Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

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Hereditary Hemorrhagic Telangiectasia (Osler–Weber– Rendu Syndrome) Alan E Guttmacher, Douglas A Marchuk and Scott O Trerotola Center for the Integration of Genetic Healthcare Technologies, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA

Reed E Pyeritz Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA This article is a revision of the previous edition article by Alan E Guttmacher, Douglas A Marchuk and Reed E Pyeritz, volume 2, pp 1200–1213, © 2007, Elsevier Ltd.

49.1 INTRODUCTION 49.1.1 Historic Perspective The evolution of our recognition and understanding of hereditary hemorrhagic telangiectasia (HHT; OMIM 187300) begins with the descriptive science of the nineteenth century and continues through the current era of molecular medicine. Only in the past two 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 died at the age of 60 of what was said to be “ruptured blood vessel of the lungs” (1). Even with no mention of such other symptoms and signs as telangiectasias, this likely represents 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 who, in 1896, first reported the combination of telangiectases and hereditary epistaxis as a discrete entity, and one that he distinguished from the more widely known hemophilia (2). 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). The remainder of the first half of the twentieth 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 septal dermoplasty for persistent epistaxis by William Saunders and others (6) 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 (7). The finding in the 1980s by Bruce Jacobson and others of a patient registry that soon grew into the Hereditary Hemorrhagic Telangiectasia Foundation International 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-like kinase 1 (ACVRL1) on chromosome 12 (see Section 49.2.3) (8,9).

© 2013, Elsevier Ltd. All rights reserved.

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

That both genes were involved in the transforming growth factor beta (TGFβ) and bone morphogenetic protein (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 (10,11). The last years of the twentieth century and the first decade of the twenty-first century witnessed other advances, such as the establishment of the first animal (mouse) models for HHT (12–15) and the identification of families segregating features of both juvenile polyposis and HHT due to mutations in SMAD4 (16).

49.1.2 Prevalence Several population-based surveys suggest the prevalence is at least one per 5000–8000 (17). In the County of Fyn, Denmark, the prevalence is 15.6 per 100,000 (18). In the Netherlands Antilles, the prevalence is much higher, 1 per 1331, at least in part due to founder effect in an island population (19). 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.

49.2 PHENOTYPE AND NATURAL HISTORY 49.2.1 Overview The fundamental problem 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 problems involve 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 telangiec­ tases are close to the surface and have very thin walls, they bleed easily. This accounts for nosebleeds being an early sign of HHT, and gastrointestinal (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. 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. The condition is often misdiagnosed, both because the features vary considerably among those affected (even within a single family), and features accumulate over the lifespan of patients. Formal studies of quality of life show that the clinical complications of HHT, especially epistaxis, have a significant negative impact (20). Both marked inter- and intrafamilial variabilities characterize HHT. Interfamilial variability is due, in part, to different mutations in different genes. Intrafamilial variability is typical of many dominant disorders (21); the precise biology by which it occurs in HHT is still unknown. 49.2.1.1 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 quickly refill when the pressure is released. This distinguishes telangiectases from a petechia and an angiokeratoma, which do not blanch, and a cherry angioma, which at best may blanch minimally. In HHT, punctuate telangiectases can appear anywhere on the skin or mucus membranes, but are most common on the fingers, palms, face, lips, buccal cheek, and tongue (Figure 49-1). Microscopy of the nail folds often shows dilated loops between capillaries and can be an early diagnostic sign (22). 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. 49.2.1.2 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

CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

(A)

(C)

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(B)

(D)

FIGURE 49-1  Dermal and mucocutaneous features of HHT. A. Digits. B. Ear. C. Lips. D. Tongue. 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. 49.2.1.3 Gastrointestinal.  Bleeding from mucosal telangiectases in any portion of the GI track 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. One uncommon form of HHT is associated with juvenile polyposis and is due to mutations in SMAD4 (16). 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 (23). 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. 49.2.1.4 Central Nervous System.  Three forms of developmental lesions and one acquired form are common in the brain and spinal column in HHT (24). Telangiectases, venous malformations, and cerebral arteriovenous malformations (CAVMs) 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 (25); however, this study also showed that angiography is more sensitive for both detecting and characterizing cerebral lesions. The risk of bleeding from any of these lesions is also unclear; one study suggested a risk of 0.5% per year (26), whereas another found a risk of 1.4–2.0% per year (27). In terms of cerebral hemorrhage of any cause, the risk for a man younger than 45 years of age was 20 times greater in HHT (27). 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 (28,29). The major acquired lesion is brain abscess, which is thought because of paradoxic embolization of bacteria through a PAVM (30).

