46.Osler-Weber-Rendu DiseasePerry A Soriano, MD, Staff Surgical Oncologist, Division of General Surgery, The Everett ClinicJames Petros, MD, Associate Professor of Surgery, Program Director, Surgical Residency Program, Department of Surgery, Boston University School of Medicine; James F McKinsey, MD, FACS, Associate Professor of Clinical Surgery, Columbia University College of Physicians and Surgeons; Site Chief, Department of Surgery, Division of Vascular Surgery, Columbia University Medical Center

Updated: Dec 15, 2008

Introduction

In 1864, Sutton described a disorder of epistaxis and degeneration of the vascular system that would later bear the names Osler-Weber-Rendu disease (OWRD) and hereditary hemorrhagic telangiectasia (HHT).[1 ]

Benjamin Guy Babington noted the syndrome’s familial nature in his 1865 paper "Hereditary Epistaxis.".[2 ]

Henri Rendu first emphasized the hallmark blanching cutaneous and mucous membrane angiomata of HHT and differentiated this disease from hemophilia.[3 ]Subsequently, Sir William Osler and Frederick Parks Weber published detailed descriptions of the syndrome that, along with Rendu, bears their names).[4,5 ]

The term, hereditary hemorrhagic telangiectasia (HHT) was coined by the pathologist Hanes in 1909.[6 ]

With the development of gastrointestinal endoscopy, Renshaw described the "millet seed to pinhead sized bright red spots" typical of mucosal HHT.[7 ]

Problem

HHT is an autosomal dominant disorder manifested by mucocutaneous telangiectases and arteriovenous malformations (AVMs), a potential source of serious morbidity and mortality. Lesions can affect the nasopharynx, central nervous system (CNS), lung, liver, and spleen, as well as the urinary and GI tracts.[8 ]Epistaxis is the most common manifestation, and gastrointestinal bleeding is also prevalent.[9 ]Onset of symptoms may be delayed until the fourth decade of life (approximately 90% of patients manifest by age 40 y) or later decades.[10,11 ]

Diagnosis of HHT is made clinically by the Curaçao criteria, established in June 1999 by the Scientific Advisory Board of the HHT Foundation International, Inc.[12 ]More stringent than previous guidelines, the goals of its use are to improve patient care and to standardize research.

The HHT diagnosis is classified as definite if 3 criteria are present, possible or suspected if 2 criteria are present, and unlikely if fewer than 2 criteria are present. The Curaçao criteria are as follows:

1. Epistaxis - Spontaneous, recurrent nosebleeds2. Telangiectases - Multiple at characteristic sites (lips, oral cavity, fingers, nose)3. Visceral lesions - Such as gastrointestinal (GI) telangiectasia (with or without bleeding),

pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM4. Family history - A first-degree relative with HHT

Shovlin et al emphasized the varied presentation of HHT among families and even within the same family.[13,14,12 ]Cutaneous findings may be subtle; epistaxis, the most common overt feature, is also common in the general population. Given the lack of consensus on the number of episodes or degree of epistaxis necessary for diagnosis, the criteria highlight that "nosebleeds should occur spontaneously on more than one occasion, with night-time bleeds being particularly suspicious."

Genetic testing of patients and their family members can confirm the presence of mutations within implicated genes, most commonly endoglin (ENG) or ALK-1 involved in HHT types 1 and 2, respectively.[15 ]

Frequency

HHT affects varied racial and ethnic groups and occurs in a wide geographic distribution. Men and women are affected equally.[16 ]

United States: In Vermont, frequency has been estimated at 1 case per 16,500 persons.[8 ]

Europe and Asia: In Europe and Japan, incidence is estimated to be between 1 in 5000 to 8000 people.[17,18 ]

Specific populations: Incidence may vary considerably between populations. The highest rates are seen in parts of the Dutch Antilles among the Afro-Caribbean population with a prevalence of between 1 case per 200 persons and 1 per 1,331 in the Curaçao and Bonaire regions.[19,20 ]Prevalence in the French department of Ain is 1 case per 2351 persons and in France overall, 1 per 8345.[10 ]Other examples include the Danish island of Funen, 1 per 3500, and in northern England, 1 in 39,216.[21,11 ]

Etiology

HHT is an autosomal dominant disorder attributed to genetic mutations that involve signaling of transforming growth factor beta (TGF-b), an important pathway in vascular formation and repair.[14 ]Defects in at least 4 genes are implicated in HHT. Mutations in ENG (encoding the endoglin protein) characterize HHT type 1 and involve chromosome 9, 9q33-34.[22 ]Mutations of ALK1 (encoding activin receptor-like kinase 1), also called ACVRL1 (activin A receptor kinase, type II like 1), are implicated in HHT type 2 and involve chromosome 12, 12q13.[23 ]

A third locus involves mutations of chromosome 5 (5q31.1-32) and is distinct from hereditary benign telangiectasia (HBT), a gene defect in RASA1 (chromosome 5q14).[15 ]

Mutations of a fourth gene, MADH4 (encoding SMAD4) is described in the HHT-juvenile polyposis overlap syndrome (JPHT).[24 ]JPHT is also autosomal dominant, involves chromosome 18, and combines clinical manifestations of HHT and juvenile polyposis. Consequently, at least the following 4 types of HHT are known: HHT type 1, HHT type 2, HHT type 3 and JPHT.

