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Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is a rare inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), usually resulting in excessive bleeding (hemorrhaging). Chronic nosebleeds are often the first apparent symptom associated with hereditary hemorrhagic telangiectasia. Malformation of various blood vessels may result in abnormalities affecting various organ systems of the body including the lungs, brain, and liver. Hereditary hemorrhagic telangiectasia is inherited as an autosomal dominant trait.
The symptoms associated with hereditary hemorrhagic telangiectasia vary from case to case. Some individuals may experience symptoms during infancy or early childhood; others may show no symptoms (asymptomatic) until the thirties, forties or later in life.
In many cases, the first apparent symptom of hereditary hemorrhagic telangiectasia is nosebleeds (epistaxis). Recurrent nosebleeds occur in 90 to 90% of individuals with HHT. Nosebleeds occur because of the formation of small red lesions (telangiectases) in the mucous membranes lining the inside of the nose. Telangiectases occur when there is abnormal widening (dilation) of groups of small blood vessels and most often affect the skin and the mucous membranes of the body. The tongue, lips, face, ears, and fingers are the areas most often affected by telangiectases. Telangiectases may develop at any age including during infancy, but usually become apparent during the thirties or forties.
Telangiectasic or similar lesions also occur in the gastrointestinal tract and in additional organs, including the lungs, brain, spinal cord and liver. While recurrent nosebleeds may be apparent at any age, they most often begin around puberty. Gastrointestinal bleeding (hemorrhaging), which affects about 20%, does not present until the fourth decade of life or later. Affected individuals with gastrointestinal bleeding may have dark, bloody stools (melena) or episodes of blooding vomit (hematemesis).
Because bleeding episodes become more severe with age, they often lead to chronically low levels of iron in circulating red blood cells (anemia). Anemia may result in chest pain, shortness of breath, and/or fatigue.
Some individuals with hereditary hemorrhagic telangiectasia develop abnormal widening of larger blood vessels (arteriovenous malformations or AVMs). AVMs, which are sometimes referred to as large telangiectases, affect internal organs such as the lungs, brain, spinal cord, and liver.
Approximately 30 percent of individuals with hereditary hemorrhagic telangiectasia develop AVMs of the lungs (pulmonary arteriovenous malformations or PAVMs). PAVMs may result in fatigue, difficulty breathing (dyspnea), episodes of coughing up of blood (hemoptysis), headaches, abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis), and/or abnormally increased levels of red cells in the blood (polycythemia). Serious neurological complications, including brain abscesses and the possibility of a stroke, may occur secondary to a PAVM.
AVMs of the brain exist in 10-20% of individuals with HHT and may result in headache, dizziness (vertigo), and seizures. In rare cases, individuals with AVMs of the brain may experience vision (visual) and hearing (auditory) problems such as double vision (diplopia). However, usually they are asymptomatic prior to a hemorrhagic event. AVMs affecting the spinal cord are less common and may result in pain in the back and/or loss of feeling or functions of the arms and legs.
In some cases, arteriovenous malformations may also form in the liver. The exact frequency of liver (hepatic) involvement in HHT is unknown, with estimates ranging from eight percent to 30 percent of cases. Individuals may experience high blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension) and abnormalities of the bile ducts (biliary disease). The bile ducts are narrow tubes through which bile passes from the liver to the first section of the small intestine. Abnormalities of bile ducts may result in failure of bile to flow to the small intestine instead becoming trapped in the liver, resulting in yellowing of the skin and the whites of the eyes (jaundice).
Some affected individuals with liver involvement develop heart failure. Heart failure may occur because over time the heart is forced to work extra hard (hyperdynamic circulation) to compensate for extra or excessive blood flow resulting from a large arteriovenous malformation between the hepatic vein and the hepatic artery.
Hereditary hemorrhagic telangiectasia is inherited as an autosomal dominant trait. In rare cases, the disorder occurs randomly as the result of a spontaneous genetic change (i.e., new mutation).
Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, only a single copy of the disease gene (received from either the mother or father) is required to cause the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy, regardless of the sex of the resulting child.
Researchers have identified two separate types of hereditary hemorrhagic telangiectasia. Hereditary hemorrhagic telangiectasia type I is caused by a gene on chromosome 9 and is probably associated with a greater frequency of pulmonary arteriovenous malformations.