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

49.2.1.5 Lung.  The single clinical finding that is most likely to prompt consideration of the diagnosis of HHT is the PAVM (Figure 49-2A). It remains uncertain as to what fraction of people with an apparently isolated PAVM actually has HHT. In part, many patients do

FIGURE 49-2  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. (Reprinted with permission from Ref. 139.) B. A simple PAVM. C. A complex, large PAVM. (Reprinted with permission from Ref. 139.)

not undergo detailed screening of the rest of their lungs to detect small lesions. In addition, molecular genetic screening has been available since 2003. PAVMs should be looked for carefully in any person with, or at risk for, HHT, including infants (31), 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 (32,33). 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 not uncommon (~10% over a lifetime), and can be life-threatening when massive (34). Chronic right-to-left shunting can also lead to pulmonary hypertension and failure of the right side of the heart. Infants and children should be screened for PAVMs since they may have one or more of clinical importance. Typically, however, PAVMs emerge in adolescence and young adulthood. A lesion has a tendency to expand over time, and new ones emerge, which emphasizes the need for life-long assessment. Some young adults will have no evidence of an intrapulmonary shunt, and are unlikely to develop any. A small fraction of patients with HHT have pulmonary hypertension unrelated to their degree of shunting. These patients typically have a mutation in ALK1. Some families with primary pulmonary hypertension but without signs of HHT have mutations in ALK1 (OMIM 178600; see Chapter 48). 49.2.1.6 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-to-hepatic vein connections (35,36). 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% (37,38). Discrepancies in prevalence relate to methods of diagnosis, with CT and MRI being more sensitive than ultrasound and auscultation for a bruit. Angiography is not necessary for routine assessment or screening (36). 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.

CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome) 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 (39) 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 (35). Neither percutaneous liver biopsy nor retrograde cholangiopancreatography is usually necessary, and either is of increased risk in HHT. An HHT referral center in Italy assessed 502 patients for hepatic involvement and found vascular malformations in 154 (40). Followed for a mean of 44 months, 5.2% died of hepatic complications and 25.3% suffered complications. Therapies of various types (discussed in Section 6) successfully treated two-thirds. 49.2.1.7 Other Manifestations.  Vascular malformations in the kidneys, bladder, retina, and other organs have been reported (41) as has aneurysm of the aorta and coronary arteries (42).

49.2.2 Pathology 49.2.2.1 Gross Pathology.  The fundamental problem 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 problems involve telangiectases. Because the cutaneous and mucosal telangiectases are close to the surface and have very thin walls, they bleed easily. This accounts for epistaxis being an early sign of HHT, and GI hemorrhage being a problem in adulthood. A variety of other dysplastic vascular lesions occur, including AVMs. The brain, the lung, and the liver are the primary sites of AVMs, but other organs can be involved. The vascular precursor of an AVM is established early in life, and the individual lesion expands slowly over many years. Other lesions include arterial aneurysms, dilated veins, and complex AVMs with multiple feeding arteries and a mass of channels connecting to multiple veins (Figure 49-2B). 49.2.2.2 Histology and Ultrastructure.  The absence of capillaries causes dilatation of the postcapillary venule, which is the essence of the punctuate telangiectases.

49.2.3 Genetics 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 (41,43). However, considerable intrafamilial variability occurs.