Pathophysiology

The underlying disorder in HHT is abnormal vascular architecture at discrete sites. Unaffected areas show normal vessel architecture based on ultrastructural analysis.[25 ]Thus, researchers postulate that an initiating event combined with abnormal repair results in HHT lesions.[26 ]Interactions with TGF-b signaling result in disorganized cytoskeletal structure and poor vascular tubule formation. The gene expression profiles of the vascular endothelial cells grown from HHT patients reveals dysregulation of genes involved with angiogenesis, cytoskeletal integrity, cell migration, proliferation and nitric oxide synthesis.[27 ]Telangiectases and AVM bleeding tendency is attributed to localized vessel wall weakness, in part due to abnormal remodeling resulting from an imbalance in TGF-b related functions.[14 ]

Presentation

Telangiectases of the skin and mucous membranes, epistaxis, and a positive family history comprise the classic triad of HHT. Visceral and CNS involvement may be asymptomatic but are of importance due to associated complications that may be preventable. An estimated 90% of HHT patients have spontaneous, recurrent epistaxis, 75% show skin telangiectases, 30% have hepatic or pulmonary involvement (AVMs), 15% manifest GI bleeding,[28 ]and 10-20% have CNS lesions.[29 ]A known progression in the onset of symptoms over time begins with epistaxis, then pulmonary AVM (PAVM), followed by cutaneous and mucous telangiectases.[28 ]

Skin

As Rendu described in his hallmark work, typical lesions appear as "small purplish stains, of the size of a pinhead, the largest reaching the size of a lentil." The typical telangiectasia is smaller than 5 mm and is found directly beneath the skin or mucosal surfaces.[16 ]The lesions partially blanch with pressure, although fine telangiectases may be difficult to appreciate in patients with anemia. Color ranges from bright red to violaceous to purple. Macular, papular, or punctate lesions are typical; linear or spider-patterned lesions are rarely present.

Half of patients manifest cutaneous lesions by age 30, although lesions may arise during the teenage years.[10 ]The face, lips and mouth, nares, tongue, ears, hands, chest, and feet are most often affected, in descending order of frequency and in any combination. Lesions are multiple and may be of cosmetic concern, and the number of lesions may increase with age. Bleeding is rarely clinically significant.

Nose

Recurrent epistaxis is present in 90% of patients with HHT and appears at a young age, manifesting in most patients by age 21 years.[30 ]Bleeding may be severe and spontaneously occurs from telangiectases of the nasal mucosa. Iron supplementation and blood transfusion may be required. Bleeding symptoms are progressive with increasing age and the presence of pulmonary AVM does not predict a better or worse natural history for epistaxis.[31 ]

Central nervous system

The estimated incidence of CNS involvement in HHT patients is 10-20%.[29 ]CNS manifestations are due to inherent CNS vascular lesions in one third of HHT patients, whereas most CNS complications are secondary to associated pulmonary AVMs resulting in paradoxical emboli.[32 ]Other CNS manifestations include spinal AVMs, migraine occurring in 50% of patients, seizure, and paraparesis.[33 ]Cerebral AVMs are associated with an annual hemorrhage rate of 1.4-2.0% per patient, similar to that of non–HHT cerebral AVMs.[34 ]HHT–associated cerebral hemorrhage tends to show good functional outcome.[35 ]

Spontaneous remission or regression of cerebral AVMs has been reported in 3 cases; this appears to be a recently reported and rare phenomenon.[36,37,38 ]

Lung

Pulmonary AVM, with right-to-left pulmonary shunting, is the major cause of transient ischemic attack, brain abscess, and ischemic stroke in HHT patients due to paradoxical embolization of bland or septic material into the cerebrovasculature. These symptoms may be the first manifestation of pulmonary HHT involvement or the presenting symptoms of HHT itself.[10 ]Brain abscess and stroke account for much of the 10% mortality rate seen in HHT, underscoring the importance of this often initially silent entity.[39 ]

Small AVMs with shunting of less than 25% of pulmonary blood flow are asymptomatic in half of cases. These patients show no cyanosis but demonstrate dyspnea on exertion and easy fatigability. Larger AVMs, especially when multiple, may result in dyspnea, fatigue, cyanosis, clubbing, and polycythemia.[40 ]Such severe shunting, defined as more than 25% of pulmonary blood flow, is seen in 20% of cases. Auscultation reveals a continuous thoracic bruit in half of patients with cyanosis. Cyanosis and clubbing are particularly associated with an increased risk of cerebral abscess and stroke. Unlike in hepatic AVM, increased cardiac output with high-output heart failure is unusual.

