Hereditary hemorrhagic telangiectasia

Definition

Hereditary hemorrhagic telangiectasia is an inherited condition characterized by abnormal blood vessels which are delicate and prone to bleeding. Hereditary hemorrhagic telangiectasia is also known as Rendu-Osler-Weber disease.

Description

The term telangiectasia refers to a spot formed, usually on the skin, by a dilated capillary or terminal artery. In hereditary hemorrhagic telangiectasia these spots occur because the blood vessel is fragile and bleeds easily. The bleeding may appear as small, red or reddish-violet spots on the face, lips, inside the mouth and nose or the tips of the fingers and toes. Other small telangiectasias may occur in the digestive tract.

Unlike hemophilia, where bleeding is caused by an ineffective clotting mechanism in the blood, bleeding in hereditary hemorrhagic telangiectasia is caused by fragile blood vessels. However, like hemophilia, bleeding may be extensive and can occur without warning.

— Dorothy Elinor Stonely

(medicine) An inherited disease characterized by dilatation of groups of capillaries and a tendency to hemorrhage. Also known as Osler-Rendu-Weber disease.

The dilation of small vessels and capillaries resulting from a genetic factor, with a tendency to bleed. Lesions may occur on the tongue as small, raised, red to bluish-red elevations.

Hereditary hemorrhagic telangiectasia. (Regezi/Sciubba/Jordan, 2003)

Definition

Hereditary hemorrhagic telangiectasia is a condition characterized by abnormal blood vessels which are delicate and prone to bleeding. Hereditary hemorrhagic telangiectasia is also known as Osler-Weber-Rendu disease.

Description

The term telangiectasia refers to a spot formed, usually on the skin, by a dilated capillary or terminal artery. Telangiectasia is an arterial-venous malformation (AVM) composed of small blood vessels. In hereditary hemorrhagic telangiectasia these spots occur because the blood vessel is fragile and bleeds easily. The bleeding may appear as small, red or reddish-violet spots on the face, lips, inside the mouth and nose, or the tips of the fingers and toes. Besides the skin and mouth, telangiectasias may occur in the gastrointestinal tract (GI tract), the brain, and the lungs. Unlike hemophilia, where bleeding is caused by an ineffective clotting mechanism in the blood, bleeding in hereditary hemorrhagic telangiectasia is caused by fragile blood vessels. However, like hemophilia, bleeding may be extensive and can occur without warning.

Causes and Symptoms

Hereditary hemorrhagic telangiectasia, an autosomal dominant disorder, occurs in one in 50,000 people. Recurrent nosebleeds are a nearly universal symptom in this condition. Usually the nosebleeds begin in childhood and become worse with age. A patient may begin to cough up blood or pass blood in stools. The skin changes begin at puberty, and the condition becomes progressively worse until about 40 years of age, when it stabilizes.

When to Call the Doctor

Parents should notify a doctor if a child's bleeding does not stop, or bleeding is severe, or the child has severe headaches or becomes unresponsive. Frequent nosebleeds should be followed up with the pediatrician.

Diagnosis

The physician looks for red spots on all areas of the skin, but especially on the upper half of the body and in the mouth and nose and under the tongue. Bleeding in the GI tract can cause the stool (feces) to be darker than normal.

Treatment

There is no specific treatment for hereditary hemorrhagic telangiectasia. The bleeding resulting from the condition can be stopped by applying compresses or direct pressure to the area. If necessary, a laser can be used to destroy the vessel. In severe cases, the leaking artery can be plugged or covered with a graft from normal tissue. In some cases, estrogen therapy is used to reduce bleeding episodes.

Prognosis

In most people, recurrent bleeding results in an iron deficiency. It is usually necessary to take iron supplements. Patients have a normal lifespan, and many people are not aware they are affected by the disease until a family is diagnosed.

Prevention

Because it is an inherited disorder, hereditary hemorrhagic telangiectasia cannot be prevented.

Parental Concerns

Parents should be aware that frequent nosebleeds are a common sign of hereditary hemorrhagic telangiectasia. Genetic counseling is recommended for those who know the disease runs in their families. There are also support groups for those who are affected by the disease.

Resources

Books

Sutton, Amy L. Blood and Circulatory Disorders Sourcebook: Basic Consumer Health Information about the Blood and Circulatory System and Related Disorders. Detroit, MI: Omnigraphics, 2005.

Organizations

HHT Foundation International Inc. PO Box 329, Monkton, MD 21111. Web site: www.hht.org/web/.

[Article by: Mark A. Best Dorothy Elinor Stonely]

Hereditary hemorrhagic telangiectasia
Classification and external resources
ICD-10	I78.0
ICD-9	448.0
OMIM	187300 600376 601101 610655
DiseasesDB	9303
eMedicine	med/2764 ped/1668 derm/782
MeSH	D013683

In medicine, hereditary hemorrhagic telangiectasia (also known as "Osler's disease," "Osler-Weber-Rendu disease"^[1]:844, and Osler-Weber-Rendu syndrome,^[2]) is an autosomal dominant genetic disorder that leads to vascular malformations.

Contents 1 Signs and symptoms 2 Diagnosis 3 Genetics 4 Pathophysiology 5 Treatment 6 Epidemiology 7 References 8 External links

Signs and symptoms

HHT is characterised by telangiectasia (small vascular malformations) on the skin and mucosal linings, epistaxis (nosebleeds), and arteriovenous malformations (AVMs) in various internal organs. Skin and mucosa telangiectasias are most remarkable on the tongue, hands/fingers, nose, lips, mouth/throat and conjunctiva.