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49.2.3.1 HHT1 and Endoglin (ENG).  Genetic linkage for HHT families was first established to markers on chromosome 9q33–q34 (44,45). Mutations in the gene encoding endoglin were subsequently identified in HHT1 kindreds (9). Endoglin is a homodimeric integral membrane protein expressed at high levels on human vascular endothelial cells of all blood vessels (46). On endothelial cells, endoglin is the most abundant TGFβ-binding protein (47). The 90 kDa endoglin protein is encoded by a gene comprising 15 exons (48,49). In addition to the originally identified endoglin cDNA, a splice variant was detected called S-endoglin (for short endoglin), coding for an 85 kDa protein (50). The extracellular and transmembrane domains of S-endoglin and the longer endoglin 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. Although the physiologic distinctions between L- and S-endoglin are not yet completely known, in at least two assays of signaling, they differ in their response to ligand (51). 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 endoglin 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 the appropriate population helps to identify those alterations that merely represent normal sequence polymorphisms. Mutations thus far identified in the endoglin gene include missense mutations, nonsense mutations, splicesite changes, and small nucleotide insertions and deletions leading to frameshifts and premature stop codons, all found throughout most of the exons of the gene. Expression data from a number of frameshift and nonsense mutations show that many of these create unstable messages (48,52), 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 (53). Larger genomic mutations contribute to at least some of the

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

approximately 20% of HHT cases, in which no mutation can be identified in ENG, ACVRL1 or SMAD4. 49.2.3.2 HHT2 and ALK1 (ACVRL1).  A second HHT locus (HHT2; OMIM 600376) was identified in the pericentromeric region of chromosome 12 (8). A potential candidate gene, ACVRL1, encoding the ALK1 protein (activin receptor-like kinase 1), was shown to map within this interval, and mutations were identified within this gene in HHT2 families (8). ALK1 protein is expressed primarily on endothelial cells and in highly vascularized tissues. Studies using a reporter gene trap within the mouse alk1 gene suggest that its transcript is expressed most highly, and possibly exclusively, in the arterial endothelium (49,54). 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. Two groups independently demonstrated that BMP9 and the related BMP10 could specifically activate ALK1 (55,56). Subsequent studies have confirmed the critical role of BMP9/ALK1 signaling in angiogenesis. Most data support a role for ALK1/ BMP9 signaling in inhibition of angiogenesis (55–58), whereas one study concluded that this pair stimulates angiogenesis (59). These discordant results may be due to the use of different endothelial cell subtypes in each study (59) since the specific response to the signal might be modulated by the differential expression of any one of several different type II coreceptors in an endothelial cell subtype-specific manner (58). Regardless, the discovery of BMP9 as a ligand for ALK1 has spawned a new avenue of research to determine whether HHT is caused by a defect in TGFβ signaling, BMP9 signaling, or an imbalance between the two. Human ACVRL1 contains 10 exons, nine of which encode the protein sequence (60). 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 in ENG, are for the most part family specific, again leading to difficulties of confirmation by cross-referencing with previously described mutations. Careful cataloging of normal sequence variants will help in sorting out 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 endoglin. 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 (60). 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 (61). These authors developed the first functional assay for ALK1 signaling based on the discovery of BMP9 as the specific ligand for the receptor (61). 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. 49.2.3.3 HHT3.  Evidence for a third locus and gene for HHT (HHT3; OMIM 601101) was provided by a single HHT family (62) 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 (63). Higher resolution mapping has further narrowed the candidate interval to a 5.7 Mb interval (64). 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, by either disclosing the identity of a heretofore unknown factor in TGFβ/BMP signaling, or by uncovering an unrelated, but parallel signaling pathway leading to the same clinical phenotype. The prevalence of HHT3 also remains uncertain, because to date, only two HHT families have shown statistically significant linkage to this region. Nonetheless, HHT in some of the families negative for mutations in ENG, ACVRL1, and SMAD4 that have confounded diagnostic DNA testing laboratories will likely be shown to be due to mutations in this novel HHT3 gene. 49.2.3.4 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 (65). An obvious candidate gene mapping within the interval, bone morphogenetic protein endothelial receptor (BMPER), was ruled out early on by DNA sequence analysis. Loss-of-function BMPER mutations were subsequently identified in an autosomal recessive, perinatal lethal skeletal disorder diaphanospondylodysostosis (66). The HHT4 gene has yet to be identified but since there are no other obvious biological candidate genes mapping within the interval, its discovery should also prove invaluable to our understanding of HHT pathogenesis. As with HHT3, the prevalence of HHT4 remains unknown, but at least some of the families negative for mutations in ENG, ACVRL1 and SMAD4 will likely be shown to be due to mutations in this novel HHT4 gene. 49.2.3.5 Juvenile Polyposis–HHT: A Syndromic HHT Phenotype (OMIM 175050).  A number of case reports suggested an association of juvenile polyposis (JP) and HHT, or with one or more features of HHT, especially, PAVMs (67–71). 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

CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome) ligand in the TGFβ superfamily (72). It is now known that most patients with JP harboring an SMAD4 mutation display a combined syndrome of juvenile polyps and HHT (16,73). 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 (16). The combined syndromic phenotype is estimated to occur in 15–22% of individuals with an SMAD4 mutation (74), but this may be an underestimate because of a lack of recognition of the HHT phenotype in individuals with clinically silent vascular phenotypes. Thus far, only mutations in the SMAD4 gene have been identified in JP–HHT syndrome. The mutations 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 (75). 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 ALK1, screening for mutations in SMAD4 found three positive (76). 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 an 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.

49.3 ETIOLOGY 49.3.1 Molecular Pathology 49.3.1.1 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 endoglin gene are

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associated with a more severe outcome than missense mutations (77), and another suggested that truncating mutations in ALK1 were associated with a higher frequency of epistaxis and telangiectasia (78), 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 mutation in the murine endoglin gene is heavily influenced by the genetic background (that is, the particular inbred lineage) of the mice (79). Similarly, mice lacking the TGFβ1 ligand show profound differences in the resulting phenotype depending on inbred strain background carrying 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 (80–82). However, the genes underlying these modifier loci have yet to be identified in the mouse, and thus, the human orthologs cannot yet be investigated as potential modifiers of the human HHT phenotype. There is, however, 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 (endoglin) seemed to have a much higher incidence of PAVMs reported than families for whom this locus was excluded (21,43). Further analysis confirmed that this difference was genuine (83–85). 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 endoglin mutations exhibit anywhere from a twofold to up to a 10-fold higher incidence of PAVMs than patients with ALK1 mutations (78,86–88). 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 endoglin mutations than those with ALK1 mutations, and in some studies, appear to be almost exclusively found in HHT1 patients (86,88). One study found neurological complications secondary to cAVMs and pAVMs only in HHT1 patients (88). In comparison to HHT1, HHT2 patients (ALK1 mutation) more commonly exhibit gastrointestinal bleeding

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

(78) and show a higher frequency of hepatic AVMs (78,83,86,88,89), with two studies observing severe or symptomatic hepatic disease only in HHT2 (78,88). HHT2 is also associated with an increased risk to develop pulmonary hypertension (89–93). Pulmonary hypertension has also been observed in HHT1 cases (94–97). Despite the wealth of genotype:phenotype data that has emerged since 2007, the establishment of correlations such as these continue 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.

49.4 PATHOGENESIS 49.4.1 Animal Models The roles of the genes encoding endoglin and ALK1 in vascular development have also been probed by disruption of these genes in the mouse. Homozygous disruption of either genes in the mouse results in embryonic lethality because of arrested endothelial remodeling. Three different groups have disrupted the endoglin gene (12–14). The primary defect is the maturation arrest of the primitive vascular plexus of the yolk sac into defined vessels, leading to channel dilation and rupture. Embryos show distended blood yolk sac vessels by E9.5, a lack of vascular organization by E10.5, and embryos are resorbed by E11.5. Smooth muscle cell differentiation and recruitment to the vessels is also defective. Various heart defects have been reported, including abnormal cardiac looping, and enlarged cardiac ventricles and pericardial sac. Heart valve formation is also disrupted, with reduction in the size of the atrioventricular endocardial cushions and disorganization of the endothelial surface of the cushions. Thus, endoglin plays a crucial role in the heart development. Careful analysis of endoglin null mice shows that they can develop AVMs during the embryonic stage (98). These data suggest a very early defect in the maintenance of arteriovenous vascular beds. Embryos homozygous for null alk1 mutations die in utero because of the defects in vascular development (99,100). By E9.5, they show absence of mature blood vessels in the yolk sac, and the embryos are resorbed

