NORD gratefully acknowledges Andrew McAsey, NORD Editorial Intern from the University of Notre Dame, and James R. Gossage, MD, Professor of Medicine, Department of Medicine, Augusta University in Augusta Georgia, for assistance in the preparation of this report.
Summary
Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is an inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), potentially resulting in bleeding (hemorrhaging) and shunting of blood. 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. With appropriate treatment, individuals with HHT can expect a near-normal life expectancy. HHT is inherited in an autosomal dominant pattern.
Introduction
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. Phenotypic penetrance is age dependent with approximately 90% showing signs or symptoms by age 40-45 years. Some individuals may experience symptoms during infancy or early childhood; others may show few signs or symptoms until the thirties, forties or later in life.
In many patients, the first apparent symptom of HHT is nosebleeds (epistaxis). While recurrent nosebleeds may develop as early as infancy they most often begin around puberty. Recurrent nosebleeds occur in approximately 90% of affected individuals. Nosebleeds occur because of the formation of small, fragile vascular malformations (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 adolescence and later.
Telangiectases also occur in the gastrointestinal tract. Gastrointestinal bleeding (hemorrhaging), which affects about 25-30%, usually does not present until the fourth decade of life or later. Affected individuals with gastrointestinal bleeding may note dark stools – sometimes black and tarry (melena) – but only rarely do they have red blood in their stools (hematochezia) or vomit (hematemesis). Commonly, blood loss is not detected by the patient, even when it leads to anemia.
Because bleeding episodes become more severe with age, they often lead to chronically low levels of iron in the blood and eventually to a low red blood cell count (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.
Many individuals with HHT develop arteriovenous malformations (AVMs). AVMs, which are direct connections between blood vessels of larger caliber than in telangiectases, most commonly affect the lungs, brain, spinal cord, and liver. In recent years AVM have been noted in the pancreas, kidneys, and other organs, though they rarely cause complications in these locations.
Pulmonary AVMs (PAVM) are seen in about 50% of individuals with HHT and are often asymptomatic. However, they 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 abscess and stroke, may occur due to passage of blood clots or bacteria through a PAVM.
AVMs of the brain occur in about 10% 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 are seen in up to 75% of individuals with HHT. In most cases they remain asymptomatic, though over time 10-20% may develop liver or heart failure. Individuals may experience high blood pressure in the veins carrying blood from the gastrointestinal 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. Pressure on bile ducts from enlarged blood vessels 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).
Shunting of blood through liver AVM may result in excessive blood flow through the liver. Over time, high output heart failure may occur because the heart is forced to work harder to compensate for the extra blood flow through the liver, in addition to the normal blood flow to the rest of the body.
HHT is caused by changes (mutations) in five different genes. It is likely that more genes are yet to be discovered.
Mutations of the ENG gene and abnormalities of the protein it produces (endoglin) result in HHT-1. 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 endoglin, the blood vessels do not mature and there is a failure in vascular smooth muscle development.
Mutations of the activin receptor-like kinase 1 (ACVRL1) gene and abnormalities of the protein in encodes (ALK1), result in HHT-2. People with mutations in this gene are more prone to complications from liver AVMs such as liver failure and elevated pressure on the right side of the heart (pulmonary hypertension).
Approximately 1-2% of individuals with HHT have a combination of HHT and juvenile polyposis known as JPHT (or JPHHT) overlap syndrome, a disorder involving polyps in the gastrointestinal tract. This type of HHT is caused by mutations in the SMAD4 gene.
Mutations in the BMPR9 and RASA1 genes produce syndromes that share phenotypic overlap with HHT including atypical telangiectases (similar to cutaneous capillary malformations), mild nosebleeds and AVMs typically in the brain and soft tissue. Whether these syndromes are truly HHT or merely HHT look-alikes remains controversial.
With the exception of RASA1, the genes that cause HHT encode 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 formation of blood vessels (angiogenesis) is defective, causing the clinical features of HHT.
HHT is inherited in an autosomal dominant pattern. In rare cases, the disorder occurs randomly as the result of a spontaneous genetic change (i.e., new mutation). All relatives affected in a family with HHT will have the same mutation. However, in different families the causative mutation is usually different, with over 900 different mutations found within the five genes known to cause HHT.
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. The risk is the same for males and females.
