Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu Syndrome)

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www.hht.org 1 Publication of this Learn More About HHT brochure was made possible by a grant from Ambry Genetics. Ambry Genetics is a CLIA-certified and CAP-approved laboratory that focuses on comprehensive diagnostic testing that meets the needs of the individual clinician. Ambry Genetics testing menu includes three HHT genes with cost-effective reflex pathways and testing for additional conditions via exome sequencing and next-gen sequencing panels.

The information (in particular, the medical and scientific information) contained in this brochure is provided with the understanding that the HHTFI is a voluntary health organization and is not engaged in rendering medical advice or recommendations on diagnosis or treatment of the HHT syndrome. The material provided is designed for educational and informational purposes only and as a benefit and service in furtherance of the HHTFI mission. The HHT syndrome is a complex, multi-organ disorder that can only be properly diagnosed and managed by skilled and trained health care professionals. The information contained in this brochure should not replace necessary consultations with qualified health care professionals.

PRIVACY STATEMENT Your personal information is private and is not shared with a third party outside of the HHT Foundation.

2 HEREDITARY HEMORRHAGIC TELANGIECTASIA Welcome to the HHT Foundation

Hereditary Hemorrhagic Telangiectasia (HHT), The HHT Foundation International, Inc. also known as Osler-Weber-Rendu Syndrome, is the only organization in the world that is a genetic blood vessel disorder that affects advocates for advancements in research, about 1 in 5,000 people worldwide. HHT does treatment and funding for HHT. not discriminate… it impacts males and females, regardless of age, from all racial and Each year, we host medical and scientific ethnic groups. conferences to educate patients and physicians about the latest research You have been affected by HHT in and treatment protocols, we publish a some way. Whether you have known that newsletter three times annually that generations of HHT exists in your family informs our members about the initiatives or you are newly diagnosed – we are here of the Foundation, we refer hundreds for you! Whether you are a health care of people to HHT specialists, we train and professional or a parent of an individual certify new HHT Treatment Centers of with HHT – we are here for you! Maybe Excellence across North America, we you have a friend with HHT and you want produce educational materials like this to understand how this disease will impact brochure, and we fund HHT research. their life – we are here for you! Now that you know HHT runs in your Any medical diagnosis can be scary but family, consider becoming a member of the HHT Foundation, along with our the HHT Foundation so that you can be partnering medical institutions known as HHT kept current in the latest developments of a Treatment Centers of Excellence, are here disease that affects you and the ones you to relieve your anxiety. You are one of the love. Your support allows us to continue lucky ones…. It is believed that 90% of those dedicating our time and resources to who have HHT don’t know that they have the important work necessary to identify the disease. These people are at great risk the remaining 90% of people who don’t of experiencing a catastrophic event. You, know they have HHT and fund research however, have been diagnosed and there breakthroughs. It is through our partnership are physicians specializing in HHT that are with you, that great advances and a cure are waiting to take care of you and other within our reach. members of your family affected by this disease.

Marianne S. Clancy Executive Director HHT Foundation International, Inc.

It is our mission to find a cure for HHT while saving lives and improving the well-being of individuals and families affected by HHT. To achieve this mission, we will: • Educate patients and medical professionals • Fund research • Provide linkages between people affected by HHT • Collaborate with multidisciplinary HHT Treatment Centers worldwide • Advocate for and support those with HHT • Engage the scientific and medical community

www.hht.org 3 The earliest symptom of HHT is usually nosebleeds, often developing in adolescence.

DIAGNOSTIC CRITERIA for HHT

The four diagnostic criteria for HHT are blood under high pressure flows directly can lead to serious complications. Every- listed below. A person has definite HHT into a vein without first having to squeeze one with HHT should undergo screen- if they meet at least three criteria and through very small capillaries. This place ing for lung and brain AVMs because if possible HHT if they meet two. Persons where an artery is connected directly to these are detected, they can be treated. with less than two criteria are unlikely to a vein tends to be a fragile site that can The HHT Foundation recommends that have HHT. rupture and bleed. all patients and families with HHT be • Recurrent and spontaneous nosebleeds, assessed at an HHT Treatment Center which may be mild to severe. We usually call a blood vessel that is for proper screening and treatment. • Multiple telangiectasias on the skin of the abnormal in this way a telangiectasia hands, lips or face, or inside of the nose (tel-AN-jee-eck-TAZE-ee-ya) if it involves SIGNS and SYMPTOMS of HHT or mouth. Telangiectasias are small red small blood vessels. The telangiectasias spots that disappear when pressed upon. most commonly occur on the skin of the About 95% of people with the gene for • Arteriovenous Malformations (AVMs) or face and hands and the lining of the nose HHT will eventually develop signs or telangiectasias in an organ including the and mouth. The telangiectasias on the symptoms of HHT, usually by the age lungs,brain,liver, intestines, stomach, and lining of the nose cause recurrent nose- of 40. However, just because a person spinal cord. bleeds, the most common symptom of reaches the age of 50 without symptoms • A first-degree relative (brother, sister, HHT. Telangiectasias can also occur in the of HHT does not mean that they are parent or child) who meets these same digestive tract, particularly in the stomach not affected. They may have subtle signs criteria for definite HHT or has been and small bowel. There are a number of on physical exam and lab testing that diagnosed through genetic testing. different treatments available for bleed- only a doctor familiar with HHT might ing from telangiectasias in the nose and detect. The earliest symptom of HHT is What is HHT? digestive tract. usually nosebleeds, often developing in adolescnece. Patients also start to develop HHT is a hereditary disorder (passed down When the abnormal artery to vein con- small red spots, or telangiectasias, on the through generations) that is character- nection occurs in a larger blood vessel, face, mouth, and fingers. Other common ized by abnormal blood vessels. A person it is called an arteriovenous malforma- symptoms include shortness of breath, with HHT has a tendency to form blood tion (AVM). Some people with HHT will exercise intolerance, fatigue, migraine vessels that lack normal capillaries between also have AVMs in one or more organs. headaches, seizures, abdominal pain, leg an artery and vein. This means that arterial AVMs occurring in the lungs and brain and swelling, and intestinal bleeding.