Hereditary hemorrhagic telangiectasia type II is caused by a gene on chromosome 12 and has been proven to be associated with symptoms and manifestations similar to those seen with HHT type I.
A third type of HHT is suspected, but no gene has been identified.
The gene that causes HHT type I, and the protein it produces (encodes), is called endoglin. Endoglin is found on the surface of the cells that line the inside of the blood vessels. Studies indicate that most families affected by HHT type I have a unique mutation within the endoglin gene. Scientists believe that endoglin binds to transforming growth factor-B (TGF-B). In mice that are deficient in endogolin, the blood vessels do not mature and there is a failure in vascular smooth muscle development. Scientists are studying how endoglin affects humans.
The gene on chromosome 12 that causes HHT type II is known as the activin receptor-like kinase 1 (ALK1) gene.
Symptoms of hereditary hemorrhagic telangiectasia occur because of abnormalities affecting blood vessels. There are two main types of blood vessels: arteries, which carry blood away from the heart, and veins, which carry blood to the heart. Very tiny blood vessels known as capillaries connect arteries to veins. Individuals with hereditary hemorrhagic telangiectasia lack these capillaries, which results in the abnormal connection of arteries directly to veins (arteriovenous malformations or telangiectases). Arteriovenous malformations are fragile, and thus can rupture, resulting in escessive bleeding. This bleeding may occur for no apparent reason (spontaneously) or because of trauma.
Hereditary hemorrhagic telangiectasia affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in at least 10 people per 100,000. However, becomes some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized. HHT is known to be under-diagnosed. This makes it difficult to determine the true frequency of hereditary hemorrhagic telangiectasia in the general population.
Symptoms of the following disorders can be similar to those of hereditary hemorrhagic telangiectasia. Comparisons may be useful for a differential diagnosis:
Von Willebrand disease is an inherited blood clotting disorder characterized by prolonged bleeding. Blood clotting is slowed due to a deficiency of the von Willebrand factor protein and factor VIII protein (the factor VIII complex). Also, blood cells that form clots (platelets) do not stick normally, causing excessively slow clotting time. Increased risk of excessive bleeding following surgery, dental procedures or injury occurs in individuals with this disorder. With proper treatment and appropriate precautions, few individuals face long-term complications potentially associated with von Willebrand disease. Von Willebrand disease has occurred in individuals who also have hereditary hemorrhagic telangiectasia. (For more information on this disorder, choose "von Willebrand" as your search term in the Rare Disease Database.)
Calcinosis-Raynaud's-Sclerodactyly-Esophageal dysfunction-Telangiectasia syndrome (CREST syndrome) is a combination of various symptoms, and is usually due to scleroderma. Scleroderma is a rare disorder characterized by thickening and hardening of the skin. Calcinosis is the abnormal accumulation of deposits of calcium salts under the skin and in various organs of the body Raynaud's phenomenon involves painfully cold fingers and toes caused by dilation or constriction of small vessels in response to cold. Sclerodactyly is a form of scleroderma localized to the fingers and toes (digits). Dysfunction of the lower esophagus results in heartburn (acid reflux into the throat and mouth) and possible scarring. The esophagus may eventually have areas that are narrowed (strictures), and swallowing may become difficult. In some cases, esophageal dysfunction is not prominent. These cases are often referred to as CRST syndrome. Telangiectases are also present is this disorder. (For more information, choose "Scleroderma" as your search terms in the Rare Disease Database.