HHT affects males and females in equal numbers. Symptoms can occur at any age. The disorder is estimated to occur in approximately 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 and family history, a thorough clinical examination, and imaging studies to identify characteristic findings in organs. An international group of experts on HHT established diagnostic criteria for HHT. The four criteria are: recurrent spontaneous nosebleeds; the presence of multiple telangiectases in characteristic locations; the presence of internal (visceral) telangiectases or AVMs; and a family history of definite HHT. A diagnosis is definite if at least three of the four criteria are present.
Molecular genetic testing is available to determine if a mutation is present in ENG, ACVRL1, SMAD4, RASA1 or BMPR9 genes. This testing is particularly important for children of an affected parent whose mutation is known because each child has 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 criteria for definite HHT.
Clinical Testing and Work-Up
After a diagnosis of HHT has been made from clinical assessment, detailed family history and/or genetic testing, an individual with HHT should have screening for asymptomatic AVMs and treatment of existing problems. Current symptoms will be identified and severity assessed for best possible treatment (for example nosebleeds). Standard screening tests for adults in North America include bloodwork to look for iron deficiency anemia, brain MRI with gadolinium to look for brain AVM, contrast echocardiography to look for PAVM and liver imaging (ultrasound, MRI or CT with contrast) to look for liver AVM. Pediatric patients should have a brain MRI with gadolinium and also be screened for lung AVM but the optimal method is controversial; some Centers use contrast echocardiography while others use pulse oximetry. If contrast echocardiography shows more than mild right to left shunting, CT of the chest with or without contrast is usually the next step to look for pulmonary AVM. If the child’s brain has no vascular malformations, the imaging should be repeated at least one more time in late adolescence. If the brain is unaffected in late adolescence, then it does not need to be screened again. Finally, 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 to determine appropriate treatments or frequency of additional screening for AVMs
Treatment
The treatment of HHT is directed at specific symptoms present in each individual, as well as surveillance for undiagnosed AVMs. The Cure HHT Foundation has posted recommendations on its website (https://curehht.org/) regarding screening and treatment for various AVM.
All patients with nosebleeds should use some type of nasal lubrication to prevent nosebleeds such as Vaseline, saline spray, or other products. Nasal trauma such as hard blowing, bumping or picking should be avoided. If conservative measures are insufficient, then oral tranexamic acid or surgical ablation using laser, bipolar cautery, coblation or sclerotherapy should be considered. Tranexamic acid is an antifibrinolytic agent that has been shown to be beneficial in two randomized clinical trials and seems to help about 50% of patients. Surgical ablation is best performed by a specialist (rhinologist) experienced with HHT and is usually >90% effective but the benefit typically lessens after 3-12 months. For patients who fail moisturization, tranexamic acid and ablative measures, systemic antiangiogenic agents should be considered (see below under Investigational Therapies). More aggressive surgical therapies including nasal closure and skin grafts are possible when the patient remains severely anemic from nasal blood loss.
Patients with even small PAVM should receive antibiotic prophylaxis before dental procedures below the gum line, dental hygiene and potentially non-sterile surgeries such as rectal surgery. Small PAVM should also be monitored for growth every 5-10 years with either CT scanning or contrast echocardiography, depending on the patient. For patients with PAVMs that have a feeding artery of >2-3 mm in diameter, transcatheter embolization therapy, usually with coils or plugs, is currently recommended.
Brain AVMs are usually treated by surgical removal, embolization, or treatment of the affected area with focused radiation (gamma knife). Such treatment should usually be provided at an HHT center or other center with expertise in brain vascular malformations.
Because of the risk of complications, treatment of AVMs affecting the liver is usually only undertaken if an individual has symptomatic liver failure or high output heart failure. First line treatment for heart failure includes diuretics and correction of anemia and atrial fibrillation if present. For refractory cases, liver transplantation or intravenous bevacizumab might be considered, though the optimal choice is controversial at this time.
For patients with bleeding AVMs of the gastrointestinal tract, especially if associated with anemia, endoscopy with cautery is usually the first line treatment, although it should be used sparingly. For persistent bleeding and/or anemia, tranexamic acid or antiangiogenic agents such as intravenous bevacizumab should be considered.