4 HEREDITARY HEMORRHAGIC TELANGIECTASIA www.hht.org 5 How does HHT affect a person?

Telangiectasias in the nose, along with colon (large intestines), but most commonly, ties (clots, bacteria, air bubbles) before the nosebleeds they cause, are the most the stomach and the upper part of the the blood circulates to the brain. With a common sign of HHT. About 90% of people small intestines are involved. Telangiectasias PAVM, these capillaries are missing and the with HHT will ultimately develop recurring in the GI tract do not cause pain or artery connects directly to the vein. If the nosebleeds by the time they reach their discomfort. Symptoms of GI bleeding are artery leading into the PAVM is larger than forties.The average age at which nosebleeds black or bloody stools and/or anemia; often 2-3 mm in diameter, small blood clots can begin is 12, but they can begin as early patients don’t notice any changein the stool travel through the PAVM and go to the brain as infancy, or as late as adulthood. The but instead are found anemic through blood causing a stroke. Bacteria can travel through nosebleeds can be as infrequent as a few work. Anemia can cause fatigue, shortness even smaller PAVMs and result in brain times a year or can occur daily. When a of breath, chest pain or lightheaded feelings. abscesses (a brain infection). Stroke and nosebleed occurs it can last anywhere from brain abscess can be life-threatening seconds to hours. The amount of blood lost or disabling. Fortunately, PAVMs are almost may be one or two drops, or enough to always easily treatable. require an emergency blood transfusion. Brain AVMs are found in about 5-20% The Epistaxis Severity Score (ESS) is a way of people with HHT and can also be to monitor the severity of your nosebleeds successfully treated in most cases. They and their response to treatment. This is a can be life-threatening or disabling if they simple score that is calculated automati- bleed. Since they often do not cause cally when you answer six simple questions warning symptoms prior to bleeding, we about your nosebleeds. You can access the recommend screening for them in all ESS tool through the HHT Foundation people with HHT, even infants. Other website at www.hht.org. types of brain vascular malformations may be seen in HHT patients, such as telan- Telangiectasias on the skin of the hands, giectasias and venous malformations. It is face and mouth are also found in about not clear if these malformations are seen 95% of all people with HHT. However, any more commonly in HHT patients, these often do not become apparent until but they are usually harmless and most do the 30s or 40s. They appear as small red to not require treatment. purplish spots, usually pinpoint to pinhead size. In some individuals with HHT they Spinal AVMs are more rare, less than 1%, become quite prominent by late adulthood; but can also be treated. They can cause pain in others they are more subtle. These telan- Approximately 40% of people with HHT in the area of the back over the spine, or loss giectasias on the hands, face or in the mouth have AVMs in the lungs (pulmonary AVM or of feeling or function in an arm or leg. can bleed, but they are less likely to bleed PAVM). People with HHT1 (ENG) are 5-10 than those in the nose. Both telangiectasias times more likely to have PAVMs than people Liver AVMs are found in 32-74% of of the skin and nose have a tendency to with HHT2 (ACVRL1). PAVMs, particularly people with HHT, but only cause symp- become more numerous with increased age. during pregnancy, have a risk of rupturing toms in an estimated 8%. AVMs in the liver However, not all red spots are telangiectasias. when blood volume tends to increase. This occasionally cause heart failure, usually later Red spots on the chest, belly or upper arms can be life-threatening. However, there are in life. Heart failure can occur if the heart are common in people without HHT and are additional concerns about untreated PAVMs. has been overworked for years, pumping usually called cherry angiomas. Normally, the lung arteries get smaller and extra blood through the low resistance smaller as they go deeper into the lungs, pathway of a liver AVM (shunt), as well as About 80% of those with HHT have telan- similar to the branches of a tree. At through all the normal vessels of the body. giectasias in their stomach or intestines, but the ends of these artery branches, hair- There are several other even more rare and only 20% develop obvious gastrointestinal like blood vessels called capillaries join the complex complications that can result when bleeding. Again, it can range from mild to arteries and veins. These capillaries per- HHT affects the liver. Few physicians outside severe. Telangiectasias can be found anywhere form many important functions including of clinics that specialize in HHT are familiar in the gastrointestinal system, including the allowing passage of oxygen into the blood with these complications. esophagus,stomach, small intestines, and as well as filtering the blood of impuri-

4 HEREDITARY HEMORRHAGIC TELANGIECTASIA www.hht.org 5 Nearly everyone with HHT will have inherited the disorder from a parent who also has HHT.

What causes HHT? genes that can cause HHT. Having a the copy with the mutation. A child who mutation in an HHT-associated gene inherits the gene with the mutation will HHT is caused by a change (a “muta- causes some blood vessels to form have HHT. A child who inherits the normal tion”) in one of several HHT-associated improperly leading to symptoms of HHT. copy of the gene will not have inherited genes. Changes in one of two of the HHT. Therefore, each time a person with genes, endoglin (ENG-HHT1) and activin How is HHT inherited? HHT has a child, there is a 1 in 2 chance receptor-like kinase 1 (ACVRL1-HHT 2) (50%) that the child will have HHT. are responsible for most cases of HHT. Each child born to an HHT parent has a Changes in another gene, SMAD-related 50% chance of inheriting the HHT gene Nearly everyone with HHT will have protein 4 (SMAD4), cause a combined mutation. One copy of each gene is inherited the disorder from a parent who syndrome of juvenile polyps of the gastro- inherited from the father and the other also has HHT. In rare cases, a change in an intestinal tract and HHT. At least two copy from the mother. People with HHT HHT gene occurs in only an egg or sperm other unidentified genes also appear to have one normal copy of the HHT gene cell of someone who does not have HHT cause HHT in a smaller number of and one mutated copy. When a person themselves. In these cases, the resulting individuals. There are hundreds of different with HHT has a child, he or she will either child will have HHT, although the parents mutations in each of the three known pass on the normal copy of the gene, or are unaffected.

