2006;140:2155–62. [59] Baert AL, Casteels-Van Daele M, Broeckx J, et al. Generalized juvenile polyposis with pulmonary arteriovenous malformations and hypertrophic osteoarthropathy. AJR Am J Roentgenol 1983;141:661–2. [60] Schumacher B, Frieling T, Borchard F, et al. Hereditary hemorrhagic telangiectasia associated with multiple pulmonary arteriovenous malformations and juvenile polyposis. Z Gastroenterol 1994;32:105–8. [61] Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001;28:184–7. [62] Gallione C, Aylsworth AS, Beis J, et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet 2010;152A:333–9. [63] Gallione CJ, Richards JA, Letteboer TG, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet 2006;43:793–7. [64] Bayrak-Toydemir P, McDonald J, Markewitz B, et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet 2006;140:463–70. [65] Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med 2007;9:14–22. [66] Bourdeau A, Faughnan ME, McDonald ML, et al. Potential role of modifier genes influencing transforming growth factor- beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia. Am J Pathol 2001;158:2011–20.

136

SECTION 1 

Cardiovascular Disorders

[67] Bonyadi M, Rusholme SA, Cousins FM, et al. Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice. Nat Genet 1997;15:207–11. [68] Tang Y, Lee KS, Yang H, et al. Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis. Genomics 2005;85:60–70. [69] Tang Y, McKinnon ML, Leong LM, et al. Genetic modifiers interact with maternal determinants in vascular development of Tgfb1(−/−) mice. Hum Mol Genet 2003;12:1579–89. [70] Kawasaki K, Freimuth J, Meyer DS, et al. Genetic variants of Adam17 differentially regulate TGFbeta signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci U S A 2014;111:7723–8. [71] Letteboer TG, Benzinou M, Merrick CB, et al. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. Front Genet 2015;6:67. [72] Berg JN, Guttmacher AE, Marchuk DA, et al. Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet 1996;33:256–7. [73] Letteboer TG, Mager HJ, Snijder RJ, et al. Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia. Am J Med Genet 2008;146A:2733–9. [74] Sabba C, Pasculli G, Lenato GM, et al. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007;5:1149–57. [75] Harrison RE, Flanagan JA, Sankelo M, et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 2003;40:865–71. [76] Smoot LB, Obler D, McElhinney DB, et al. Clinical features of pulmonary arterial hypertension in young people with an ALK1 mutation and hereditary haemorrhagic telangiectasia. Arch Dis Child 2009;94:506– 11. [77] Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325–34. [78] Reichenberger F, Wehner LE, Breithecker A, et al. [Pulmonary hypertension in hereditary haemorrhagic telangiectasia]. Pneumologie 2009;63:669–74.

[79] David L, Mallet C, Keramidas M, et al. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res 2008;102:914–22. [80] Bidart M, Ricard N, Levet S, et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell Mol Life Sci 2012;69:313–24. [81] Brown MA, Zhao Q, Baker KA, et al. Crystal structure of BMP-9 and functional interactions with pro-region and receptors. J Biol Chem 2005;280:25111–8. [82] Mallet C, Lamribet K, Giraud S, et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet 2015;24:1142–54. [83] Wooderchak-Donahue WL, McDonald J, O’Fallon B, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet 2013;93:530–7. [84] David L, Mallet C, Mazerbourg S, et al. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 2007;109:1953–61. [85] Park JE, Shao D, Upton PD, et al. BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. PLoS One 2012;7:e30075. [86] Scharpfenecker M, van Dinther M, Liu Z, et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 2007;120:964–72. [87] Suzuki Y, Ohga N, Morishita Y, et al. BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. J Cell Sci 2010;123:1684–92. [88] Upton PD, Davies RJ, Trembath RC, et al. Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells. J Biol Chem 2009;284:15794–804. [89] Baeyens N, Larrivee B, Ola R, et al. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol 2016;214:807– 16. [90] Jerkic M, Rivas-Elena JV, Prieto M, et al. Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J 2004;18:609–11. [91] Toporsian M, Gros R, Kabir MG, et al. A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res 2005;96:684–92.