In a recent review, patients with a solitary pulmonary AVM had HHT 36% of the time. With multiple lesions, the rate of HHT was 57%. Overall, up to 60% of patients with pulmonary AVM have HHT. Conversely, a 20% incidence of pulmonary AVM can be expected in patients with HHT. ENG mutations of HHT type 1 are associated with a 30% incidence of pulmonary AVM versus 3% for HHT type 2 ALK1 mutations.[41 ]

A multicenter review from Lyon, France by a large collaborative group (Groupe d’Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires), which studies rare pulmonary disorders or "orphan" disorders, examined the characteristics of 126 HHT patients.[42 ]Between 1985 and

2004, 79 women and 47 men, mean age 34 +/-17 years, were examined. AVM was detected on screening in 29% of patients, incidentally detected by imaging in 15%, detected secondary to dyspnea in 22%, and secondary to CNS symptoms in 13%. Dyspnea on exertion was present in 56% of patients. Thirteen cases of cerebral abscess were found, of which 54% were found concurrent with the diagnosis of HHT and detection of pulmonary AVM. Eighty-three percent underwent treatment for their AVMs, 23% by surgical resection and 71% via embolization.

Diffuse pulmonary AVM was examined in 36 individuals out of a consecutive series of 821 AVM patients in Italy. The study showed an 81% association with HHT (29 of 36 patients). Diffuse AVM was associated with female gender and bilaterality. This was a high-risk group with 9 deaths occurring in patients with bilateral involvement. Causes of mortality were hemoptysis of bronchial artery origin (2 patients), duodenal ulcer with hemorrhage (1 patient), spontaneous liver necrosis (3 patients), cerebral hemorrhage (1 patient), cerebral abscess (1 patient), and operative death during lung transplantation (1 patient).[43 ]

Despite shunt formation across the pulmonary tree from AVMs, HHT is also associated with pulmonary hypertension. Lung tissue of HHT patients with pulmonary hypertension appears histologically similar to that of patients with primary pulmonary hypertension. This manifestation of HHT is associated with ALK1 gene mutations.[44 ]

Gastrointestinal tract

GI bleeding develops in 25-30% of patients with HHT.[45 ]Usually manifesting in the fifth or sixth decade, lesions can arise in any portion of the GI tract, although they most commonly involve the stomach and small bowel. Nodular angiomas are visualized on endoscopy and are similar to cutaneous telangiectases in appearance.[21 ]GI bleeding is the most common visceral manifestation of HHT, presents later than epistaxis, and has been shown in both HHT-1 and HHT-2 families.[46 ]Massive transfusion requirements of more than 100 units of blood have been reported.[47 ]The presence and number of lesions detected in the stomach and duodenum on upper endoscopy correlates with the detection of lesions in the jejunum, although large (greater or equal to 5mm) upper tract lesions do not necessarily suggest the presence of large jejunal lesions.[45 ]

Liver

Thirty to 60% of patients with HHT have liver involvement.[48 ]Although many patients are asymptomatic,[49 ]high-output heart failure, hepatomegaly, portal hypertension, encephalopathy, biliary manifestations of right upper quadrant pain and jaundice, and liver failure are described.[50

]The 3 most common clinical patterns are high-output cardiac failure, portal hypertension, and biliary disease. The biliary manifestations include biliary obstruction or sepsis in association with biliary strictures, dilatation, and bile cysts.[51 ]

Patients with clinically significant liver lesions most often present with hyperdynamic circulation (cardiac indexes of 4.6-6.8 L/min/m2).[52 ]This phenomenon may be observed without symptoms of heart failure and is due to shunting from hepatic artery to hepatic vein, portal vein to hepatic vein, or both. Shunting from the hepatic artery to the portal vein causes arterialization of the

portal system with nodular transformation of parenchyma without fibrous septa, a condition termed pseudocirrhosis.

HHT and pregnancy

A study of 262 pregnancies in 111 HHT patients was published in 2008.[53 ]The authors examined all pregnancies in 111 women diagnosed with HHT and pulmonary AVM between 1995-2005, whether or not HHT was known at the time of the first pregnancy. Most pregnancies proceeded normally. Thirteen patients had adverse events: major pulmonary AVM bleed in 1%, maternal death in 1%, and stroke in 1.2% (not all HHT related). In women experiencing a life-threatening event, prior knowledge of HHT or pulmonary AVM was associated with improved survival (P = 0.041).

Experience with a small series of 7 women suggests transcatheter embolization of pulmonary AVM can be accomplished safely by a skilled interventional radiologist after 16 weeks gestation.[54 ]

Indications

Indications for intervention vary according to site of involvement and presentation. For example, severe epistaxis refractory to ablative treatment may benefit from septoplasty. Control of intermittent GI bleeding may be managed medically; however, brisk hemorrhage may require endoscopic treatment or surgical resection. Embolization or surgical resection is indicated for pulmonary arteriovenous malformation (AVM) if it is localized and accessible with the goal of limiting the risks of embolic CNS complications, hemodynamic sequelae, or hemorrhage. Hemodynamically significant shunt from hepatic AVM may be amenable to embolization to stabilize heart failure or encephalopathy. Extensive or symptomatic liver disease may warrant evaluation for liver transplantation.

Relevant Anatomy

Please refer to Histologic Findings for information regarding lesion morphology.