66 HEREDITARYHEREDITARY HEMORRHAGIC HEMORRHAGIC TELANGIECTASIA TELANGIECTASIA WHY IS IT IMPORTANT TO SCREEN FOR MANIFESTATIONS OF HHT? The recommended screening guidelines for each organ impacted by HHT are outlined in the Clinical Guidelines, published in the Journal of Medical Genetics, located in the resource section of the HHT Foundation website, www.hht.org.

Nosebleeds and skin telangiectasia are original tests are too old, the old test is not patient before and after treatment for the most obvious signs of HHT but of high enough quality, or the old test was PAVMs.s there are many hidden manifestations that performed a little differently. • CT scan of the lungs: This is like a can contribute to life-threatening events. 3-dimensional high-resolution X-ray of Therefore, it is important to gain an • Contrast Echocardiogram (bubble your lungs. If “X-ray dye” is used, an IV understanding of how HHT impacts the echo): The recommended test of choice will need to be started. internal organs. There are several tests that everyone who is known or • Pulmonary Angiogram: A catheter suspected to have HHT should have. is inserted through a large vein in either These are called screening tests since your leg or neck, and is passed up into the abnormality is looked for prior to its the arteries of the lungs. This involves causing a problem. Lung and brain AVMs one or more injections of “X-ray dye” into the arteries to expose the AVM.

