NORD gratefully acknowledges Andrew McAsey, NORD Editorial Intern from the University of Notre Dame, and Reed E. Pyeritz, MD, PhD, William Smilow Professor of Medicine & Professor of Genetics, Vice-chair for Academic Affairs, Department of Medicine, Senior Fellow, Leonard Davis Institute for Health Economics, Perelman School of Medicine at the University of Pennsylvania, Smilow Center for Translational Research, for assistance in the preparation of this report.
Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is an inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), usually resulting in bleeding (hemorrhaging). Chronic nosebleeds are often the first sign and malformation of various blood vessels may result in abnormalities affecting the lungs, brain, spinal cord, and liver. A variety of treatments exist for the various features of HHT to improve quality of life and prevent life-threatening complications Individuals with HHT have a near-normal life expectancy. HHT is inherited as an autosomal dominant trait.
HHT was first described by Henry Gawen Sutton in 1864. With similar symptoms to hemophilia the two diseases were differentiated by Henri Jules Louis Marie Rendu in 1896. William Osler connected the disease’s presence in families to establish it as an inherited disorder. In 1907 Frederick Parkes Weber continued the characterization of the disease, writing a report on a series of cases. In 1909, the name "hereditary hemorrhagic telangiectasia" was coined, but alternate names based on the scientists who first characterized it have also been commonly used. Since its first identification, HHT has been an underdiagnosed disease, affecting more than a million people worldwide.
The symptoms associated with HHT vary from person to person. Differences in disease expression (phenotype) partially reflect the specific gene that is mutated in HHT. 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 HHT is nosebleeds (epistaxis). Recurrent nosebleeds occur in most affected individuals. Nosebleeds occur because of the formation of small red lesions (telangiectases) in the mucous membranes lining the inside of the nose. Telangiectases occur when capillaries fail to develop between arterioles and venules and most often affect the skin and the mucous membranes. The tongue, lips, face, ears, and fingers are the areas most often affected. Telangiectases may develop at any age including during infancy, but usually become apparent during adolesence and later.
Telangiectases 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 25-30%, does not present until the fourth decade of life or later. Affected individuals with gastrointestinal bleeding rarely have dark, bloody stools (melena) or episodes of bloody vomit (hematemesis). Most often, blood loss is not detected by the patient but leads to anemia.
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. Gastrointestinal bleeding can often be slow, chronic and intermittent, with few noticeable symptoms until the onset of anemia.
Most individuals with HHT develop arteriovenous malformations (AVMs). AVMs, which are direct connections between blood vessels of larger caliber than in telangiectases, affect the lungs, brain, spinal cord, and liver.
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 stroke, may occur due to passage of blood clots or bacteria through a PAVM.
AVMs of the brain exist in a minority 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 and hearing problems such as double vision (diplopia). However, usually they are asymptomatic prior to a hemorrhagic event. AVMs affecting the spinal cord (approximately 1% of those with HHT) are less common and may result in pain in the back and/or loss of feeling or functions of the arms and legs.
Liver vascular malformations may not cause symptoms or can results in liver or heart failure. 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).
Heart failure may occur because over time the heart is forced to work extra hard (hyperdynamic circulation) to compensate for excessive blood flow between the hepatic vein and the hepatic artery.
HHT 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). Families with HHT will have the same mutation, but otherwise the causative mutations across different are often different, with 600 different mutations found within the four genes known to cause HHT.
Human traits, including the classic genetic diseases, are the product of the interaction of two copies of a gene 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 gender of the resulting child.
Researchers have identified four genes that cause HHT. at least one and perhaps more genes are yet to be discovered.
One gene that causes HHT (ENG), 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. Scientists believe that endoglin binds to transforming growth factor-beta (TGF-ß). In mice that are deficient in endogolin, the blood vessels do not mature and there is a failure in vascular smooth muscle development.
Another gene that causes HHT is activin receptor-like kinase 1 (ACVRL1) gene. People with mutations in this gene are somewhat more prone to liver AVMs and to elevated pressure on the right side of the heart (pulmonary hypertension).
