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 Disability Information - Osler-Weber-Rendu Syndrome also known as Hereditary Hemorrhagic Telangiectasia (HHT)

 

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 General Information

Hereditary hemorrhagic telangiectasia, also known as HHT or Osler-Weber-Rendu syndrome, is inherited as an autosomal dominant trait. Affected children develop red or reddish-purple collections of abnormal blood vessels called telangiectases (spider-like, macular, or papular spots).

The telangiectases can be seen on the lips and tongue and the nasal mucosa. Other areas such as the face and ears may be involved and internal vascular abnormalities can occur in the brain, lungs, throat and larynx, gastrointestinal tract, liver, bladder, and vagina.

Frequent nosebleeds in children may be an early sign but the easily visible, characteristic vascular lesions (telangiectases) on the tongue and lips may not appear until puberty. The telangiectases bleed easily. Bleeding into the head (brain hemorrhage, stroke) may cause varied neurological symptoms such as seizures. If severe, this brain hemorrhage may be fatal.

Some patients only discover that they have this condition when they cough up blood and a chest X-ray shows an abnormality called an arterio-venous malformation. Some patients have enough large or multiple arterio-venous malformations in the lungs to cause shortness of breath.

   

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The HHT Foundation was formed in 1990 to aid and support persons with Hereditary Hemorrhagic Telangiectasia (HHT) also known as Osler-Weber-Rendu Syndrome; to provide patients, families and doctors with educational information; to foster an exchange of information about the diagnosis and treatment of HHT between patients, physicians, researchers, genetic counselors, charitable organizations, government agencies, industry, academic institutions and the general public; to raise funds for genetic and clinical research and for sponsoring special scholarships for studies pertaining to HHT.  Visit the HHT Foundation online at http://www.hht.org/web/.

 

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 Medical Information

Osler-Weber-Rendu Syndrome

http://www.emedicine.com/ped/topic1668.htm
Author: Norman A Silver, MD, Assistant Professor, Department of Emergency Medicine, University of Manitoba, Winnipeg, Canada
Coauthor(s): Kent Stobart, MD, MSc, FRCPC, Associate Professor, Department of Pediatrics, Stollery Children's Hospital

INTRODUCTION

 

Background: Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia, is an autosomal dominant disorder identified typically by the triad of telangiectasia, recurrent epistaxis, and a positive family history for the disorder. The major cause of morbidity and mortality due to this disorder lies in the presence of multiorgan arteriovenous malformations (AVMs) and the associated hemorrhage that may accompany them. The disease has a wide spectrum of presentations; patients may be asymptomatic or have multiple organ involvement, presenting at any age. Treatment mainly is supportive and consists of controlling and treating the bleeding. The prognosis of the disease is good as long as bleeding is promptly recognized and adequately controlled.

Pathophysiology: The clinical manifestations of Osler-Weber-Rendu disease are caused by the development of abnormal vasculature, including telangiectases, AVMs, and aneurysms. The main defect in some families is in the mutation of the protein endoglin, a receptor for transforming growth factor beta, which has a role in tissue repair and angiogenesis. 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 telangiectases.

Clinically, nasal telangiectasia is more likely to bleed than the cutaneous telangiectasia. This may be because of stronger tissue-supporting telangiectases in the skin, as opposed to the relatively weak mucous membranes. AVMs are abnormal tortuous vessels with both arterial and venous components. The larger AVMs can cause some left-to-right shunting and, if sufficiently large, may contribute to high-output cardiac failure. Loss of the muscularis layer and disturbance of the elastic lamina of vessel walls may give rise to aneurysms in multiple organ systems. Most commonly, telangiectases involve the mucous membranes, the skin, the conjunctiva, the retina, and the GI tract. AVMs are found in the lungs, brain, and liver.


Frequency:

In the US: Prevalence is 1-2 cases per 100,000 population.
Internationally: The worldwide prevalence is 1-2 cases per 100,000 population, with a much higher incidence in the Danish island of Fyn, the Dutch Antilles, and parts of France.
Mortality/Morbidity: Patients are at risk for hemorrhage from multiple sites (especially the nasal mucosa), pulmonary hemorrhage, high-output cardiac failure, ischemic stroke, migraines, and paradoxical emboli. Fewer than 10% of patients die of complications of the disease.