Although there is not PAVMs larger than a certain size should be embolized to prevent complications like yet a way to prevent brain abscesses and strokes. For smaller PAVMs, antibiotics prior to most dental work the telangiectasias or and certain other non-sterile invasive proce- AVMs from occurring, dures, like colonoscopy, are recommended. most can be treated for PAVM screening in adults and also Until PAVMs are excluded by testing, a used in older children and adolescents. person over the age of 10 with known or once they occur This test uses sound waves (ultrasound) suspected HHT should take antibiotics to determine if injected saline bubbles can before all dental cleanings, work and oth- get through the lung circulation and be er medical procedures which have a risk of are the only problems associated with HHT seen back in the heart, on the left side. This introducing bacteria into the bloodstream. for which we recommend pre-symptomat- is called a shunt. It is a very sensitive test but ic, preventive screening. A screening test not everyone with a “positive” or “abnor- To screen for Brain AVMs an MRI with and will: 1) determine whether you meet the mal” bubble echo test has a without gadolinium dye is recommended. criteria for a diagnosis of HHT and 2) look Pulmonary AVM large enough to re- Since brain AVMs have been known to for pulmonary (lung) AVMs and cerebral quire treatment by embolization. To cause brain hemorrhage even in infants, a (brain) AVMs since these can cause serious determine if treatment is necessary, a brain MRI early in life is recommended. life-threatening events without warning. chest CT scan should be done if the bubble echo is more than minimally Other than in the brain and lungs, HHT Screening for Pulmonary AVMs (PAVM) is abnormal. can be screened as the symptoms dependent on the age of the individual, warrant. With this in mind, a yearly evaluation • Chest X-ray: A standard X-ray of the and to a lesser degree, their symptoms. by a physician familiar with the wide lungs to look at the size of your heart Preferably, individuals with HHT will have spectrum of symptoms associated with and the condition of your lungs. had screening for PAVMs by the time of HHT is recommended, along with an their early teens. If a pregnant woman has • Shunt test: During this test you breathe annual check of ferritin levels, hematocrit, not had a recent evaluation for PAVM, it pure oxygen for 15 minutes with a nose and hemoglobin. Without periodic check- is imperative for her to do so as soon as clip on, and then a small sample of ups with an HHT expert, HHT related pregnancy is recognized. In many cases, an arterial blood is collected from an artery medical problems are often missed, HHT Treatment Center will be able to use in your wrist. This is not a routine screen- misdiagnosed or mismanaged which can tests performed by another facility unless the ing test but rather is used to assess a lead to catastrophic events. www.hht.org 7 CAN HHT BE TREATED? Yes. Although there is not yet a way to treatment that is usually considered is some and safety of these drugs. We encourage prevent the telangiectasias or AVMs from type of medicated spray/ointment or some patients to participate in these research occurring, most can be treated once they type of coagulation therapy. studies if they have permission from their occur. They should be treated if they are doctor. either causing a significant problem (as Medical Treatment: Coagulation therapy is in the case of frequent nosebleeds) or often the quickest way to stop nosebleeds, Surgical Treatment: Septal Dermoplasty if they have a high risk to cause a problem but there is some controversy as to the and Young’s Nasal Closure Procedure are (such as a stroke from a lung AVM or brain best way to do this. Many experts believe surgical treatment options for nosebleeds, AVM). The current recommended treat- that laser coagulation therapy is preferable but are usually only considered when nose- ment for a telangiectasia or AVM depends to electric and chemical cautery because bleeds are severe, significantly affecting on both its size and location in the body. it causes less damage to the inside of the one’s quality of life and coagulation therapy nose. However, some experts have re- has repeatedly failed to help. Septal Treatment of Recurring Nosebleeds ported good success with bipolar electric dermoplasty replaces the thin lining of cautery. Regardless of the method used, the nose with a graft of thicker skin from The Epistaxis Severity Score (ESS) is a way it is important to have coagulation therapy somewhere else on the body. When to monitor the severity of your nosebleeds by someone who has expertise in treat- performed by an ENT experienced with and their response to treatment. This is a ment of HHT patients. Most patients who treating HHT patients, it can significantly simple score that is calculated automati- undergo coagulation therapy see significant reduce or stop nosebleeds, often for two cally when you answer six simple questions improvement for a period of time, but it or more years. Daily care of the nose about your nosebleeds. You can access the usually needs to be repeated periodically. is required after septal dermoplasty to ESS tool through the HHT Foundation Sprays and ointments containing medicines keep the nose moist and clean. Also website at www.hht.org. like estrogen, bevacizumab (Avastin), and new vessels can grow around the graft tranexamic acid have been used in small and nosebleeds may return. In the Home Treatment: Through one or more numbers of patients and are currently being Young’s procedure, the nostrils are sewn treatments, an Otolaryngologist (ENT) studied in clinical trials. closed so a person no longer breathes can significantly improve the severity through their nose. This therapy is quite of nosebleeds for almost everyone, Several small research studies have effective but the downside is that taste although it is rare for these treatments to suggested that various oral therapies can and smell are affected. permanently cure one’s nosebleeds. Nose- help some patients for whom the local bleeds sometimes respond satisfactorily to therapies (i.e. home moisturizing care and Embolization: This procedure blocks an simple treatments that can be implement- laser therapy) have not been successful. artery which, in most cases, stops severe ed at home. It is very important to avoid Birth control pills have been used the most, nosebleeds that have been unresponsive any injury to the nose such as picking or and while they do seem to help some to other treatments. This procedure is blowing hard. Humidification of the air and patients, they have significant side effects. usually only effective for 6-8 weeks; other lubrication of the nose (with saline spray) Drugs that affect either the formation of arteries enlarge and cause recurrence. This can reduce nosebleeds. If home treatments clots or blood vessels are being investi- therapy for the nose should be used only on do not result in a satisfactory reduction in gated (i.e., estrogens, tamoxifen, n-ace- an emergency basis until more durable nosebleed frequency or severity, the next tylcysteine, bevzcizumab (Avastin), and therapies can be started. others) to examine the effectiveness 8 HEREDITARY HEMORRHAGIC TELANGIECTASIA Treatment of Pulmonary (Lung) mon cause of hemorrhagic stroke in HHT Treatment of Symptomatic Liver AVM families. Research is currently being Involvement conducted to determine what genetic and Pulmonary AVM (PAVM) are seen in clinical factors signal high risk hemorrhage Liver AVMs are currently treated only if a about 40% of patients, and are especially from brain AVMs in HHT patients. It is patient shows signs of heart failure or other common if someone else in your family has recommended that all children of HHT significant problems. Embolization of liver them. However, about 30-40% of patients families be screened for brain AVMs as early AVM has led to severe complications in sev- have PAVM large enough to require treat- as birth and throughout adolescence (until eral patients and therefore is not usually first ment. PAVM are potentially one of the post-puberty) to monitor the development line treatment. most serious complications of HHT because of new BAVM. they can result in strokes or brain abscesses. Current treatment options for liver AVM The good news is that these complications Embolization: A small catheter is passed include standard heart failure treatment, can be prevented in almost all cases. through an artery in the leg and then into liver transplantation, and possibly medica- the arteries of the brain. A small balloon or tions like bevacizumab (Avastin). Decisions Embolization: A tiny metal coil or a small glue is inserted which stops the blood flow regarding treatment of liver AVM are balloon is inserted to block off the artery into the AVM and lessens the risk of stroke. made on a case-by-case basis and should that leads into or “feeds” the PAVM. This Typically, this procedure is successful more be managed by an HHT Treatment stops the blood flow to the PAVM which than 95% of the time and has a relatively Center physician who is very familiar with eliminates the occurrence of a potentially low complication rate. the liver manifestations of HHT. life-threatening complication.This is accomplished by passing a small catheter through Surgical Removal: A surgical procedure to Abnormal blood vessels in the liver a vein in the leg and then passing it up to place a clip on the AVM or to remove the (AVM) are common in HHT but usu- the arteries of the lungs. This procedure is AVM. This procedure is fully curative,but has ally require no treatment. When liver usually performed under conscious sedation. a higher complication rate than embolization. abnormalities are detected by X-rays or blood tests, it is vitally important that Surgical Removal: A surgical procedure to Gamma Knife: A type of focused radiation the following procedures NOT BE remove the part of the lung that con- that destroys the AVM tissue. This is often DONE without seeking the opinion tains the PAVM. Because of the success done after embolization to ensure that the of an HHT Treatment Center physician: of embolization, surgery is rarely necessary. AVM is cured. • LIVER EMBOLIZATION (blocking If you have a known PAVM or if you Treatment of Intestinal AVM the hepatic artery with particles); have not been screened to determine if • LIVER BIOPSY (sampling the liver tis you have a PAVM, you should take the A large percentage of patients with HHT sue with a small needle); following precautions: have intestinal AVM, but only 20% of HHT • ERCP (endoscopic retrograde cholan- • Take antibiotics before any invasive patients develop significant stomach or giopancreatography—which is passing proceures like dental cleaning, surgical intestinal bleeding. Bleeding usually does not a tube through the mouth into stomach, procedure, or colonoscopy. occur before age 50. These AVM can usually duodenum, and biliary ducts). • A .22 micron IV filter is recommended be detected by endoscopy, which involves to keep air out of the IV line (does not inserting a flexible tube with a camera on The invasive procedures listed above can apply to blood transfusions) *see full the end through your mouth or rectum to potentially make an HHT patient much disclosure on p.13. look inside the intestines, and treated with a worse if not done in consultation with • Avoid blood thinners or nonsteroidal laser. Other treatments include oral hormone an HHT specialist. Similarly, routine anti-inflammatory medicines like aspirin pills (estrogen and danazol) and tranexamic screening for liver abnormalities is not and ibuprofen as they can worsen acid (Amicar). Research has not proven the recommended by most HHT Centers bleeding tendencies. effectiveness or potential risks of these at this time. Sudden events leading to • Return to your HHT Treatment center treatments. serious disability, such as those that every 3-5 years so that you can be moni- occur from lung and brain AVMs in tored for development of new PAVM. The biggest problem with intestinal bleed- HHT patients, do not occur from liver ing is that it leads to anemia. Anemia is gen- involvement in HHT. Treatment of Cerebral (Brain) AVM erally treated by a hematologist. Common It is thought that 5-20% of HHT patients remedies include oral or intravenous iron have at least one Brain AVM (BAVM). therapy and blood transfusion. Without treatment, BAVM are a com- www.hht.org 9 SCREENING CHILDREN FROM AN HHT FAMILY