Aggressive iron replacement therapy, either orally or by infusion, should be used to treat anemia secondary to the nose or GI bleeding associated with HHT. Blood transfusions are a last resort if frequent iron infusions and other therapies are not successful in reaching the target hemoglobin (usually >7 g/dl for most patients).
Intravenous bevacizumab is an antiangiogenic drug that can be given on an intermittent basis to reduce nosebleeds and anemia, and perhaps also GI bleeds. Based on several large uncontrolled trials it helps approximately 70-80% of patients and is fairly well tolerated by HHT patients, though serious side effects such as blood clots can occur in a minority of patients.
Other antiangiogenic agents that are under investigation include oral pazopanib, oral thalidomide, oral pomalidomide, oral doxycycline and others. Small uncontrolled trials of the first three suggest benefit to nosebleeds and GI bleeds, while doxycycline has shown some benefit for nosebleeds.
Estrogen and progesterone therapy, either alone in combination, have been given in an uncontrolled fashion to prevent recurrent bleeding associated with HHT. Reports of the effectiveness of these treatments have varied in the medical literature and they are also associated with the potential complication of blood clots. Further research is needed to determine the long-term safety and effectiveness of these treatments for HHT.
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
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Guttmacher AE, Marchuk DA, Trerotola SO, and Pyeritz RE. Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). In: Rimoin DL, Pyeritz RE, Korf BR (eds). Emery and Rimoin’s Essential Medical Genetics. Oxford: Academic Press, 2013;192-5.
JOURNAL ARTICLES
Al-Samkari, et al. An international, multicenter study of intravenous bevacizumab for bleeding in HHT: the InHIBIT Bleed study. Hematologica, 2020 Jul 16. doi:10.3324/haematol.2020.261859.
Faughnan ME, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Annals of Internal Medicine. 2020 Dec 15;173(12):989-1001. doi:10.7326/M20-1443.
Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW, et al. Pazopanib reduces bleeding in hereditary hemorrhagic telangiectasia? Angiogenesis. 2019 Feb;22(1):145-155. doi.org/10.1007/s10456-018-9646-1.
McDonald J, Wooderchak-Donahue W, VanSant Webb C, et. al.Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Frontiers in Genetics. 2015; 6:1-8.
Gaillard S, et al. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. Journal of thrombosis and hemostasis. 2014; Sep;12(9):1494-502. doi: 10.1111/jth.12654. Epub 2014 Jul 29.
Bernhardt BA, Zayac C, Trerotola SO, Asch DA, Pyeritz RE. Cost savings through molecular diagnosis for hereditary hemorrhagic telangiectasia. Genet Med. 2012; 14:604-10. doi: 10.1038/gim.2011.56. PMID: 22281938
Karnezis TT and Davidson TM. Efficacy of intranasal bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. The Laryngoscope. 2011;121.3: 636-638.
McDonald J, Bayrak-Toydemir P, and Pyeritz RE. Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management and pathogenesis. Genet Med. 2011;13:607.
Trerotola SO, Pyeritz RE. PAVM embolization: an update. AJR 2010;195:837-45.
Govani,FS and Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. European Journal of Human Genetics. 2009:17.7: 860-871.
Jameson JJ and Cave DR. Hormonal and antihormonal therapy for epistaxis in hereditary hemorrhagic telangiectasia. The Laryngoscope. 2004:114.4: 705-709.amcaseyFuchizaki, Uichiro, et al. Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). The Lancet . 2003:362.9394:1490-1494.
Sabbà C, Gallitelli M, and Palasciano G. Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. New England Journal of Medicine. 2001: 345.12:926-926.
INTERNET
McDonald J, Pyeritz RE. Hereditary Hemorrhagic Telangiectasia. 2000 Jun 26 [Updated 2017 Feb 2]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1351/ Accessed April 13, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 187300; Last Update: 08/22/2019 Available at https://omim.org/entry/187300. Accessed April 13, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University;Entry No: 600376; Last Update: 08/22/2019; Available at https://omim.org/entry/600376. Accessed April 13, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University;Entry No: 601101; Last Update:12/22/2010; Available at https://omim.org/entry/601101. Accessed April 13, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University;Entry No: 615506; Last Update 11/01/2013; Available at https://omim.org/entry/615506. Accessed April 13, 2021.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University;Entry No: 175050; Last Update: 04/02/2018. Available at https://omim.org/entry/175050 Accessed April 13, 2021.
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