by E10.5. Histological analysis of the mutant embryos shows excessive fusion of capillary plexus into cavernous vessels. Hyperdilation of large vessels and deficient differentiation and recruitment of smooth muscle cells are also evident. The endocardium and myocardium are also immature, suggesting a role for ALK1 in heart development. ALK1 function in vivo has also been probed using the powerful zebrafish (Danio rerio) experimental system. A germline mutation in the zebrafish ALK1 orthologous gene (acvrl1) or morpholino knockdown of its transcript results in dilated cranial vessels because of an increased number of endothelial cells (101). The increase in endothelial cell number in the acvrl1-mutant fish is consistent with the majority of cell signaling studies that find that ALK1/ BMP9 signaling inhibits angiogenesis. The zebrafish system has also been exploited to investigate the in vivo effects of ALK1 mutations found in HHT2 patients (102), and to explore the phenotypic consequence of loss of TAK1, a downstream kinase that is activated by ALK1 (103). Loss of TAK1 in the zebrafish mirrors the ALK1-mutant phenotype, and TAK1 overexpression can rescue the animals from the phenotypic consequences of loss of ALK1. Morpholino knockdown of both ALK1 and TAK1 shows a synergistic effect on the vascular phenotype. These combined data suggest that TAK1 might be a novel HHT gene, or possibly a genetic modifier of the clinical phenotype. In mice heterozygous for both ENG and ALK1 knockouts, the proper genetic model for the HHT phenotype shows that an HHT-related phenotype will develop over time. Lesions such as cutaneous or mucocutaneous telangiectasias as well as visceral AVMs are observed and these resemble the lesions seen in human patients (13,79,104–106). Detailed immunohistochemical characterization of the vessels of mice heterozygous for a mutation in endoglin has led to the hypothesis that HHT involves a generalized vascular abnormality that includes dilated postcapillary venules, vascular walls lacking smooth muscle cells, and irregular collagen and elastin staining (106). Bleeding was associated with regions of inflammation, which may provide a clue to therapy for the bleeding associated with the human patients. The endoglin mouse model has been used to investigate the earliest events in the pathogenesis of HHT-­associated vascular dysplasia. In addition to its role in TGFβ signaling, the mouse models have uncovered a role for endoglin in the regulation of vascular tone. Resistance arteries from Eng+/− mice display an endothelial nitric oxide synthase (eNOS)-dependent dilation and impairment of the myogenic response (107). Endoglin physically associates with eNOS (107) and also regulates eNOS expression at the transcriptional level via Smad2-dependent TGFβ signaling (108). Endoglin-deficient endothelial cells exhibit uncoupled eNOS activity, producing less NO, and instead generating more eNOS-derived superoxide (107). Intriguingly, the uncoupled activity was not observed in the lungs of newborn Eng+/− mice, but increased as the

CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome) mice aged to adulthood (109). This age-dependent eNOS uncoupling correlated with vasorelaxation in the adult mice, and may explain the development of the pulmonary lesions in adolescents with HHT. The data from the Eng+/− mice also suggest a molecular explanation for the association of HHT with pulmonary hypertension. The HHT1 mouse model exhibits increased right ventricular systolic pressure, degeneration of the distal pulmonary vasculature, and muscularization of the small arteries of the lung, each of which can be attributed to uncoupled eNOS activity (110). These physiologic analyses of the blood vessels in HHT mouse models have helped to elucidate the underlying pathogenesis of HHT. These models suggest that even the “normal” (nonlesional) vessels in HHT harbor an intrinsic structural or physiological defect. The connection with vasodilation, the myogenic response, and nitric oxide levels has provided novel and testable hypotheses concerning the nature of the initiation events leading to vascular lesion development. Increased superoxide may create endothelial cell damage, and this may be an important clue to the initiation of vascular lesion development. Although the mechanisms whereby endoglin and ALK1 affect TGFβ signaling pathways are rapidly coming into focus, their specific roles in modulating vascular endothelial and smooth muscle cell properties are just beginning to be elucidated. Despite these positive signs, the specific factor or factors responsible for vascular lesion formation remain unknown. A reduction to 50% of functional endoglin or ALK1 levels is compatible with development of a normal vascular system in utero since there is no evidence of increased miscarriage in HHT families. Yet mutation carriers are at nearly 100% risk of developing the vascular lesions observed in HHT. The vascular lesions in HHT are localized to discrete regions within specific organs in the affected tissue, with little evidence of pathology outside the lesions themselves. This suggests that some genetic, physiological, or mechanical event initiates the formation of each vascular lesion. The pathobiology of the disease may be related to remodeling of the vascular endothelium following an unknown initiating event. TGFβ1 mediates vascular remodeling through effects on extracellular matrix production by endothelial cells, stromal interstitial cells, smooth muscle cells, and pericytes. Perturbations in the TGFβ signaling pathway in HHT may lead to altered repair of vascular endothelium and remodeling of the vascular tissue via changes in expression profiles of extracellular matrix proteins. Continued clinical research on this disorder, in combination with studies of animal models and basic biochemical characterization of the signaling pathways involved, will play an important role in elucidating the pathogenesis of HHT.