Not all children show signs of HHT (i.e., nosebleeds and “red spots” on the skin). Children without nosebleeds or other symptoms of HHT can have AVMs in their lungs or brain that require intervention.³ In fact, potentially life-threatening manifestations of HHT have been identified in asymptomatic children under 12 years of age.¹ • If a family has had genetic testing, then all children in the family should be tested against the identified gene mutation. • If the family gene has not been identified, then a clinical evaluation will be required.

All children diagnosed with HHT should receive a pediatric screening for HHT. A screening appointment consists of a thorough history, a physical examination, pulse oximetry, a contrast (or bubble) echocardiogram (CE), and brain magnetic resonance imaging (MRI) with and without contrast.¹ If a child’s initial screening is not conducted at an HHT Center, it would be recommended that all patients with a positive MRI or an abnormal echobubble test consult an HHT Treatment Center for consideration of more invasive testing and further treatment.

According to the Clinical Guidelines², there is not consensus on the recurring tests of children with HHT. However, it is recommended by most HHT Centers that: • Children with possible or confirmed HHT should be screened for Brain AVM in the first year of life (or at the time of diagnosis) and at least one follow-up MRI at puberty since brain AVM development appears to correlate with times of growth. References • Lung AVM screening is recom- 1. Sekarski, L., Spangenberg, L. (2011). Hereditary 3. Mei-Zahav, M. et al. (2006). Symptomatic children mended every 3-5 years, if a pulse Hemorrhagic Telangiectasia: Children Need Screening with Hereditary Hemorrhagic Telangiectasia. Archives of Pediatric Adolescent Medicine, 160, 596-601. oximetry test result is 97% or higher. If a Too. Pediatric Nursing, Vol. 37, No. 4, 163-168. pulse oximetry result is lower than 97%, 2. Faughnan, M. et al. (2009). International Guidelines 4. Olitsky, S. (2010). Hereditary Hemorrhagic Telangi- ectasia: Diagnosis and Management. American Family or a child is short of breath, additional for the diagnosis and management of Hereditary Hemorrhagic Telangiectasia. Journal of Medical Physician, Vol. 82, No. 7, 785-790. tests or treatment may be required. Genetics, 48(2), 73-87. Advance online publication. Doi:10.1136/jmg.2009.069013.

10 HEREDITARY HEMORRHAGIC TELANGIECTASIA Should your Child be Screened re-perfusion after embolization than adults. for Lung AVM? This may be due to the fact that they are growing and thus their blood vessels are Since the 1980’s we have learned a great growing too. This means that children need deal about pulmonary (lung) arteriove- to be followed closely after embolization to nous malformations (PAVMs) in adults. make sure that their PAVMs remain closed. We know that they frequently cause Based on the fact that neurological complications, such as stroke Based on the fact that some children did or brain abscess. Multiple studies have have complications from PAVMs, HHT some children did have shown that treatment of PAVMs is safe and medical professionals currently advocate effective. For this reason we recommend screening for PAVM in all children of a complications from screening for PAVMs in all adults. parent who has HHT. Bubble echo is the recommended screening test for PAVMs, we currently However, it is less clear what constitutes symptomatic children who have low optimal screening and treatment of PAVMs oxygen levels, complain of shortness advocate screening for in children. The largest study of PAVM in of breath, have a hard time keeping up children reported on 42 children who in sports, or have had prior neurologic all children of a parent underwent embolization of PAVM from complications. However, the best screen- 3 HHT Centers of Excellence. Neuro- ing test for asymptomatic children is with HHT. logical complications such as stroke were controversial: some HHT Treatment less common in children compared with Centers perform pulse oximetry before adults. The children that did have neuro- the age of 10 followed by bubble echo after logical complications tended to have low the age of 10-14; other HHT Treatment oxygen levels in the blood or felt short Centers perform bubble echo at all ages. of breath when exercising. Embolization The optimal management of children who techniques were simlar to those used for are diagnosed with PAVM is complicated adults except that general anesthesia or and should be done in consultation with heavy sedation were more commonly HHT Center of Excellence. required for children. Embolization was effective and well tolerated by children and about 15% required repeat embolization at some time in the future. In some children the repeat embolizations were required because blood flow returned through an embolized PAVM – so called re-perfusion. Although it is not clear-cut, some experts believe that children have more www.hht.org 11 synthesis. However, if the imbalance per- sists (such as with continued bleeding as can happen in HHT), over time the iron stores become exhausted resulting in iron deficiency anemia. It is important to realize that iron deficiency can occur in the absence of anemia. This state can be diagnosed using routine laboratory tests.