Contraindications

Contraindications to specific interventions vary with the planned procedure. Known independent comorbidities or comorbidities directly related to HHT, such as cardiac failure or pulmonary hypertension, may require initial stabilization or be specifically addressed concurrent with intervention.

Workup

Laboratory Studies

CBC count, bleeding time, and coagulation profile findings may exclude a concurrent disorder or coagulopathy.

Imaging Studies

Chest radiograph: Posteroanterior and lateral chest radiographs may reveal a mass of enlarged arteries and veins typical of pulmonary arteriovenous malformation (AVM). Commonly found in the posterior lung bases, these lesions may also be hidden by the diaphragm.

CT scanning: Helical CT scanning has been advocated as a screening method for pulmonary AVM. However, detractors believe the radiation exposure is unnecessary and the cost is prohibitive.

o CT scanning of the head is indicated in the workup of stroke and brain abscess and may reveal AVM.

o Abdominal CT scanning may be useful for liver, kidney, and splenic lesions. Magnetic resonance imaging: MRI or magnetic resonance angiography (MRA) may be

useful, when clinical suspicion is high, in identifying CNS lesions not observed with CT scanning.

Angiography: Preoperative or pre-ablative assessment of pulmonary AVM may warrant angiography for treatment planning. Mesenteric angiography may reveal a bleeding site or mesenteric AVM and facilitate appropriate surgical extirpation. As with other causes of GI bleeding, a hemorrhage rate of at least 1 mL/min is necessary for detection.

o Mesenteric angiography may reveal a bleeding site or mesenteric AVM and facilitate appropriate surgical extirpation. As with other causes of GI bleeding, a hemorrhage rate of at least 1 mL/min is necessary for detection.

o Cerebral angiography may be indicated in the preoperative workup of CNS lesions.

o Nuclear medicine bleeding scanning: GI bleeding of as little as 0.5 mL/min may be detected with technetium Tc 99m–labeled autologous RBC scanning.

Contrast echocardiography: Contrast echocardiography has been shown to reveal pulmonary AVM when pulse oximetry examination or even pulmonary angiography findings were negative. Agitated saline, with its small air bubbles, creates visible contrast that can be observed in the left atrium on echocardiography. The presence of contrast in the left atrium indicates right-to-left shunt. The ability to detect intracardiac shunts is an advantage of this study over other shunt studies.[55 ]

Other Tests

MR (magnetic resonance) angiography: Contrast-enhanced MRI scanning was shown to be appropriate for screening detection of pulmonary AVM. Planning for embolic treatment was possible with 3D reconstructed images.[56 ]

Pulse oximetry: Orthodeoxia may be detected in patients with pulmonary AVM because of increased shunting of blood through lesions in inferior areas of the lung.[57 ]

Oximetry is performed with the patient standing and supine for 10 minutes in each position.

An oxygen saturation level of less than 96% in either position has been considered to indicate further testing.

Screening for pulmonary AVM using pulse oximetry in conjunction with chest radiography has been recommended to be performed once in childhood, once after puberty, before pregnancy, and at 10-year intervals thereafter.[58 ]

Additional shunt studies: Arterial blood gas examination can also be used as a screening test for pulmonary AVM. Technetium Tc 99m–tagged albumin microspheres have also been used for shunt detection.[59 ]

Diagnostic Procedures

Endoscopy and push enteroscopy: Upper and lower GI endoscopy may reveal telangiectases or AVMs. Push enteroscopy allows visualization of proximal small bowel distal to the ligament of Treitz, although this or further intubation of the jejunum is technically demanding. Similarly, a skilled endoscopist can use a colonoscope placed proximal to the ileocecal valve to examine the distal ileum. Visualizing the entire small bowel with push enteroscopy is possible; however, general anesthesia and intraperitoneal access (laparotomy or laparoscopy) is needed to manipulate and thread the small bowel over the endoscope, which has been inserted via the mouth or rectum.

Capsule endoscopy: This innovative relatively recent tool is useful in the evaluation of occult GI bleeding of small bowel origin. Telangiectases from HHT can be visualized with this approach.[60 ]Using the capsule for diagnosis in a series of 18 patients, investigators noted small bowel involvement in patients with known gastric telangiectases in 56% of patients.[61 ]

Histologic Findings

Telangiectases manifest as focal dilatation of the postcapillary venules. Early lesions maintain a portion of intervening capillary bed. Perivascular lymphocytic infiltrate is observed. Fully developed lesions lack an intervening capillary bed. Markedly dilated arterioles and venules connect directly in a tortuous network. The mature lesion also shows lymphocytic infiltrate, as well as multiple layers of thickened smooth-muscle cells around connecting venules.[62 ]

Treatment

Medical Therapy

Epistaxis

Iron supplementation Humidification Packing Transfusion Estrogen therapy Aminocaproic acid

Electrocautery and argon beam ablation ND:YAG laser ablation

Skin lesions

Topical agents Hypertonic saline sclerotherapy Laser ablation

Pulmonary arteriovenous malformation

Multiple bilateral lesions may be treated by embolization via transluminal deployment of a balloon or coil.

