Osler-Weber-Rendu Disease (Hereditary Hemorrhagic Telangiectasia)

Updated: May 15, 2017
  • Author: Klaus-Dieter Lessnau, MD, FCCP; Chief Editor: Vincent Lopez Rowe, MD  more...
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Overview

Background

Osler-Weber-Rendu disease (OWRD) is a rare autosomal dominant disorder that affects blood vessels throughout the body (causing vascular dysplasia) and results in a tendency for bleeding. (The condition is also known as hereditary hemorrhagic telangiectasia [HHT]; the two terms are used interchangeably in this article.) The prognosis varies, depending on the severity of symptoms; generally, it is good, as long as bleeding is promptly recognized and adequately controlled.

HHT is manifested by mucocutaneous telangiectases and arteriovenous malformations (AVMs), a potential source of serious morbidity and mortality. [1] Lesions can affect the nasopharynx, central nervous system (CNS), lung, liver, and spleen, as well as the urinary tract, gastrointestinal (GI) tract, conjunctiva, trunk, arms, and fingers. [2, 3] Recurrent and severe epistaxis is the most common presentation, frequently leading to severe anemia that necessitates transfusion. [4] GI bleeding is also prevalent. [3, 5] Symptom onset may be delayed until the fourth decade of life (~90% of patients manifest by age 40 years) or later. [6, 7, 8]

The diagnosis of HHT is made clinically on the basis of the Curaçao criteria, established in June 1999 by the Scientific Advisory Board of the HHT Foundation International, Inc. [9] The four clinical diagnostic criteria are as follows:

  • Epistaxis
  • Telangiectasias
  • Visceral lesions
  • Family history (a first-degree relative with HHT)

The HHT diagnosis is classified as definite if three or four criteria are present, possible or suspected if two criteria are present, and unlikely if fewer than two criteria are present. (See DDx.)

The presentation of HHT can be highly variable among families and even within the same family. [10, 11, 9] Cutaneous findings may be subtle; epistaxis, the most common overt feature, is also common in the general population. There is no firm consensus on the number of episodes or degree of epistaxis necessary for diagnosis; according to the Curaçao criteria, nosebleeds should occur spontaneously on more than one occasion, and night-time bleeding should be considered especially suspicious. [9] (See Presentation.)

Genetic testing of OWRD patients and their family members can confirm the presence of mutations within implicated genes, most commonly the endoglin gene (ENG) in chromosome 9 or the activin receptorlike kinase type I (ALK-1) gene (ALK1) in chromosome 12 (involved in HHT type 1 and type 2, respectively). [4, 12, 13] Both ENG and ALK-1 encode putative receptors for the transforming growth factor-beta (TGF-β) superfamily that play a critical role for the proper development of the blood vessels. [14] Mutations in SMAD4 have also been identified in a subset of patients with a combined syndrome of HHT and juvenile poliposis. [14]

Screening family members for signs of OWRD is reasonable and should include a complete history, physical examination, chest radiography, and arterial blood gas testing (with measurement of the shunt fraction). (See Workup.)

Indications for intervention in OWRD vary according to site of involvement and presentation. In mild cases, no treatment is necessary. In more severe cases, treatment consists of management of bleeding via both medical and surgical options, as well as surgical management of AVMs and further sequelae. (See Treatment.)

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Pathophysiology

OWRD (ie, HHT) is the first identified human disease caused by defects in a TGF-β superfamily receptor. [14, 15] The clinical manifestations of OWRD are caused by the development of abnormal vasculature, including telangiectasias, AVMs, and aneurysms. Unaffected areas show normal vessel architecture on ultrastructural analysis. [16] Thus, researchers postulate that an initiating event combined with abnormal repair results in the lesions. [17]

Defects in the endothelial cell junctions, endothelial cell degeneration, and weakness of the perivascular connective tissue are thought to cause dilation of capillaries and postcapillary venules, which manifest as telangiectasias. Most commonly, telangiectasias involve the mucous membranes, as well as the skin, the conjunctiva, the retina, and the GI tract.

AVMs are abnormal tortuous vessels with both arterial and venous components. Larger AVMs can cause left-to-right shunting and, if sufficiently large, may contribute to high-output heart failure. Loss of the muscularis layer and disturbance of the elastic lamina of vessel walls may also give rise to aneurysms in multiple organ systems. AVMs are found in the lungs, brain, and liver.

Telangiectases and AVM bleeding tendency are attributed to localized vessel wall weakness, in part due to abnormal remodeling resulting from an imbalance in functions related to TGF-β. [11] Interactions with TGF-β 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 the following [18] :

  • Angiogenesis
  • Cytoskeletal integrity
  • Cell migration
  • Proliferation
  • Nitric oxide synthesis

HHT has been classified into the following four types, though more may exist:

  • HHT type 1
  • HHT type 2
  • HHT type 3
  • HHT−juvenile polyposis overlap syndrome (JPHT)

The genes most commonly implicated in HHT are the endoglin gene (ENG; HHT type 1) and the ALK-1 gene (ALK1; HHT type 2); other genes are less frequently involved (see Etiology). [19] Endoglin and ALK-1 are type III and type I TGF-β receptors, and both are exclusively expressed on vascular endothelial cells.