Clinical features of iron deficiency

The clinical features of iron deficiency are mainly related to anemia and include fatigue, weakness, headaches, irritability, and decreased exercise tolerance. Rarely, affected individuals can develop dry mouth, hair IIRON DEFICIENCY & HHT the amount of iron absorbed from the diet loss, and brittle fingernails. In children and needs to equal the amount of iron lost on adolescents, iron deficiency (with or with- Iron deficiency is common among people a daily basis. This is about 1mg of iron per out anemia) can also cause poor cognitive with HHT and is primarily a consequence day. The daily requirement is slightly higher function (difficulty with concentration and of bleeding from telangiectasias in the lining in adult women (2mg/day) secondary to learning, memory, school performance, of the nose and intestinal tract. Iron deficien- menstrual loss. The iron requirements etc.) and poor physical performance (run- cy tends to be both under-diagnosed and are higher during adolescent years due to ning, endurance). Further, studies have under-treated in HHT patients and can lead growth and development. Iron require- shown improvement in performance with to decreased exercise tolerance, chronic ments also increase during pregnancy and correction of the iron deficiency. A classic fatigue, and poor quality of life. the total amount of iron utilized during but uncommon finding in individuals with pregnancy, childbirth and nursing is about 1 iron deficiency anemia is a craving for ice Why do we need iron? gram. Foods that are rich in iron include red or substances like clay (referred to as ‘pica’). meats, liver, egg yolk, salmon, tuna and oysters Iron deficiency has also been associated with Iron is required for the production of (iron in these foods are in the form of Restless Leg Syndrome, a condition causing hemoglobin in red blood cells and the hemoglobin and myoglobin, referred to as an urge to repeatedly move the legs or arms protein myoglobin in muscle cells. Iron is heme-iron). Iron is also present in vegetables, because of an uncomfortable feeling in the also a component of many proteins and fruits and grains, but this iron (referred to as affect body part. enzymes in the body and plays important non-heme iron) is harder for the body to roles in energy metabolism and immunity. absorb. How do we diagnose iron The total amount of iron in an adult is about deficiency? 3-4 grams. The majority of this (about 2.5 Causes of iron deficiency grams) is present in hemoglobin within Iron deficiency should be suspected in circulating and developing red blood cells. The overwhelming cause of iron deficiency in any person with HHT who develops one About a gram of iron is present as ‘stored developed countries is blood loss. Less likely or more of the above mentioned clinical iron’ mostly in the bone marrow, liver and causes include decreased intestinal absorption features. Further evaluation should consist of spleen. Of note, women of child-bearing (e.g. Celiac disease, following gastric bypass doing the following blood work: a complete age usually have lesser amounts of stored surgery), and decreased iron intake (in extreme blood count (CBC), reticulocyte count, and iron, as they use more iron to make up for diets). Unless an individual experiences sudden an iron panel (serum iron, iron saturation, menstrual blood loss and iron requirements and massive blood loss, iron deficiency tends total iron binding capacity, ferritin). These during pregnancy, childbirth and nursing. to develop slowly over time. At first, the body together provide information on a person’s progressively uses up its’ iron stores due iron stores and whether or not an individual How much iron do we need? to an imbalance between the supply and is iron deficient/anemic. demand for iron in the body. In this early The amount of iron in the body is tightly stage people do not yet have anemia, as there regulated. As the body cannot make iron, is sufficient iron available for hemoglobin

12 HEREDITARY HEMORRHAGIC TELANGIECTASIA How do we treat iron deficiency? ing on the preparation being used. Of note, Key points preparations that contain less iron (Ferrlicit and • Iron deficiency is an important and Once a person has been diagnosed with Venofer) have the advantage of quicker infu- under-appreciated cause of symptoms iron deficiency, this should be corrected sions. On the other hand, the iron dextran and poor quality of life among individuals by replacing the iron stores. The goal is preparations (INFeD and Dexferrum) take a with HHT. to correct the iron deficiency as well as few hours to administer but offer the option of • People with HHT who suffer from replenish the body iron stores. This can be replacing the entire iron deficit in a single infusion. bleeding should be routinely screened achieved by taking iron by mouth in the form Regardless of the preparation used, intravenous for iron deficiency. The appropriate of iron supplements (tablets, liquid, suspen- iron can be associated with allergic reactions. blood tests for the physician to order sion or elixir) or by replacing iron directly Some preparations rquire the use of a small are: CBC, reticulocyte count, and iron into the vein (intravenous or IV). Generally, test dose and pre-treatment with antihistamines panel. the initial approach is to pursue oral iron (e.g. Benadryl) for this reason. • If iron deficiency is found, this should replacement. A number of oral iron be treated aggressively. Following iron replacement, one can begin • If oral iron preparations are poorly to see a rise in the hemoglobin in 2-4 weeks. tolerated or the iron deficiency is very People with HHT It is important to realize that treatment with pronounced, iron can be given intrave- iron, either oral or intravenous, will not nously in easy to give preparations. should be treated by immediately correct the anemia. Therefore, • People with HHT should be treated individuals with symptomatic anemia may by medical professionals at an HHT medical professionals need to receive an initial blood transfusion to Treatment Center of Excellence. improve their symptoms. While transfused • Care should be taken to avoid air in intra- at an HHT Treatment red blood cells contain iron (about 250mg/ venous (IV) lines. This is to prevent large unit of blood), this alone is inadequate to air bubbles from getting into the blood Center of Excellence. correct the iron deficiency. stream and causing problems (such as TIAs). This is most effectively done by prep-arations are available; consult your It is essential in individuals with HHT who using a filter in the IV line as close to the HHT Treatment Center physician for rec- have frequent nose bleeds or intestinal bleed- patient as possible. A 0.22 micron filter ommended products and dosage. It is ing to continue to aggressively treat/prevent is best if available, but a blood filter is also important to note that oral iron supplements iron deficiency. Once treatment with iron is acceptable (about 260 microns) and will can be associated with gastrointestinal side started, it is important to repeat a CBC and stop all large air bubbles (which are the effects such as nausea, bloating, and consti- iron panel in 2-3 months to assess response most dangerous ones). During a blood pation that frequently limit their use. The side to treatment. Individuals with chronic nose transfusion, a stardard blood filter is all effects appear to be related to the amount or GI bleeding who tolerate oral iron should that is needed. Please note that filters of elemental iron and, therefore, prepara- continue to take this long term. Individuals cannot be used for IV contrast injections tions that contain less elemental iron tend to that require treatment with intravenous iron like you might get for CT or MRI scans. be better tolerated. Once the hemoglobin may require repeated treatments based on becomes normal, there is still a deficiency in the severity of bleeding. the total amount of iron in the body, and it is recommended that iron treatment be continued for an additional 6 months to replace the missing iron stores in the body. In individuals with severe iron deficiency anemia or frequent/severe bleeding, oral iron may be inadequate to treat the iron deficiency. In such cases, and in individuals who do not tolerate oral iron, treatment with intravenous iron should be considered. A number of intravenous iron preparations are currently available.The number of doses of intravenous iron necessary to correct a person’s iron deficiency will vary depend- www.hht.org 13 GENETIC TESTING FOR HHT What is genetic testing for HHT? Second, genetic testing might be done in a person who definitely has HHT in order to Genetic testing for HHT consists of analyzing identify the family’s HHT-associated muta- DNA (the genetic material carried in cells) tion. Third, genetic testing might be done on of the HHT-associated genes in a labora- people in an HHT family who have minimal tory. Genetic testing is usually done on a or no symptoms of HHT but have a close small sample of blood, but can be done on a relative who has HHT. In this case, testing sample of saliva in certain cases. In a would be done for the familial mutation to given family, genetic testing should start with determine whether or not the person has someone who clearly has HHT. HHT.