Hemorrhage: Recurrent epistaxis is observed in 50-80% of patients. In half of the patients, the epistaxis becomes more serious with age, and blood transfusions are required in 10-30% of patients. Patients with pulmonary AVMs and telangiectasis of the GI tract are at risk for life-threatening hemorrhage of the lungs and GI tract.
Stroke: Strokes in patients with Osler-Weber-Rendu disease may be either hemorrhagic or ischemic. Hemorrhagic strokes are due to cerebral AVMs. Ischemic strokes are due to pulmonary AVMs, which, in addition to strokes, contribute to an increased incidence of brain abscesses. 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.
High-output cardiac failure: Uncommonly, large AVMs develop in the liver. This can cause a substantial left-to-right shunt and place a patient in cardiac failure.
Race: The disease most commonly occurs in white patients, but it has been described in patients of Asian, African, and Arabic descent.

Sex: The syndrome occurs with equal frequency and severity in both sexes.

Age: The syndrome most often presents by the third decade of life but may be clinically silent.  The most common presentation is recurrent epistaxis, which often develops prior to the second decade of life.  Pulmonary AVMs may be congenital and, therefore, diagnosed within the first year of life.

CLINICAL
 

History: Because Osler-Weber-Rendu syndrome is an autosomal dominant disease, a family history of telangiectasia and recurrent bleeding in other family members is usually present. Symptoms vary depending on the area of involvement. The main areas of involvement are the nasal mucosa, skin, the GI tract, the pulmonary vasculature, and the brain.

Nasal mucosa: Epistaxis is the most common manifestation of the disease and occurs in up to 90% of affected patients. Bleeding may occur as often as every day or as infrequently as once a month. Patients with epistaxis initially present before the second decade of life. Blood transfusions are required in 10-30% of patients.
GI tract: Recurrent painless GI bleeding occurs in 10-40% of patients and generally occurs later in life than epistaxis; typically, GI bleeding occurs around the fourth or fifth decades of life. Patients may report abdominal pain that may be due to thrombosis of alimentary AVMs.
Pulmonary vasculature
Pulmonary AVMs are present in 15-20% of patients with the disease. Half of the patients with pulmonary AVMs are asymptomatic. Dyspnea and exercise intolerance may be elicited from history. Pulmonary AVMs may cause enough right-to-left shunting to cause cyanosis, hypoxemia, and secondary polycythemia.
Hemoptysis results from either telangiectasia of the trachea and bronchi or pulmonary arteriovenous (AV) fistulas. Patients usually present around the third or fourth decades of life.
Migraine headaches are present in 50% of patients with Osler-Weber-Rendu syndrome. Although the reason is unclear, the headaches seem to be associated with pulmonary AVMs.
Brain involvement
Neurologic involvement occurs in 8-12% of patients with Osler-Weber Rendu syndrome. A history of headache, seizures, and focal neurologic symptoms may be found on questioning. An area of ischemic brain surrounding a cerebral AVM or an intracerebral hematoma may cause these symptoms.
Stroke and brain abscess are more common in patients with Osler-Weber-Rendu syndrome compared to the healthy population. This is due to loss of the normal filtering function of the pulmonary vasculature in patients with pulmonary AVMs. These AVMs allow thrombotic and septic emboli to travel to the brain. Untreated patients have a 2% risk of stroke and a 1% risk of brain abscess per year.
Fatigue: Fatigue may be elicited on history and may be due to an iron deficiency anemia caused by recurrent blood loss.
Visual disturbances: Visual disturbances may be noted, possibly caused by intraocular hemorrhage. Patients may notice bloody tears, which are due to conjunctival telangiectases.
Liver involvement: Liver involvement may cause right upper quadrant (RUQ) pain, jaundice, symptoms of high-output cardiac failure, and bleeding from esophageal varices. The cardiac failure is caused by a large left-to-right shunt that can occur between the hepatic arteries and veins. Occasionally, patients with Osler-Weber-Rendu syndrome may present with atypical cirrhosis.
Physical: The areas involved dictate the signs that may be found on physical examination.