49.5 DIAGNOSIS Until very recently, the diagnosis of HHT could only be made on clinical grounds. However, with the

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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 currently 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 (111). 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 USA, where many health economic issues are quite different from Canada (112). 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 telangiectasias, 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 telangiectasias (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 telangiectasias, and family history is present, the diagnosis of HHT is both straightforward and rarely incorrect. 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 pulmonary AVM prove to have HHT (this is especially true if there are multiple PAVMs). Similarly, GI telangiectasias 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 Curacao criteria, devised by a number of clinicians from

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

around the world experienced in the disorder (11). The four criteria in this construct are as follows: • Epistaxis • Multiple

telangiectasias at characteristic sites (lips, oral cavity, fingers, nose) • Visceral lesions (such as GI telangiectasias 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 Curacao 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” (11).

49.6 MANAGEMENT 49.6.1 Mucocutaneous Telangiectasias Lesions on the tongue, lips, and fingers may bleed when traumatized. Photocoagulation with a laser can be effective in stopping acute bleeding. Smaller lesions can be eliminated, and this is of some cosmetic utility around the face.

49.6.2 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 telangiectasias 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. Cauterizing agents, such as silver nitrate, may be useful for an initial, small bleed, but are useless for large ones. 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 septenopalatine and ethmoid arteries supply about two-thirds 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 telangiectasias, 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 septal dermoplasty. In this major procedure, the inferior turbinate is resected and a skin autograft is placed by suturing to the septum superiorly and then packing the nose (113). 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. 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 quality of life. 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 (114–116). 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, nonradomized series. The anti-VEGF drug, bevacizumab, given topically or systemically, holds promise (117,118) but can be associated with severe adverse effects. Thalidomide and tranexamic acid also being studied more systematically, now that case reports and small series demonstrating encouraging results have appeared (119). 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.

49.6.3 Central Nervous System Vascular malformations present at birth are usually asymptomatic, but large venous malformations and CAVMs, in the absence of bleeding, may cause problems

CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome) 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 (26,120). Brain abscess, due to paradoxic 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 blood stream. 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.

49.6.4 Lung Plain chest radiography, pulse oximetry, arterial blood gases, or a combination thereof are insensitive for 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 (121). 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 CT scan. If contrast does not appear for four to eight heart beats, then there is likely a shunt in the pulmonary circulation. However, a few percent of “normal” individuals will have delayed passage of a few bubbles (122,123). Whether this represents a “false positive” or the presence of small and clinically irrelevant intrapulmonary shunts is unclear. Quantity of the contrast in the left atrium is a rough guide to the number and size of the PAVMs. Delayed appearance of more than a few bubbles requires follow-up imaging. The standard protocol to address the size, number, and location of PAVMs is a high-resolution CT scan of the lung before and after injection of radio-opaque contrast. 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. Until the early 1980s, patients with a PAVM of any cause were not treated unless they had recurrent