Three different kinds of genetic tests for Because the most easily identified features of HHT are available. “Sequencing” of the HHT such as telangiectasias and nosebleeds genes involves looking at the precise often do not appear until adolescence or sequence of building blocks in the sample later, it is particularly difficult to determine of DNA to see if there is any abnormal- whether young “at-risk” individuals have ity. “Targeted Sequencing” looks to see if inherited HHT from an affected parent. one particular mutation that was previously Anyone with a parent or sibling with HHT identified in another family member is would be considered “at-risk”. If genetic present or absent. “Deletion and testing is not used, all at-risk children should Duplication” testing looks to see if there is be screened for brain and lung AVMs using a piece of the gene that is missing or procedures that will require sedation, or duplicated. general anesthesia, in young children. If an HHT mutation has already been identified For a person who meets clinical diagnostic in a family, genetic testing of at-risk family criteria for HHT, genetic testing by sequen- members for this known mutation will allow cing and deletion and duplication testing of identification of which family members carry ENG (HHT1) and ACVRL1 (HHT2) will the mutation and need to be screened for detect a mutation in approximately 87% of AVMs, and which do not carry the mutation those tested. If testing of ENG and ACVRL1 and therefore do not need further screen- is negative, sequencing of SMAD4 identifies ing. This could potentially eliminate the need a mutation in an additional 2% of people for procedures which require sedation or diagnosed with HHT. For about 10-15% anesthesia in children. of people with HHT, the laboratory will not find a mutation in one of the known What are possible results from HHT genes. genetic testing for HHT?

Why would genetic testing for HHT Possible results from HHT genetic testing be done? depends of the type of genetic test done. Typically “full” gene analysis for the HHT Genetic testing for HHT is done for several genes is done in the first person tested in reasons. First, it may be useful in confirm- a family, and “single mutation” analysis for ing a diagnosis of HHT in someone who is those subsequently tested. suspicious for HHT, but who does not meet established clinical diagnostic criteria based When full gene analysis is performed, on their observable symptoms alone. In there are three possible results: such a person, finding a mutation in one of the HHT associated genes can confirm that • Positive for a “deleterious” (HHT- the person has HHT. causing) mutation. This result means that the laboratory found a mutation in one

14 HEREDITARY HEMORRHAGIC TELANGIECTASIA of the HHT associated genes, and the cost $2,000 or more. Once a mutation has mutation is thought to cause HHT. This been identified in the family, testing of other result would confirm that the person family members for that mutation typically tested has HHT. A positive result would costs $200-$400 (2013). Genetic testing is also make it possible to test other people usually covered by insurance, including in the family for the precise mutation Medicare and some state Medical Assistance found in order to determine if they have Programs. Several of the laboratories per- or do not have HHT. forming genetic testing will assist patients and providers with obtaining verification of insur- • Negative. This result means that the ance coverage. Although a letter of medical laboratory did not find a mutation in one necessity may sometimes be requested, ge- of the HHT-associated genes. There are netic testing is generally covered as a regular several reasons for a negative result. laboratory test. Rarely, insurance policies will First, the person tested might not have specifically exclude genetic testing. HHT. Second, the person tested does have HHT, but carries a mutation in an Does testing positive for a HHT-associated gene that hasn’t yet mutation in an HHT gene lead been identified and therefore was not to discrimination? tested. Third, the person might have a mutation in one of the HHT genes that There is no evidence that testing positive was tested, but the current techniques for a mutation in an HHT-associated gene used for testing were not able to pick up results in discrimination in obtaining medical the person’s HHT mutation. insurance. Some people are worried that if they test positive, they will have trouble • Variant of uncertain significance. This obtaining or keeping health insurance cov- result means that the laboratory found erage. The possibility of genetic discrimina- a change in one of the HHT associated tion in employment and health insurance is genes, but it is not possible to predict reduced with the passage of the federal whether or not it causes HHT. Genetic Information Nondiscrimination Act of 2008 (GINA). GINA prohibits a health When single mutation analysis for the insurer or employer from discriminating HHT-associated mutation has already against an individual based on that person’s been identified in the family, there are two genetic risk for future disease. Genetic test The HHT Foundation possible results. results cannot be used by health insurers as a basis for determining eligibility or premiums, strongly encourages • Positive. This result means that the nor can they be used by employers as a basis person carries the HHT gene mutation for hiring, firing or other terms of employ- individuals and families present in the family. This person does ment. Nearly all states also have laws pro- have HHT. hibiting various forms of discrimination based to arrange genetic • Negative. This result means that the on genetic test results. Protections through person does not carry the HHT gene GINA and various state laws should lessen testing through health mutation present in the family. This the risk of the misuse of genetic information. person therefore did not inherit HHT. These protections do not extend to life care providers who insurance coverage, however. How much does genetic testing for understand all of the HHT cost, and will my insurance pay for it? complexities and