Embolization has been shown to be effective in closing shunts and should be weighed with surgery as an option for addressing pulmonary AVM.[42 ]

GI bleeding

Estrogen-progesterone therapy Transfusion Aminocaproic acid Endoscopic photoablation or electrocautery

CNS arteriovenous malformation

Embolotherapy Stereotactic radiosurgery

Further details

Aminocaproic acid blocks the conversion of plasminogen to plasmin and thus acts as a powerful inhibitor of fibrinolysis. Although coagulation is thought to be normal in hemorrhagic telangiectasia (HHT), some investigators believe the cause of bleeding tendency is multifactorial. Increased plasminogen-activator activity has been demonstrated in the telangiectatic vessel walls of some patients with HHT.

Epistaxis is often recurrent, requiring multiple treatments. Severe epistaxis requires surgical treatment. Moderate and mild forms can be treated medically or with endoscopic ablation.

Rebeiz developed a classification for epistaxis that defines mild epistaxis as a few episodes per week without transfusion requirement. Moderate epistaxis is defined as 1-2 episodes per day and requiring fewer than 10 transfusions in the patient's lifetime; the severe form is daily epistaxis lasting longer than 30 minutes and requiring more than 10 transfusions in the patient's lifetime.[63 ]

A small prospective randomized trial (26 patients) from Germany of topical estrogen (0.5mg of 0.1% estriol ointment twice daily) after argon beam coagulation in HHT patients with recurrent epistaxis suggested improved outcome over argon beam coagulation with application of a control ointment.[41 ]

Surgical Therapy

Epistaxis

Patients with recurrent intractable epistaxis despite medical treatment or with severe epistaxis may consider more aggressive intervention. Ablative therapy, for example, with the use of the ND:YAG laser, has been shown to be effective, although multiple treatments are often required.[64 ]Septodermoplasty decreases but does not obviate the need for repeated laser ablation.[65 ]

Pulmonary arteriovenous malformation

Surgical resection can effectively address localized lesions. Diffuse, multiple small AVMs smaller than 1.5 cm can be observed. As with non–HHT AVMs, an enlarging or symptomatic lesion should be resected. Small solitary lesions in a patient with HHT should be considered for resection because of the tendency to enlarge over time. Special consideration is necessary in women planning pregnancy, as progression of pulmonary shunt and fatal rupture has been described.[66 ]

Gastrointestinal bleeding

A distinction is made between the malformations of HHT and lesions of angiodysplasia, both of which tend to manifest with age. The lesions of HHT are most often diffuse, and extensive surgical resection is generally not indicated for episodic bleeding but may be indicated for massive hemorrhage.

Hepatic arteriovenous malformation

Liver transplantation is an option in patients with symptomatic hepatic HHT presenting with life-threatening conditions such as hepatobiliary sepsis and severe cardiopulmonary changes.[67 ]In 40 patients with median 70 month follow-up, patient and graft actuarial survival was 82.5% at 10 years.

Indications for transplantation included cardiac failure (n=14 patients), biliary necrosis with hepatic failure (n=12), severe portal hypertension (n=5), or a combination of 2 or more of these conditions (n=9). Also, a brief report of 2 HHT patients undergoing liver transplantation for cardiac failure was previously published.[68 ]The patients had normal cardiac function 2 and 3 years after transplantation. Hepatic embolization in patients with extensive liver involvement has been discouraged due to potential complications of liver parenchymal or biliary necrosis with ensuing sepsis.[67 ]

Central nervous system arteriovenous malformation

Neurosurgical resection may be indicated in select lesions. Embolotherapy and radiotherapy may be alterative options depending on lesion morphology.

Preoperative Details

Please refer to the following eMedicine articles for further information:

Lower GI Bleeding Upper GI Bleeding Arteriovenous Malformations Intracranial Arteriovenous Malformation Arteriovenous Fistulae, Pulmonary

Follow-up

Long-term, systematic follow-up is indicated. Known lesions may recur or progress and new manifestations of the syndrome may develop over time.

Children who have a parent with HHT carry a 50% chance of harboring the same genetic mutation. Pulmonary AVM screening and long-term follow-up is advocated beginning in childhood.[69 ]

Complications

Identification of pulmonary and cerebral arteriovenous malformations (AVMs) may prevent hemorrhagic or embolic complications that can be devastating. Most interventions can be accomplished via catheter-based therapies that obviate the need for surgical intervention, such as thoracotomy or craniotomy. Either approach, however, has risks, including death or stroke. Therefore, when identified, optimal management of AVMs may require a multidisciplinary approach.

Similarly, syndromes resulting from severe hepatic disease, such as encephalopathy, portal hypertension, and heart failure may require cooperation between many disciplines for example, cardiology, gastroenterology, interventional radiology, and transplant surgery.

A greater awareness of hemorrhagic telangiectasia (HHT) may improve early diagnosis and detection of visceral involvement before significant clinical complications occur.

Outcome and Prognosis

Despite varied and progressive manifestations of the syndrome the majority of hemorrhagic telangiectasia (HHT) patients have a normal life expectancy. A small increase in mortality is

seen in patients presenting at a younger age (less than 60 y) with severe HHT symptoms due to visceral involvement.[17 ]

Future and Controversies

Prospective trials that determine ideal management of hemorrhagic telangiectasia (HHT) are limited by the small and varied population and by the multiorgan nature of the disease. A coordinated team approach is recommended.