Mutations in another gene that can cause familial pulmonary hypertension, BMPR9, is occasionally associated with the vascular features of HHT.
A distinct type of HHT is a rare combination of HHT and juvenile polyposis, a disorder involving polyps in the gastrointestinal tract. This type of HHT is caused by mutations in SMAD4.
The genes which cause HHT all code for proteins involved in the TGF-ß/BMP (for bone morphogenic protein) superfamily of signaling. This group of proteins helps regulate many cellular functions such as cell survival, proliferation, and differentiation. With malfunctioning signaling, the cells of blood vessels cannot form correctly (angiogenesis), causing the symptoms of HHT.
HHT affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in at least 1 per 5,000 people. However, because some affected individuals develop few obvious symptoms and findings, the disorder often remains unrecognized. HHT is known to be underdiagnosed. This makes it difficult to determine the true frequency of HHT in the general population.
A diagnosis of HHT is made based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. An international group of experts on HHT 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 HHT. A diagnosis is confirmed if three of the four criteria are present.
Molecular genetic testing is available to determine if a mutation is present inENG, ACVRL1, SMAD4, or BMPR9. This testing is particularly important for children of an affected parent because they have a 50% chance to inherit the mutation for HHT but may be too young to show signs. Appropriate screening and treatment, if necessary, can begin earlier for those found to carry an abnormal gene. Genetic testing will detect the mutation in nearly 90% of people who meet clinical diagnostic criteria.
Clinical Testing and Work-Up
After a diagnosis of HHT has been made from a clinical assessment and detailed family history, an individual with HHT will begin the process of screening for asymptomatic manifestations for the disease and treatment of existing problems. Current symptoms will be identified and severity assessed for best possible treatment (for example nosebleeds). Then, patients will be referred to organ specialists for the various systems affected by HHT (lungs, liver, gastrointestinal tract, brain). Those specialists will consult with the patient, using their current symptoms and family history to determine frequency of screening of AVMs, in the lungs, heart, brain, and liver. The screening process is ongoing throughout the life of individuals with HHT, and if an AVM is discovered, the organ specialist will determine appropriate course of action for treatment.
The treatment of HHT 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 website (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. If conservative measures are insufficient, then the patient should be seen by a specialist (rhinologist) experienced with HHT. Ablation, using a laser of telangiectases in the nasal mucosa can provides relief. More aggressive surgical therapies are possible when the patient is severely anemic from nasal blood loss. Several experimental medical therapies are being studied.
Transcatheter embolization is currently the recommended treatment for lung AVMs that have a feeder artery that can be entered by a catheter.
AVMs 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 AVMs affecting the liver is only undertaken if an affected individual is in liver or heart failure. Screening for liver AVMs will only take place if the patient is symptomatic. Liver transplants offer a more long term treatment for liver failure, but with greater risk.
Treatment of telangiectases or AVMs of the gastrointestinal tract is undertaken using endoscopic laser treatment when significant bleeding (hemorrhaging) is present which has led to uncontrollable anemia. There have been some experimental treatments to treat gastrointestinal bleeding with hormone treatments or antifibrinolytic treatments, but the effectiveness and safety of these techniques are still unknown.
Iron replacement therapy, either orally or by transfusing iron dextran, are used to treat anemia secondary to the nose or GI bleeding associated with HHT. Blood transfusions are a last resort.
Antifibrinolyic drugs such as tranexamic acid have been found to have mixed results in treating nosebleeds in individuals and carry a risk of developing blood clots elsewhere.
Bevacizumab (Avastin) has been used experimentally to reduce the number and severity of nosebleeds in persons with HHT. While results are promising in reducing nosebleeds, the proper dosing, route of administration and treatment frequency for individuals with HHT has yet to be determined.
Estrogen and progesterone therapy, either alone in combination, have been used experimentally to prevent recurrent bleeding associated with HHT. 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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