Skin
The most obvious finding on physical examination is telangiectases. These may be found on the oral mucosa, nasal mucosa, skin, and conjunctiva.
Cyanosis and clubbing may be present in patients with pulmonary AVMs. These develop because of right-to-left shunting.
Liver involvement can cause jaundice.
CNS: If a previous stroke, brain abscess, or intracerebral hematoma has occurred, patients may present with focal neurologic signs.
Respiratory system: In the presence of pulmonary AVMs, the patient may be tachypneic, cyanotic, and have clubbing. A pulmonary bruit may be heard best on inspiration.
Cardiovascular system: Patients may be cyanotic because of right-to-left pulmonary shunting or pale because of anemia. Patients may have a hyperdynamic circulation if they have hepatic involvement and a large left-to-right shunt. Hyperdynamic circulation may be exacerbated by anemia.
GI system
Examination of the oral mucosa reveals telangiectases in 58-79% of patients. Rectal examination may reveal frank blood.
Signs of liver involvement include jaundice, hepatomegaly, and a RUQ bruit or thrill.
Eyes: Funduscopic examination may reveal retinal telangiectasis and hemorrhages. Bloody tears may be present because of conjunctival telangiectases.
Causes: The disease is caused by an inherited defect. Currently 2 loci have been identified associated with Osler-Weber-Rendu syndrome, one on chromosome arm 9q33-q34 and a second on chromosome arm 12q. Chromosome arm 9q34 harbors the endoglin gene, which encodes for a homodimeric integral membrane glycoprotein expressed at high levels on human vascular endothelial cells. Several mutations of the endoglin gene have been reported in family members affected with Osler-Weber- Rendu syndrome. Chromosome arm 12q harbors the activin receptorlike kinase 1 (ALK1), which encodes for a surface receptor for the transforming growth factor beta superfamily of ligands. Several families with Osler-Weber-Rendu syndrome harbor mutations of ALK1.

Other Problems to be Considered:

Crest syndrome
Louis-Bar syndrome
Ataxia-telangiectasia
Essential telangiectasia
Acne rosacea
Actinically damaged skin
Dermatomyositis
Rothmund-Thomson syndrome
Scleroderma

Lab Studies:

Currently, no widely available laboratory studies exist to confirm the diagnosis of Osler-Weber-Rendu syndrome. In some large centers, a genetic test is available that tests for mutations in the endoglin gene found on chromosome 9 and the activin receptorlike kinase gene found on chromosome 12. However, some laboratory tests may be helpful in identifying some complications of Osler-Weber-Rendu.
Complete blood cell count
Hemoglobin may be decreased because of chronic bleeding and iron deficiency anemia, or the patient may be polycythemic because of chronic hypoxemia from a right-to-left shunt.
Platelets may be normal or slightly increased.
The white blood cell count should be within the reference range unless an infectious complication, such as a brain abscess, is present.
Prothrombin time and activated partial thromboplastin time: These results should be normal, unless severe liver involvement is present.
Arterial blood gas
If a right-to-left shunt is present, the pO2 is low.
Performing a hyperoxic test with the arterial blood gas confirms the diagnosis of a right-to-left shunt. A minor increase in the arterial partial pressure of oxygen while the patient is on 100% oxygen indicates the presence of a shunt. In the absence of a shunt, the arterial partial pressure of oxygen should increase to a much larger extent.
Screening with a hyperoxic test is shown to have 100% sensitivity and 40% specificity for the detection of pulmonary AVMs in patients with Osler-Weber-Rendu syndrome who are suspected of having an AVM.
 