Screening for pulmonary arteriovenous malformation (AVM) continues to generate controversy, with helical CT scanning being advocated by some investigators and chest radiographs with pulse oximetry being advocated by others. Contrast echocardiography has also proven effective and has the advantage of identifying intracardiac shunts, whereas arterial blood gases or pulse oximetry shunt studies do not. Contrast echocardiography is noninvasive and has been shown to be highly sensitive.[55 ]MR angiography provides an additional alternative that appears highly effective in detecting lesions as well as planning for intervention.[56 ]Multiple studies would likely be complimentary.

Work in identification of specific gene mutations continues, and multiple distinct mutations involving at least 4 specific genes are described.[70 ]Early diagnosis of family members or confirmation with genetic testing of patients who fulfill Curaçao criteria may assist in the identification of those patients most at risk for specific sequelae. Participation in research and clinical trials, when available, will aid in discovery or clarification of the most appropriate interventions for this disease.

Recent preclinical work targeting the endoglin protein, also called CD-105, has shown promising results in cancer-related research.[71 ]Such studies may complement concurrent HHT–specific research in developing new therapies.

Multimedia

Media file 1: Typical symptoms in a patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the cheeks.

Media file 2: Close-up view of typical symptoms of patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the lips.

Media file 3: Close-up view of typical symptoms in a patient with Osler-Weber-Rendu syndrome with red nodules and starry telangiectasia on the cheeks.

References

1. Sutton HG. Epistaxis as an indication of impaired nutrition, and of degeneration of the vascular system. Med Mirror. 1864;769-81.

2. Babington BG. Hereditary epistaxis. Lancet. 1865;362-363.3. Rendu M. Epistaxis repetees chez un sujet porteur de petits angiomes cutanes et

muquex. Bull Mem Soc Med Hop Paris. 1896;13:731.4. Osler W. On a family form of recurring epistaxis associated with multiple telangiectases

of the skin and mucous membranes. Bull Johns Hopkins Hosp. 1901;12:333-7.5. Weber FP. Multiple hereditary developmental angiomata (telangiectases) of the skin and

mucous membranes associated with recurring haemorrhages. Lancet. 1907;ii:160-2.6. Hanes FM. Multiple hereditary telangiectasis causing hemorrhage (hereditary

hemorrhagic telangiectasia). Bull Johns Hopkins Hosp. 1909;20:63-73.7. Shepherd JA. Angiomatous conditions of the gastro-intestinal tract. Br J

Surg. Mar 1953;40(163):409-21. [Medline].8. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N

Engl J Med. Oct 5 1995;333(14):918-24. [Medline].9. Haitjema TJ, van Snippenburg R, Disch FJ, Overtoom TT, Westermann CJ. [Recurrent

epistaxis: sometimes Rendu-Osler-Weber disease]. Ned Tijdschr Geneeskd. Nov 2 1996;140(44):2157-60. [Medline].

10. 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. Mar 1989;32(3):291-7. [Medline].

11. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. Aug 1992;29(8):527-30. [Medline].

12. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu- Osler-Weber syndrome). Am J Med Genet. Mar 6 2000;91(1):66-7. [Medline].

13. Shovlin CL, Hughes JM. Hereditary hemorrhagic telangiectasia. N Engl J Med. Feb 1 1996;334(5):330-1; discussion 331-2. [Medline].

14. Shovlin CL, Letarte M. Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax. Aug 1999;54(8):714-29. [Medline].

15. Cole SG, Begbie ME, Wallace GM, et al. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet. Jul 2005;42(7):577-82. [Medline].

16. Schoen FJ. Cotran RS, Vinay K, Collins T. Robbins Pathologic Basis of Disease. 5th. WB Saunders; 1994:509.

17. Kjeldsen AD, Oxhoj H, Andersen PE, et al. Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia. Chest. Aug 1999;116(2):432-9. [Medline].

18. Dakeishi M, Shioya T, Wada Y, et al. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat. Feb 2002;19(2):140-8. [Medline].

19. Jessurun GA, Kamphuis DJ, van der Zande FH, et al. Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations. Clin Neurol Neurosurg. Sep 1993;95(3):193-8. [Medline].

20. 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 A. Feb 1 2003;116A(4):324-8. [Medline].

21. Vase P, Grove O. Gastrointestinal lesions in hereditary hemorrhagic telangiectasia. Gastroenterology. Nov 1986;91(5):1079-83. [Medline].

22. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. Dec 1994;8(4):345-51. [Medline].

23. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. Jun 1996;13(2):189-95. [Medline].

24. 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. Mar 13 2004;363(9412):852-9. [Medline].

25. Braverman IM, Keh A, Jacobson BS. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol. Oct 1990;95(4):422-7. [Medline].

26. van Laake LW, van den Driesche S, Post S, Feijen A, Jansen MA, Driessens MH, et al. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation. Nov 21 2006;114(21):2288-97. [Medline].