CHAPTER 3 

Hereditary Hemorrhagic Telangiectasia

[92] Srinivasan S, Hanes MA, Dickens T, et al. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum Mol Genet 2003;12:473–82. [93] Oh SP, Seki T, Goss KA, et al. Activin receptor-like kinase 1 modulates transforming growth factor-b1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 2000;97:2626–31. [94] Park SO, Lee YJ, Seki T, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 2008;111:633–42. [95] Park SO, Wankhede M, Lee YJ, et al. Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Investig 2009;119:3487–96. [96] Tual-Chalot S, Mahmoud M, Allinson KR, et al. Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression. PLoS One 2014;9:e98646. [97] Garrido-Martin EM, Nguyen HL, Cunningham TA, et al. Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models–brief report. Arterioscler Thromb Vasc Biol 2014;34:2232–6. [98] Zhang R, Han Z, Degos V, et al. Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation. Angiogenesis 2016;19:451–61. [99] Choi EJ, Walker EJ, Shen F, et al. Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. Cerebrovasc Dis 2012;33:540–7. [100] Han C, Choe SW, Kim YH, et al. VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. Angiogenesis 2014;17:823–30. [101] Walker EJ, Su H, Shen F, et al. Arteriovenous malformation in the adult mouse brain resembling the human disease. Ann Neurol 2011;69:954–62. [102] Walker EJ, Su H, Shen F, et al. Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain. Stroke 2012;43:1925– 30. [103] Torsney E, Charlton R, Diamond AG, et al. Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality. Circulation 2003;107:1653–7. [104] Coulson PS, Wilson RA. Portal shunting and resistance to Schistosoma mansoni in 129 strain mice. Parasitology 1989;99 Pt(3):383–9.

137

[105] Sorensen LK, Brooke BS, Li DY, et al. Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor. Dev Biol 2003;261:235–50. [106] Nomura-Kitabayashi A, Anderson GA, Sleep G, et al. Endoglin is dispensable for angiogenesis, but required for endocardial cushion formation in the midgestation mouse embryo. Dev Biol 2009;335:66–77. [107] Mahmoud M, Allinson KR, Zhai Z, et al. Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res 2010;106:1425–33. [108] Jin Y, Muhl L, Burmakin M, et al. Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nat Cell Biol 2017;19:639–52. [109] Choi EJ, Chen W, Jun K, et al. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia. PLoS One 2014;9:e88511. [110] Jonker L, Arthur HM. Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech Dev 2002;110:193–6. [111] Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–7. [112] Pierelli L, Bonanno G, Rutella S, et al. CD105 (endoglin) expression on hematopoietic stem/progenitor cells. Leuk Lymphoma 2001;42:1195–206. [113] Cho SK, Bourdeau A, Letarte M, et al. Expression and function of CD105 during the onset of hematopoiesis from Flk1(+) precursors. Blood 2001;98:3635–42. [114] Ojeda-Fernandez L, Recio-Poveda L, Aristorena M, et al. Mice lacking endoglin in macrophages show an impaired immune response. PLoS Genet 2016;12:e1005935. [115] Tian H, Ketova T, Hardy D, et al. Endoglin mediates vascular maturation by promoting vascular smooth muscle cell migration and spreading. Arterioscler Thromb Vasc Biol 2017;37:1115–26. [116] Chen H, Brady Ridgway J, Sai T, et al. Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development. Proc Natl Acad Sci U S A 2013;110:11887–92. [117] Larrivee B, Prahst C, Gordon E, et al. ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell 2012;22:489–500. [118] Ricard N, Ciais D, Levet S, et al. BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 2012;119:6162–71. [119] Levet S, Ciais D, Merdzhanova G, et al. Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood 2013;122:598–607.

