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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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