27. Fernandez-L A, Garrido-Martin EM, Sanz-Rodriguez F, Pericacho M, Rodriguez-Barbero A, Eleno N, et al. Gene expression fingerprinting for human hereditary hemorrhagic telangiectasia. Hum Mol Genet. Jul 1 2007;16(13):1515-33. [Medline].

28. Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J. Jan 2003;79(927):18-24. [Medline].

29. Fulbright RK, Chaloupka JC, Putman CM, et al. MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol. Mar 1998;19(3):477-84. [Medline].

30. Romer W, Burk M, Schneider W. [Hereditary hemorrhagic telangiectasia (Osler's disease)]. Dtsch Med Wochenschr. Apr 24 1992;117(17):669-75. [Medline].

31. AAssar OS, Friedman CM, White RI Jr. The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. Sep 1991;101(9):977-80. [Medline].

32. Garcia-Monaco R, Taylor W, Rodesch G, et al. Pial arteriovenous fistula in children as presenting manifestation of Rendu-Osler-Weber disease. Neuroradiology. Jan 1995;37(1):60-4. [Medline].

33. Krings T, Chng SM, Ozanne A, Alvarez H, Rodesch G, Lasjaunias PL. Hereditary hemorrhagic telangiectasia in children: endovascular treatment of neurovascular malformations: results in 31 patients. Neuroradiology. Dec 2005;47(12):946-54. [Medline].

34. Easey AJ, Wallace GM, Hughes JM, et al. Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations? Data from 22,061 years of HHT patient life. J Neurol Neurosurg Psychiatry. Jun 2003;74(6):743-8. [Medline].

35. Maher CO, Piepgras DG, Brown RD Jr, et al. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke. Apr 2001;32(4):877-82. [Medline].

36. Cloft HJ. Spontaneous regression of cerebral arteriovenous malformation in hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol. Jun-Jul 2002;23(6):1049-50. [Medline].

37. Du R, Hashimoto T, Tihan T, et al. Growth and regression of arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia. Case report. J Neurosurg. Mar 2007;106(3):470-7. [Medline].

38. Leung KM, Agid R, terBrugge K. Spontaneous regression of a cerebral arteriovenous malformation in a child with hereditary hemorrhagic telangiectasia. Case report. J Neurosurg. Nov 2006;105(5 Suppl):428-31. [Medline].

39. Press OW, Ramsey PG. Central nervous system infections associated with hereditary hemorrhagic telangiectasia. Am J Med. Jul 1984;77(1):86-92. [Medline].

40. White RI Jr, Lynch-Nyhan A, Terry P, et al. Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy. Radiology. Dec 1988;169(3):663-9. [Medline].

41. 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. Mar 1996;33(3):256-7. [Medline].

42. Cottin V, Chinet T, Lavolé A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore). Jan 2007;86(1):1-17. [Medline].

43. Pierucci P, Murphy J, Henderson KJ, et al. New definition and natural history of patients with diffuse pulmonary arteriovenous malformations: twenty-seven-year experience. Chest. Mar 2008;133(3):653-61. [Medline].

44. 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. Aug 2 2001;345(5):325-34. [Medline].

45. Proctor DD, Henderson KJ, Dziura JD, Longacre AV, White RI Jr. Enteroscopic evaluation of the gastrointestinal tract in symptomatic patients with hereditary hemorrhagic telangiectasia. J Clin Gastroenterol. Feb 2005;39(2):115-9. [Medline].

46. Abdalla SA, Geisthoff UW, Bonneau D, et al. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. J Med Genet. Jul 2003;40(7):494-502. [Medline].

47. van Cutsem E, Rutgeerts P, Vantrappen G. Treatment of bleeding gastrointestinal vascular malformations with oestrogen-progesterone. Lancet. Apr 21 1990;335(8695):953-5. [Medline].

48. Wu JS, Saluja S, Garcia-Tsao G, et al. Liver involvement in hereditary hemorrhagic telangiectasia: CT and clinical findings do not correlate in symptomatic patients. AJR Am J Roentgenol. Oct 2006;187(4):W399-405. [Medline].

49. Garcia-Tsao G. Liver involvement in hereditary hemorrhagic telangiectasia (HHT). J Hepatol. Mar 2007;46(3):499-507. [Medline].

50. Larson AM. Liver disease in hereditary hemorrhagic telangiectasia. J Clin Gastroenterol. Feb 2003;36(2):149-58. [Medline].

51. Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. Sep 28 2000;343(13):931-6. [Medline].

52. Alizad A, Seward JB. Echocardiographic features of genetic diseases: part 3. Shunts. J Am Soc Echocardiogr. Mar 2000;13(3):248-53. [Medline].

53. Shovlin CL, Sodhi V, McCarthy A, Lasjaunias P, Jackson JE, Sheppard MN. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG. Aug 2008;115(9):1108-15. [Medline].

54. Gershon AS, Faughnan ME, Chon KS, et al. Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy. Chest. Feb 2001;119(2):470-7. [Medline].

55. Nanthakumar K, Graham AT, Robinson TI, et al. Contrast echocardiography for detection of pulmonary arteriovenous malformations. Am Heart J. Feb 2001;141(2):243-6. [Medline].