138

SECTION 1 

Cardiovascular Disorders

[120] Yoshimatsu Y, Lee YG, Akatsu Y, et al. Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression. Proc Natl Acad Sci U S A 2013;110:18940–5. [121] Levet S, Ouarne M, Ciais D, et al. BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. Proc Natl Acad Sci U S A 2015;112:E3207–15. [122] Chen H, Shi S, Acosta L, et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 2004;131:2219–31. [123] Ola R, Dubrac A, Han J, et al. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun 2016;7:13650. [124] Ruiz S, Zhao H, Chandakkar P, et al. A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci Rep 2016;5:37366. [125] Roman BL, Pham VN, Lawson ND, et al. Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 2002;129:3009–19. [126] Corti P, Young S, Chen CY, et al. Interaction between alk1 and blood flow in the development of arteriovenous malformations. Development 2011;138:1573–82. [127] Rochon ER, Wright DS, Schubert MM, et al. Context-specific interactions between Notch and ALK1 cannot explain ALK1-associated arteriovenous malformations. Cardiovasc Res 2015;107:143–52. [128] Sugden WW, Meissner R, Aegerter-Wilmsen T, et al. Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues. Nat Cell Biol 2017;19:653–65. [129] Laux DW, Young S, Donovan JP, et al. Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence. Development 2013;140:3403–12. [130] Krebs LT, Shutter JR, Tanigaki K, et al. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 2004;18:2469–73. [131] Carlson TR, Yan Y, Wu X, et al. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A 2005;102:9884–9. [132] Murphy PA, Lam MT, Wu X, et al. Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc Natl Acad Sci U S A 2008;105:10901–6. [133] Krebs LT, Starling C, Chervonsky AV, et al. Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants. Genesis 2010;48:146–50.

[134] Kim JH, Peacock MR, George SC, et al. BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II. Angiogenesis 2012;15:497–509. [135] Kerr G, Sheldon H, Chaikuad A, et al. A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis 2015;18:209–17. [136] Rostama B, Turner JE, Seavey GT, et al. DLL4/ Notch1 and BMP9 interdependent signaling induces human endothelial cell quiescence via P27KIP1 and thrombospondin-1. Arterioscler Thromb Vasc Biol 2015;35:2626–37. [137] le Noble F, Moyon D, Pardanaud L, et al. Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development 2004;131:361–75. [138] Buschmann I, Pries A, Styp-Rekowska B, et al. Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development 2010;137:2187–96. [139] Lebrin F, Srun S, Raymond K, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 2010;16:420–8. [140] Ando K, Fukuhara S, Izumi N, et al. Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. Development 2016;143: 1328–39. [141] Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003;161:1163–77. [142] Lamouille S, Mallet C, Feige JJ, et al. Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Blood 2002;100:4495–501. [143] David L, Mallet C, Vailhe B, et al. Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: potential roles for JNK and ERK. J Cell Physiol 2007;213:484–9. [144] Pece-Barbara N, Vera S, Kathirkamathamby K, et al. Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway. J Biol Chem 2005;280:27800–8. [145] Rochon ER, Menon PG, Roman BL. Alk1 controls arterial endothelial cell migration in lumenized vessels. Development 2016;143:2593–602. [146] Garrido-Martin EM, Blanco FJ, Roque M, et al. Vascular injury triggers Kruppel-like factor 6 (KLF6) mobilization and cooperation with Sp1 to promote endothelial activation through upregulation of the activin receptor-like kinase 1 (ALK1) gene. Circ Res 2012;112:113–27.