The internal organs that can harbor AVMs often include the lungs, GI tract, brain, liver, and spine. In the brain and lungs, bleeding can seriously endanger life. Anemia may occur due to bleeding from digestive tract AVMs. High-output heart failure may develop in the presence of marked shunting arterial blood to the venous circulation, e.g. when AVMs are present in the liver. Cerebral vascular accidents can occur from embolization from vascular malformations of the pulmonary circulation.

Diagnosis

There are four diagnostic criteria, otherwise known as the Curacao criteria, named after the country where the meeting took place to formally define hereditary hemorrhagic telangiectasia.^[3] If three or four are met, a patient has definite HHT, while two gives a possible diagnosis:

1. Spontaneous recurrent epistaxis
2. Multiple teleangiectasias on typical locations (see above)
3. Proven visceral AVM (lung, liver, brain, spine)
4. First-degree family member with HHT

When HHT is suspected, physical examination focuses on inspecting the skin for teleangiectasias, which are usually located on the digits, pinna, and bridge of the nose. Telangiectasias can also be seen with high frequency on the tongue and palate. In addition, auscultation of the liver for presence of bruits, and heart for high-output cardiac failure should be performed. A detailed neurological examination could reveal prior evidence of a stroke.

Pulmonary AVMs can be anticipated by measuring oxygen levels, sampling arterial blood gas (ABG), and performing a 2D echocardiogram with bubble study. An X-ray or CT of the chest can show lesions; in addition, low oxygen tension (<96% or a 2% decrease upon standing) or low blood oxygen levels on ABG are required for a diagnosis. CT and MRI of the brain can demonstrate cerebral AVMs. Abdominal ultrasound with doppler study or CT can show AVMs of the liver. Upper endoscopy, enteroscopy or capsule endoscopy can show gastrointestinal involvement. Rarely, telangiectasias can be demonstrated in the large intestine by colonoscopy.

Genetics

Hereditary hemorrhagic telangiectasia has an autosomal dominant pattern of inheritance.

HHT is a genetic disorder by definition. It is inherited in an autosomal dominant manner.

Four forms have been described:

Name	OMIM	Gene/locus	Description
HHT1	187300	endoglin (9q34.1).	Endoglin is a receptor of TGFβ1 (transforming growth factor beta 1) and TGFβ3. It also interacts with zyxin and ZRP-1 with its intracellular domain, to control composition of focal adhesions and regulate organization of actin filaments. This form predisposes for pulmonary AVMs and early nosebleeds.
HHT2	600376	Alk-1 (12q11-q14)	Alk-1 (activin receptor-like kinase 1) is a TGFβ1 receptor. Less pulmonary AVMs and later nosebleeds, but an increased risk of pulmonary hypertension (supposedly due to altered TGFβ signalling or other related pathways which may lead to vascular malformations).
HHT3	601101	? at 5q31[4]?
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	175050	SMAD4 at 18q21.1
HHT4	610655	? at 7p14. [5]?	Identified in September 2006.

It is possible to test patients for the presence of mutations in endoglin, ALK-1 and SMAD4. When the mutation in an affected family member has been found it is possible to test other family members and identify those people not at risk for developing the disease.

Pathophysiology

The mechanism underlying the formation of vascular malformations is not completely understood, but signalling of transforming growth factor-β1 is most likely to be involved. Possibly, connective tissue is required to support and guide proliferating blood vessels during angiogenesis, and defects in TGF-β signalling adversely affect connective tissue and matrix production.

Treatment

There is no specific treatment for the condition, but complications can be addressed. Any patient undergoing dental work who has demonstrated pulmonary AVMs should have antibiotic prophylaxis. Anemia due to bleeding from digestive tract AVMs often necessitates repeated blood transfusions, intravenous iron therapy, and possible ablative therapy with cautery or argon plasma coagulation. Estrogen therapy is occasionally efficacious in chronic gastrointestinal blood loss. Interventional radiologists can ablate pulmonary AVMs with coil embolization. For severe nosebleeds, ENT physicians can cauterize bleeding vessels. Rarely, high output cardiac failure from hepatic AVMs necessitate liver transplantation.

Epidemiology

HHT occurs mainly in whites (1:5,000), more in certain areas of France, but much less in blacks (1 in 1 million). It is found in all continents throughout the world. It is also seen with increased frequency in Mormon families from Utah.^{[citation needed]}

However, HHT is not limited to, nor found predominantly in people of a particular ethnic background, as are some genetic disorders.^[6]

References

1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
2. ^ synd/1706 at Who Named It?
3. ^ Shovlin CL, Guttmacher AE, Buscarini E, et al. (Mar 2000). "Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)". Am J Med Genet 91 (1): 66–7. doi:10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P. PMID 10751092. 
4. ^ Cole SG, Begbie ME, Wallace GM, Shovlin CL (2005). "A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5". J. Med. Genet. 42 (7): 577–82. doi:10.1136/jmg.2004.028712. PMID 15994879. 
5. ^ Bayrak-Toydemir P, McDonald J, Akarsu N, et al. (2006). "A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7". Am. J. Med. Genet. A 140 (20): 2155–62. doi:10.1002/ajmg.a.31450. PMID 16969873. 
6. ^ International HHT Foundation FAQ page - http://www.hht.org/about-hht/faqs/#faq_16

External links

• GeneReview/NIH/UW entry on Hereditary Hemorrhagic Telangiectasia
• Online 'Mendelian Inheritance in Man' (OMIM) HHT1 -187300, 600376, 601101, 610655
• HHT.org
• Information about Hereditary Hemorrhagic Telangiectasia from Children's Hospital, Seattle.

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