Imaging Studies:

Imaging studies can be useful in diagnosing the vascular malformations found in Osler-Weber-Rendu syndrome as well as complications such as brain abscess. MRI scanning is the best imaging study and, if it is readily available, may be the only test needed.
If a pulmonary AVM is present, chest radiography may show a peripheral noncalcified coin lesion attached by vascular strands to the hilus.
CT scanning may be used to better delineate AVMs of the lung or head. It may also show larger brain abscesses.
MRI scanning is the best noninvasive test to help delineate the extent of pulmonary and CNS AVMs. It also detects telangiectases in the CNS.
Angiography is used to map the exact extent of the vascular lesions, usually when surgery is contemplated.
 

Other Tests:

Colonoscopy shows GI telangiectases as small well-defined lesions surrounded by an anemic halo.
Barium enema is useful only if an ulcer or neoplasm is suspected. GI telangiectases cannot be visualized by this examination.


Histologic Findings: Biopsy of affected areas of the skin show focal dilatations of postcapillary venules in the dermal upper-horizontal plexus. Abnormal stress fibers are present in the venule pericytes. These findings vary from other forms of hereditary telangiectasia.

Medical Care: Medical and surgical care are aimed at decreasing the amount of hemorrhage and minimizing the sequelae of chronic blood loss. Specific complications, such as brain abscess and high-output cardiac failure, are treated as they arise.

Surgical Care:

Septal dermoplasty can reduce the severity of epistaxis by 75%. It is performed by replacing the nasal mucosa with autologous skin grafts. Telangiectases may develop on the autologous skin grafts.
Life-threatening GI bleeds can be effectively treated by segmental bowel resection.
Embolization, ligation, or surgical excision is indicated for enlarging or symptomatic pulmonary AV fistulas or for intrahepatic fistulas that cause high-output cardiac failure.
Pulsed dye laser treatment can be used to photocoagulate telangiectases in the nasal mucosa. A minimum of 3 subsequent treatments may be necessary before any change in bleeding frequency or severity is observed.


Consultations:

Consultation with multiple specialists may be useful in the diagnosis and treatment of this disease. Certain specialists may only warrant consultation when certain complications arise.
Dermatologist
Pulmonologist
Hematologist
Gastroenterologist
Neurologist and neurosurgeon
Diet: In most patients, no special diet is required. Iron can be depleted if the patient experiences chronic blood loss. Folate requirements can be high if the bone marrow is chronically activated.

Activity: Most patients can continue normal activities.
 

Estrogen and/or progesterone combinations and aminocaproic acid may help control mucosal bleeding.

Drug Category: Oral contraceptives -- May be used to decrease the amount of bleeding. Combination oral contraceptives have been shown to be more effective than estrogen alone in GI bleeding.Drug Name
Norethindrone acetate and ethinyl estradiol (Yasmin, Loestrin 1.5/30) -- Used to decrease mucosal bleeding. Probably works by strengthening mucosal tissues and thereby making them more resistant to trauma.
Adult Dose Ethinyl estradiol: 30 mcg PO qd
Norethindrone: 1.5 mg PO qd
Use until bleeding controlled
Pediatric Dose Not well established; use adult doses for older children
Contraindications Documented hypersensitivity; thrombophlebitis or thromboembolic disorders; history of stroke; coronary artery disease; active liver disease; carcinoma of the breast; undiagnosed vaginal bleeding; ophthalmic vascular disease; pregnancy
Interactions May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control
Pregnancy X - Contraindicated in pregnancy
Precautions Women >35 y who smoke are at increased risk of serious adverse effects on the heart and blood vessels; caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease
Drug Category: Antifibrinolytics -- Used to enhance hemostasis when fibrinolysis contributes to bleeding.Drug Name
Aminocaproic acid (Amicar) -- Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Used to prevent or treat mucosal bleeding caused by bleeding disorders or trauma.
Adult Dose 3.5 g IV initially, then 1 g/h until bleeding stops; not to exceed 8 h treatment duration
3.5 g/dose PO tid/qid for 3-4 d
Topical: Insert a gauze soaked in a 10% solution of aminocaproic acid into the nasal cavity
Pediatric Dose 50-100 mg/kg IV infused over 30-60 min, then 30-50 mg/kg/h until bleeding stops; not to exceed 8 h treatment duration
50 mg/kg/dose PO tid/qid for 3-4 d
Topical: Administer as in adults
Contraindications Documented hypersensitivity; evidence of active intravascular clotting process; disseminated intravascular coagulation ([DIC] because aminocaproic acid can be fatal in patients with DIC, differentiate between hyperfibrinolysis and DIC)
Interactions Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Reduce dose in cardiac, renal, or hepatic disease

Further Inpatient Care:

Admit for control of bleeding and complications as they occur.