The binding of TGF-β to the type II TGF-β receptor on endothelial cells, which is accelerated in the presence of endoglin, results in the phosphorylation of the type I TGF-β receptors ALK-5 and ALK-1. Endoglin and ALK-1 bind directly to bone morphogenetic protein (BMP)-9 and BMP-10 and mediate their defects in conjunction with the type II BMP receptor (BMPR II). [20, 21] Phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively. [22]

The activated Smad proteins dissociate from the type I TGF-β receptor, bind to Smad4, and enter the nucleus to transmit TGF-β signals by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between the two signaling pathways involving ALK-5 and ALK-1 is important in determining the properties of endothelial cells during angiogenesis.

Histopathologic studies reveal large, irregular, thinly walled blood vessels, but the pathogenesis has not been fully established. One theory states that systemic nevus vascular damage may not be equally expressed in all individuals with HHT. Individuals with blood group type O are affected more often, whereas males and females are affected equally. Coagulation abnormalities and increased fibrinolytic activity in the lesions may contribute to the tendency for bleeding.

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Etiology

OWRD (ie, HHT) is a disorder that is inherited in an autosomal dominant fashion, [23, 24] though 20% of patients are unaware of a positive family history, partly because the lesions may be minimal and because 10% of patients have no episodes of bleeding. The homozygous condition probably is fatal.

HHT is attributed to genetic mutations that involve signaling of TGF-β. [11] Defects in at least four genes are implicated in its development, [25]  as follows:

  • Mutations of ENG (encoding endoglin) - These characterize HHT type 1 and involve chromosome 9, 9q33-34 [26]
  • Mutations of ALK1 (encoding ALK-1), also called ACVRL1 (activin A receptor kinase type II-like 1) - These are implicated in HHT type 2 and involve chromosome 12, 12q13 [27]
  • Mutations of chromosome 5 (5q31.1-32) - These are distinct from hereditary benign telangiectasia (HBT), a gene defect in RASA1 (chromosome 5q14) [12]
  • Mutations of SMAD4/MADH4 (encoding Smad4) - These are described in JPHT, [28, 29] which is also autosomal dominant, involves chromosome 18, and combines clinical manifestations of HHT and juvenile polyposis

The first two (HHT types 1 and 2) account for approximately 85% of cases.

In addition, some families show no links to any of the known loci. One patient with HHT and pulmonary hypertension with no mutation in ENG, ACVRL1, or SMAD4 but was found to have a nonsense mutation in BMPR2. [30]

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Epidemiology

United States statistics

OWRD (ie, HHT) is rare in North America. The reported incidence is 1-2 cases per 100,000 population annually. The overall prevalence is estimated to be approximately 1-2 cases per 10,000 population. However, the prevalence may be underestimated because many cases may be asymptomatic. [31] In Vermont, the frequency has been estimated at 1 case per 16,500 population. [2] The disease has a clinical penetrance of 97%.

International statistics

The worldwide prevalence is 1 case per 5000-10,000 population In Europe and Japan, the frequency is estimated to be between 1 in 5000 to 8000 people. [4, 14, 32, 33] The prevalence of HHT in a Danish population increased from 13.8 cases per 100,000 population in 1974 to 15.6 cases per 100,000 population in 1995. [34]

The frequency 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 1331 persons in the Curaçao and Bonaire regions. [35, 36] In the French department of Ain, the prevalence is 1 case per 2351 persons; in France overall, it is 1 per 8345. [6] Other examples include the Danish island of Funen (1 per 3500) and northern England (1 per 39,216). [37, 7]

Age-, sex-, and race-related demographics

HHT may occur in children, in whom a tendency to bleed may be the first symptom. [38] However, it is far more common during puberty or adulthood. The syndrome most often manifests by the second or third decade of life, though it may also be clinically silent. Pulmonary AVMs may be congenital and therefore may present within the first year of life. The risk of GI tract bleeding increases in patients older than 50 years.

HHT occurs with equal frequency and severity in males and females. [39] Although it most commonly occurs in whites, it has a wide geographic distribution and has been described in people of Asian, African, and Arabic descent.

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Prognosis

Overall, life expectancy appears to be shortened by OWRD (ie, HHT) [40] ; nevertheless, with appropriate screening and aggressive management, life expectancy for the majority of patients may approach that of the normal population. Mortality shows an early peak at age 50 years and a later peak at 60-79 years related to acute complications. [32]

The prognosis is highly dependent on the severity of the disease—in particular, on the degree of systemic involvement, especially pulmonary, hepatic, and CNS involvement. Only 10% of patients die of complications of HHT.

The prevalence of brain AVM in HHT1 patients is 1000-fold higher than the prevalence in the general population (10 in 100,000), and in HHT2 patients it is 100-fold higher. [15] Pulmonary and CNS arteriovenous aneurysms may appear later in life. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract. Other sites of bleeding may include sites in the kidney, spleen, bladder, liver, meninges, and brain.

Strokes may be either hemorrhagic or ischemic. Of patients who have pulmonary AVMs, 2% per year are estimated to have a stroke, and 1% per year are estimated to develop a brain abscess. Retinal arteriovenous aneurysms occur only rarely. Patients are also at risk for high-output cardiac failure, migraines and further sequelae.

Frequent nosebleeds and melena may result from telangiectasia in the nose and GI tract. Patients with the severe form of HHT have heavy bleeding and resultant iron-deficiency anemia. Recurrent epistaxis is observed in as many as 90% of patients. In half the patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients.

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