CHAPTER 3 

Hereditary Hemorrhagic Telangiectasia

[147] Jahnsen ED, Trindade A, Zaun HC, et al. Notch1 is pan-endothelial at the onset of flow and regulated by flow. PLoS One 2015;10:e0122622. [148] Melchionna R, Porcelli D, Mangoni A, et al. Laminar shear stress inhibits CXCR4 expression on endothelial cells: functional consequences for atherogenesis. FASEB J 2005;19:629–31. [149] Topper JN, Cai J, Qiu Y, et al. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A 1997;94:9314–9. [150] Vorderwulbecke BJ, Maroski J, Fiedorowicz K, et al. Regulation of endothelial connexin40 expression by shear stress. Am J Physiol Heart Circ Physiol 2012;302:H143–52. [151] Yoshizumi M, Kurihara H, Sugiyama T, et al. Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem Biophys Res Commun 1989;161:859–64. [152] Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow change in the canine carotid artery. Am J Physiol 1980;239:H14–21. [153] Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 1986;231:405–7. [154] Bernabeu MO, Jones ML, Nielsen JH, et al. Computer simulations reveal complex distribution of haemodynamic forces in a mouse retina model of angiogenesis. J R Soc Interface 2014;11. [155] Cohen JH, Faughnan ME, Letarte M, et al. Cost comparison of genetic and clinical screening in families with hereditary hemorrhagic telangiectasia. Am J Med Genet 2005;137:153–60. [156] Bernhardt BA, Zayac C, Trerotola SO, et al. Cost savings through molecular diagnosis for hereditary hemorrhagic telangiectasia. Genet Med 2012;14:604–10. [157] Baxter M, Erby L, Roter D, et al. Health screening behaviors among adults with hereditary hemorrhagic telangiectasia in North America. Genet Med 2017;19:659–66. [158] Ruiz-Llorente L, Gallardo-Vara E, Rossi E, et al. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin Ther Targets 2017;21:933–47. [159] Papaspyrou G, Schick B, Al Kadah B. Nd:YAG laser treatment for extranasal telangiectasias: a retrospective analysis of 38 patients with hereditary hemorrhagic telangiectasia and review of the literature. ORL J Otorhinolaryngol Relat Spec 2016;78:245–51. [160] Grigg C, Anderson D, Earnshaw J. Diagnosis and treatment of hereditary hemorrhagic telangiectasia. Ochsner J 2017;17:157–61.

139

[161] Ross DA, Nguyen DB. Inferior turbinectomy in conjunction with septodermoplasty for patients with hereditary hemorrhagic telangiectasia. The Laryngoscope 2004;114:779–81. [162] Lund VJ, Darby Y, Rimmer J, et al. Nasal closure for severe hereditary haemorrhagic telangiectasia in 100 patients. The Lund modification of the Young’s procedure: a 22-year experience. Rhinology 2017;55:135–41. [163] Richer SL, Geisthoff UW, Livada N, et al. The Young’s procedure for severe epistaxis from hereditary hemorrhagic telangiectasia. Am J Rhinol Allergy 2012;26:401–4. [164] Klepfish A, Berrebi A, Schattner A. Intranasal tranexamic acid treatment for severe epistaxis in hereditary hemorrhagic telangiectasia. Arch Intern Med 2001;161:767. [165] Saba HI, Morelli GA, Logrono LA. Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 1994;330:1789–90. [166] Sabba C, Gallitelli M, Longo A, et al. Orthotopic liver transplantation and hereditary hemorrhagic telangiectasia: do hepatic vascular malformations relapse? A long term follow up study on two patients. J Hepatol 2004;41:687–9. [167] Contis A, Gensous N, Viallard JF, et al. Efficacy and safety of propranolol for epistaxis in hereditary haemorrhagic telangiectasia: retrospective, then prospective study, in a total of 21 patients. Clin Otolaryngol 2017;42:911–7. [168] Whitehead KJ, Sautter NB, McWilliams JP, et al. Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial. J Am Med Assoc 2016;316:943–51. [169] Dupuis-Girod S, Ambrun A, Decullier E, et al. Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangectasia: a randomized clinical trial. J Am Med Assoc 2016;316:934–42. [170] Fang J, Chen X, Zhu B, et al. Thalidomide for epistaxis in patients with hereditary hemorrhagic telangiectasia: a preliminary study. Otolaryngol Head Neck Surg 2017;157:217–21. [171] Brinjikji W, Nasr DM, Wood CP, et al. Pulmonary arteriovenous malformations are associated with silent brain infarcts in hereditary hemorrhagic telangiectasia patients. Cerebrovasc Dis 2017;44:179–85. [172] Stephan MJ, Nesbit GM, Behrens ML, et al. Endovascular treatment of spinal arteriovenous fistula in a young child with hereditary hemorrhagic telangiectasia. Case report. J Neurosurg 2005;103:462–5. [173] Nanthakumar K, Graham AT, Robinson TI, et al. Contrast echocardiography for detection of pulmonary arteriovenous malformations. Am Heart J 2001;141:243–6.