Further Outpatient Care:


Monitor for symptoms and signs of blood loss and for chronic anemia.
Screen patients for pulmonary and CNS AVMs at the time of diagnosis and at the onset of any suggestive symptoms and signs.


In/Out Patient Meds:

Medications include oral contraceptives and aminocaproic acid, which are used to decrease the amount of mucosal bleeding.
Humidification of the ambient air helps decrease the amount of mucosal bleeding.
Iron and folate supplementation may be needed because of chronic blood loss and a chronically activated bone marrow.


Transfer:

Transfer may be necessary for further diagnostic evaluation and surgical interventions.
 

Complications:

Hemorrhagic or ischemic stroke
Brain abscess
High-output congestive heart failure
Chronic GI bleeding and anemia
Portal hypertension with esophageal varices
Pulmonary hemorrhage
Liver cirrhosis


Prognosis:

Most patients have a normal life expectancy. Only 10% of patients die from complications of their disease.
Patient Education:  Educate patients on the complications of the disease. Explain the autosomal dominant inheritance of the disease to patients.

Medical/Legal Pitfalls:

Failure to screen for complications such as pulmonary AVMs and cerebral vascular malformations
Failure to inform patients of the autosomal dominant nature of the condition and to counsel accordingly
Special Concerns: No special issues exist surrounding pregnancy in patients with Osler-Weber-Rendu syndrome.

 

Miscellaneous Bibliography
 

Brant AM, Schachat AP, White RI: Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). Am J Ophthalmol 1989 Jun 15; 107(6): 642-6[Medline].
Gillis MC: Amicar. In: Compendium of Pharmaceuticals and Specialties. 31st ed. Ottawa, Canada: Canadian Pharmaceutical Association; 1996: 56.
Gillis MC: Loestrin. In: Compendium of Pharmaceuticals and Specialties. 31st ed. Ottawa, Canada: Canadian Pharmaceutical Association; 1996: 784-786.
Haitjema T, Westermann CJ, Overtoom TT: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): new insights in pathogenesis, complications, and treatment. Arch Intern Med 1996 Apr 8; 156(7): 714-9[Medline].
Harries PG, Brockbank MJ, Shakespeare PG, Carruth JA: Treatment of hereditary haemorrhagic telangiectasia by the pulsed dye laser. J Laryngol Otol 1997 Nov; 111(11): 1038-41[Medline].
Hereditary Hemorrhagic Telangiectasia Foundation International: 1997 Summary of HHT. 2000; Available at: http://www.hht.org.
Isaacs E: Aminocaproic acid. In: Pediatric Drug Dosage Handbook. 8th ed. Ottawa, Canada: Winnipeg Health Sciences Center and CSHP; 1998: 161.
Kikuchi K, Kowada M, Sasajima H: Vascular malformations of the brain in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). Surg Neurol 1994 May; 41(5): 374-80[Medline].
Kjeldsen AD, Oxhoj H, Andersen PE: Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia. Chest 1999 Aug; 116(2): 432-9[Medline].
Marchesani F, Cecarini L, Pela R: Pulmonary arteriovenous fistula in a patient with Rendu-Osler-Weber syndrome. Respiration 1997; 64(5): 367-70[Medline].
Mitchell RO, Austin EH 3d: Pulmonary arteriovenous malformation in the neonate. J Pediatr Surg 1993 Dec; 28(12): 1536-8[Medline].
Peery WH: Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). Am J Med 1987 May; 82(5): 989-97[Medline].
Shovlin CL, Hughes JM, Scott J: Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet 1997 Jul; 61(1): 68-79[Medline].

NOTE: Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

 

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