Ataxia telangiectasia (AT) is a complex genetic neurodegenerative disorder that may become apparent during infancy or early childhood. The disorder is characterized by progressively impaired coordination of voluntary movements (ataxia); the development of reddish lesions of the skin and mucous membranes due to permanent widening of groups of blood vessels (telangiectasia); and impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency), resulting in increased susceptibility to upper and lower respiratory infections (sinopulmonary infections). Individuals with AT also have an increased risk of developing certain malignancies, particularly of the lymphatic system (lymphomas), the blood-forming organs (e.g., leukemia), and the brain. In individuals with AT, progressive ataxia typically develops during infancy and may initially be characterized by abnormal swaying of the head and trunk. With disease progression, the condition leads to an inability to walk (ambulation) by late childhood or adolescence. Ataxia is often accompanied by difficulty in speaking (dysarthria); drooling; and an impaired ability to coordinate certain eye movements (oculomotor apraxia), including the occurrence of involuntary, rapid, rhythmic motions (oscillations) of the eyes while attempting to focus upon certain objects (fixation nystagmus). Affected children may also develop an unusually stooped posture and irregular, rapid, jerky movements that may occur in association with relatively slow, writhing motions (choreoathetosis). In addition, telangiectasias may develop by mid-childhood, often appearing on sun-exposed areas of the skin, such as the bridge of the nose, the ears, and certain regions of the extremities, as well as the mucous membranes of the eyes (conjunctiva). AT is inherited as an autosomal recessive trait. (For more information, choose "Ataxia-Telangiectasia" as your search terms in the Rare Disease Database.
A diagnosis of hereditary hemorrhagic telangiectasia is made based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. An international group of experts on HHT recently established diagnostic criteria for HHT. The four criteria are: recurrent nosebleeds; the presence of multiple telangiectases in characteristic locations; the presence of internal (visceral) telangiectases or AVMs; and a family history of hereditary hemorrhagic telangiectasia. A diagnosis is confirmed if three of the four criteria are present.
Molecular genetic testing is available to determine if a mutation is present in either the endoglin gene or the ALK-1 gene. This testing is particularly important for children of an affected parent because they have a 50% chance to inherit the gene for HHT. Appropriate screening and treatment, if necessary, can begin earlier for those found to carry an abnormal gene. Molecular genetic testing for HHT is being conducted at ARUP Laboratories in Salt Lake City, The University of Pennsylvania, and at HHT Solutions in
The treatment of hereditary hemorrhagic telangiectasia is directed at specific symptoms present in each individual, as well as surveillance for undiagnosed AVMs. The Hereditary Hemorrhagic Telangiectasia Foundation has posted recommendations on its Web site (www.hht.org) that include brain MRI procedures to screen for cerebral AVM upon diagnosis. For patients with confirmed diagnosis, starting at 10 years of age, some combination of contrast echocardiography, chest CT or chest x-ray and arterial blood gas determination to screen for pulmonary AVM approximately every five years is recommended.
Nosebleeds can often be temporarily relieved with lubrication or the application of pressure to the affected areas. Additional treatments include the application of a compress saturated with drugs (e.g. phenylephrine) that tighten blood vessels (vasoconstrictors) to the ruptured lesion. Ablation, using a laser, of telangiectases in the nasal mucosa also provides temporary relief.
Long-term remission of recurrent nosebleeds may sometimes be achieved with septal dermoplasty. Dermoplasty is a procedure in which a thick layer of skin is grated to replace the mucous membranes that line the interior of the nose.
Transcatheter embolization is currently the recommended treatment for lung AVMs that have a feeder artery greater than 3 mm.
Arteriovenous malformations of the brain are usually treated by surgical removal, embolization, or treatment of the affected area with radiation. Specific therapy for AVMs affecting the brain varies from case to case.
Because of the risk of complications, treatment of arteriovenous malformations affecting the liver is only undertaken if an affected individual is in liver or heart failure.
Treatment of telangiectases or arteriovenous malformations of the gastrointestinal tract is undertaken using endoscopic laser treatment when significant bleeding (hemorrhaging) is present which has led to uncontrollable anemia.
Iron replacement therapy, either orally or by transfusing iron dextran, are used to treat anemia secondary to the nose or GI bleeding associated with hereditary hemorrhagic telangiectasia. Blood transfusions are a last resort.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
Estrogen and progesterone therapy, either alone in combination, have been used experimentally to prevent recurrent bleeding associated with hereditary hemorrhagic telangiectasia. Reports of the effectiveness of these treatments have varied in the medical literature. Further research is needed to determine the long-term safety and effectiveness of these treatments for HHT.
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 187300; Last Update: 11/9/00 Entry No: 600376; Last Update: 4/7/00; Entry No: 601101; Last Update: 7/5/96.
Report last updated: 2008/04/02 00:00:00 GMT+0