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hemoptysis, severe arterial desaturation, or high-output heart failure. Then, the segment or segments of lung with the offending or largest PAVMs were resected. Unfortunately, because PAVMs in HHT can progress over time, this surgical approach could be used only a limited number of times. Robert White, a radiologist, and Peter Terry, a pulmonologist, at Johns Hopkins Hospital developed the ability to occlude PAVMs by means of balloons inserted into the feeding artery and then filled with saline containing radio-opaque dye (124,125). This approach, since modified to involve wire coils that invoke a thrombus in the feeding artery, has revolutionized the management of the lung in HHT. Now, under fluoroscopic guidance, four to six or more PAVMs can be treated in one session (Figure 49-3). Complications include pleuritic chest pain that typically resolves in a few days, failure to occlude feeder vessels completely (more common in complex AVMs or when a feeding artery is large), transient ischemic episode, rare paradoxic embolization of a device, and recannalization (126–128). Until recently, PAVMs with feeding arteries of <3 mm diameter were left untreated. However, some episodes of cerebral embolization occurred (129), and we and others now recommend occluding any PAVM that can be reached by a catheter. This aggressive approach requires an expert interventional radiologist who has considerable experience with HHT. After all PAVMs that can be occluded are, the patient should have a repeat CT scan in 6 months to document that all remain occluded (i.e. that no recanalization has occurred). Subsequently, a CT scan should be performed every five years to monitor emergence or growth of any additional lesions (Figure 49-4). 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 (130). Any patient diagnosed with HHT during pregnancy should undergo high-­ resolution CT of the lung with contrast. Embolotherapy is indicated during pregnancy for PAVMs that can be reached by an intervention catheter (131).

49.6.5 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. Patients who have hepatic encephalopathy can be treated with nitrogen restriction and lactulose. Those with high-output cardiac failure respond initially to diuretics. The therapy of last resort is liver transplantation. Unfortunately, because tests of liver function often

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

FIGURE 49-3  Fifty-two-year-old woman with known right upper lobe PAVM. Patient was followed for 14 years at another institution and told

treatment was not needed. She has obvious 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 vasclar occluder show occlusion of PAVM. H. Representative image from coronal CT reconstruction 6 months after embolization. Sac has almost completely disappeared. Characteristic appearance of Aplatzer device (arrow). Patient reported marked improvement in her exercise tolerance. (Reprinted with permission from Ref. 139.)

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 of 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 will remain to be studied (116).

CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

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(135) but the site or sites of chronic blood loss usually remain obscure.

49.6.7 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 (136). 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.

FIGURE 49-4  Multiple, treated and untreated PAVMs in one lung. (Reprinted with permission from Ref. 139.)

49.6.6 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 telangiectasias from the oral cavity to the duodenum and from the rectum to the ileocecal valve. The number of telangiectasias roughly correlates with the anemia and transfusion requirement (132). Any lesion that appears to be bleeding can be cauterized. However, there is no point in attempting to treat every telangiectasias, especially if repeated endoscopies are contemplated. Capsule endoscopy confirms that telangiectasias exist throughout the jejunum and ileum; but push enterostomy or major surgery are rarely required (133). 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 (132,134). Similarly, experimental agents such as thalidomide and bevacizumab are worth studying (118,119). Selective mesenteric arteriography can reveal intestinal AVMs that can be embolized

49.6.8 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 (137). The Hereditary Hemorrhagic Telangiectasia Foundation International (www.hht.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 33 centers worldwide, including 15 in North America. The Foundation also sponsors national conferences for patient education and support, and biennial international research symposia.

49.6.9 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 died at twice the rate of the population average (18). 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 (138). Life expectancy was not related to gender or to genotype.

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

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 U.S. National Institutes of Health, and while in residence at the Brocher Foundation, Hermance, Switzerland. We also thank all of our colleagues who shared their published and unpublished work and commented on sections of this chapter.

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CHAPTER 49  Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome) Biography



 eed Pyeritz, completed his PhD and MD at Harvard and trained in internal medicine at the R Peter Bent Brigham Hospital in Boston and medical genetics at the Johns Hopkins Hospital in Baltimore. He is a professor of Medicine and Genetics at the Raymond and Ruth Perelman School of Medicine of the ­University of Pennsylvania in Philadelphia, where he directs the Center for the Integration of Genetic Healthcare Technologies and serves as vice-chair for academic affairs of the Department of Medicine. He is a senior fellow in both the Center for Bioethics and the Leonard Davis Institute for Health ­Economics. His research has focused on several areas, including clinical investigations of heritable disorders of ­connective tissue and cardiovascular diseases, especially those affecting the thoracic aorta. Currently he is studying how more refined methods of investigating genetic variation, such as cytogenomic arrays and whole genome sequencing, actually increase the level of uncertainty in applying the results clinically.