140

SECTION 1 

Cardiovascular Disorders

[174] Woods TD, Harmann L, Purath T, et al. Small- and moderate-size right-to-left shunts identified by saline contrast echocardiography are normal and unrelated to migraine headache. Chest 2010;138:264–9. [175] Velthuis S, Buscarini E, Mager JJ, et al. Predicting the size of pulmonary arteriovenous malformations on chest computed tomography: a role for transthoracic contrast echocardiography. Eur Respir J 2014;44:150–9. [176] Vorselaars VM, Velthuis S, Snijder RJ, et al. Follow-up of pulmonary right-to-left shunt in hereditary haemorrhagic telangiectasia. Eur Respir J 2016;47:1750–7. [177] Trerotola SO, Pyeritz RE, Bernhardt BA. Outpatient single-session pulmonary arteriovenous malformation embolization. J Vasc Interv Radiol 2009;20:1287–91. [178] Woodward CS, Pyeritz RE, Chittams JL, et al. Treated pulmonary arteriovenous malformations: patterns of persistence and associated retreatment success. Radiology 2013;269:919–26. [179] Gershon AS, Faughnan ME, Chon KS, et al. Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy. Chest 2001;119:470–7. [180] Gefen AM, White AJ. Asymptomatic pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia. Pediatr Pulmonol 2017;52:1194–7. [181] Liu ZC, Lu XF, Yang H, et al. Clinical outcomes of patients with severe hepatic hereditary hemorrhagic telangiectasia after banding of the hepatic artery and banding/ligation of branches of the hepatic artery. Eur J Vasc Endovasc Surg 2016;51:594–601. [182] Chavan A, Luthe L, Gebel M, et al. Complications and clinical outcome of hepatic artery embolisation in patients with hereditary haemorrhagic telangiectasia. Eur Radiol 2013;23:951–7.

[183] Felli E, Addeo P, Faitot F, et al. Liver transplantation for hereditary hemorrhagic telangiectasia: a systematic review. HPB 2017;19:567–72. [184] Longacre AV, Gross CP, Gallitelli M, et al. Diagnosis and management of gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol 2003;98:59–65. [185] Ingrosso M, Sabba C, Pisani A, et al. Evidence of small-bowel involvement in hereditary hemorrhagic telangiectasia: a capsule-endoscopic study. Endoscopy 2004;36:1074–9. [186] Alam MA, Sami S, Babu S. Successful treatment of bleeding gastro-intestinal angiodysplasia in hereditary haemorrhagic telangiectasia with thalidomide. BMJ Case Reports 2011;2011. [187] Wang XY, Chen Y, Du Q. Successful treatment of thalidomide for recurrent bleeding due to gastric angiodysplasia in hereditary hemorrhagic telangiectasia. Eur Rev Med Pharmacol Sci 2013;17:1114–6. [188] Cruikshank RP, Chern BW. Bevacizumab and hereditary haemorrhagic telangiectasia. Med J Aust 2011;194:324–5. [189] Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74–8. [190] Vorselaars V, Velthuis S, van Gent M, et al. Pulmonary hypertension in a large cohort with hereditary hemorrhagic telangiectasia. Respiration 2017;94:242–50. [191] Shovlin CL. Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia. Front Genet 2015;6:101. [192] Bari O, Cohen PR. Hereditary hemorrhagic telangiectasia and pregnancy: potential adverse events and pregnancy outcomes. Int J Womens Health 2017;9:373–8. [193] Trerotola SO, Pyeritz RE. PAVM embolization: an update. AJR Am J Roentgenol 2010;195:837–45.