56. Schneider G, Uder M, Koehler M, et al. MR angiography for detection of pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. AJR Am J Roentgenol. Apr 2008;190(4):892-901. [Medline].

57. Robin ED, Laman D, Horn BR, et al. Platypnea related to orthodeoxia caused by true vascular lung shunts. N Engl J Med. Apr 22 1976;294(17):941-3. [Medline].

58. Faughnan ME, Hyland RH, Nanthakumar K, et al. Screening in hereditary hemorrhagic telangiectasia patients. Chest. Aug 2000;118(2):566-7. [Medline].

59. Thompson RD, Jackson J, Peters AM, et al. Sensitivity and specificity of radioisotope right-left shunt measurements and pulse oximetry for the early detection of pulmonary arteriovenous malformations. Chest. Jan 1999;115(1):109-13. [Medline].

60. Hahne M, Riemann JF. Vascular Abnormalities. In: Atlas of Capsule Endoscopy. Given Imaging; 2002:Ch 7, 73-81.

61. Ingrosso M, Sabbà C, Pisani A, et al. Evidence of small-bowel involvement in hereditary hemorrhagic telangiectasia: a capsule-endoscopic study. Endoscopy. Dec 2004;36(12):1074-9. [Medline].

62. Jacobson BS. Hereditary hemorrhagic telangiectasia: A model for blood vessel growth and enlargement. Am J Pathol. Mar 2000;156(3):737-42. [Medline].

63. Rebeiz EE, Bryan DJ, Ehrlichman RJ, et al. Surgical management of life-threatening epistaxis in Osler-Weber-Rendu disease. Ann Plast Surg. Aug 1995;35(2):208-13. [Medline].

64. Shah RK, Dhingra JK, Shapshay SM. Hereditary hemorrhagic telangiectasia: a review of 76 cases. Laryngoscope. May 2002;112(5):767-73. [Medline].

65. Harvey RJ, Kanagalingam J, Lund VJ. The impact of septodermoplasty and potassium-titanyl-phosphate (KTP) laser therapy in the treatment of hereditary hemorrhagic telangiectasia-related epistaxis. Am J Rhinol. Mar-Apr 2008;22(2):182-7. [Medline].

66. Shovlin CL, Winstock AR, Peters AM, et al. Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. QJM. Dec 1995;88(12):879-87. [Medline].

67. Lerut J, Orlando G, Adam R, et al. Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European liver transplant registry. Ann Surg. Dec 2006;244(6):854-62; discussion 862-4. [Medline].

68. Thevenot T, Vanlemmens C, Di Martino V, Becker MC, Denue PO, Kantelip B, et al. Liver transplantation for cardiac failure in patients with hereditary hemorrhagic telangiectasia. Liver Transpl. Jul 2005;11(7):834-8. [Medline].

69. Curie A, Lesca G, Cottin V, et al. Long-term follow-up in 12 children with pulmonary arteriovenous malformations: confirmation of hereditary hemorrhagic telangiectasia in all cases. J Pediatr. Sep 2007;151(3):299-306. [Medline].

70. Gedge F, McDonald J, Phansalkar A, et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. Apr 2007;9(2):258-65. [Medline].

71. Dallas NA, Samuel S, Xia L, et al. Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clin Cancer Res. Apr 1 2008;14(7):1931-7. [Medline].

72. Checketts SR, Burton PS, Bjorkman DJ, et al. Generalized essential telangiectasia in the presence of gastrointestinal bleeding. J Am Acad Dermatol. Aug 1997;37(2 Pt 2):321-5. [Medline].

73. Dhingra JK, Shah RK, Shapshay SM. Hereditary Hemorrhagic Telangiectasia: A Review of 67 Cases. American Laryngological, Rhinological and Otological Soc. Jan 2000.

74. Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med. Jan 1999;245(1):31-9. [Medline].

75. Kjeldsen AD, Vase P, Oxhoj H. Hereditary hemorrhagic telangiectasia. N Engl J Med. Feb 1 1996;334(5):331-2. [Medline].

76. Marchuk DA. The molecular genetics of hereditary hemorrhagic telangiectasia. Chest. Jun 1997;111(6 Suppl):79S-82S. [Medline].

77. Moussouttas M, Fayad P, Rosenblatt M, et al. Pulmonary arteriovenous malformations: cerebral ischemia and neurologic manifestations. Neurology. Oct 10 2000;55(7):959-64. [Medline].

78. Saba HI, Morelli GA, Logrono LA. Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med. Jun 23 1994;330(25):1789-90. [Medline].

Keywords

Osler-Weber-Rendu disease, OWRD, Osler-Weber-Rendu syndrome, OWRS, hereditary hemorrhagic telangiectasia, HHT, Rendu-Osler-Weber disease, ROWD, pulmonary arterial venous malformation, PAVM, epistaxis, nosebleed, gastrointestinal bleeding, GI bleeding, contrast echocardiography, activin receptor-like kinase 1, ALK-1, endoglin, ENG, HHT-juvenile polyposis overlap syndrome, JPHT