The cost of genetic testing varies among limitations of genetic laboratories and according to type of testing needed. Testing to initially determine which testing for HHT. mutation is present in a family can potentially www.hht.org 15 I have HHT and want to know if my How do I go about arranging for What happens if my family is children have HHT. What do I do? genetic testing? one of those where it is not possible to find a mutation in First, you should find out if anyone in Genetic testing can be arranged through one of the HHT genes? your family with HHT has had genetic an HHT Center of Excellence, through a testing. If someone has, and the familial medical genetics clinic, or sometimes In such a family, genetic testing cannot be HHT-causing mutation has been identi- through a primary care provider or spe- used to figure out who does and who fied, your children can be tested for that cialty physician. The laboratories offering does not have HHT. At-risk members of mutation to find out if they have HHT. If genetic testing for HHT employ genetic HHT families without detectable mutations not, a family member, who clearly has counselors who can assist providers with should have a focused clinical evaluation HHT, should have genetic testing by test ordering, facilitate sample collection and for HHT by a physician very familiar with genetic sequencing followed by dele- shipping, and help with interpretation the signs and symptoms of the disorder. tion duplication analysis if sequencing is of results. Providers can also call one Physicians who don’t regularly see HHT negative to determine what mutation is of the HHT Centers of Excellence and ask patients often miss the signs, and don’t causing the HHT in your family. There is to speak with a genetic counselo about understand the risk of HHT to young chil- currently about an 87% probability that such genetic testing. The testing labs (which can dren in the family, even those without ob- testing will identify your HHT-associated be identified through www.hht.org vious nosebleeds or telangiectasias. HHT mutation. Your children can then be test- and www.genetests.org) also include informa- experts generally recommend that children ed for that specific mutation to determine tion on their websites that addresses many born to parents with HHT have screening whether or not they have HHT. Children common questions about genetic testing. for brain AVMs as early in life as possible, who do not carry the mutation do not have unless HHT can specifically be ruled out by HHT and do not need further follow-up. If the family cannot travel to an HHT mutation testing. Children who carry the mutation would then Center and their healthcare provider is be screened for complications of HHT, unable to order HHT genetic testing him Important Note!! particularly for AVMs in the brain and lungs. or herself, genetic testing can often be New HHT-associated genes will be identified in the obtained through a genetic counselor (who future, and genetic testing technologies will change can be identified through National Society and improve in the future. Therefore, people from HHT families in which a mutation has not been of Genetic Counselors (www.nsgc.org), or identified should periodically check back with the through a genetics clinic (which are listed testing laboratory or a genetics professional to find on the website www.geneclinics.org). out if additional testing would be useful.

16 HEREDITARY HEMORRHAGIC TELANGIECTASIA WHAT IS THE IMPACT OF HHT ON PREGNANCY?

Most women with HHT can have a nor- and she has no abnormal blood vessels in pregnant women with HHT. However, the mal pregnancy and delivery with no more the organs, then there is no reason to think published experience in the last few years has risk for complications than women in the that her pregnancy or delivery is high-risk. been reassuring and can help dispel some general population. HHT pregnancies are On the other hand, if a woman’s HHT of the myths and concerns about risks for sometimes considered “high-risk”, but this footprint includes lung AVMs, then several pregnancy in women with HHT. is not necessarily always the case…some steps and precautions need to be taken to women with HHT can benefit from a minimize risk, and in some cases this may be Myth #1: Women with HHT are at “high-risk” clinic approach, but others don’t considered a high-risk pregnancy. risk of excessive bleeding (from the really need this. The key is information uterus) during or after delivery. and consultation with an HHT expert, to What does the term high-risk help the pregnant woman make the best pregnancy really mean? There is no evidence of this. In fact, the decisions for herself and her baby. experience is that women with HHT are no First, it doesn’t necessarily mean that the more likely to bleed excessively at delivery This means being aware of the extent of the risks are extraordinary, but rather that they or after delivery than women in the general HHT in the Mother (her “HHT footprint”) are higher than in the general population. population. and planning accordingly, rather than sim- A high-risk pregnancy is one in which some ply assuming that HHT is not a problem, condition puts the mother or the develop- Here’s why: People with HHT don’t have or conversely assuming that the pregnancy ing fetus, or both, at an increased risk for a clotting disorder. So, they are not more is high-risk due to the simple presence of complications during or after pregnancy likely to bleed with an injury, trauma or HHT. By the “HHT footprint”, we mean a and birth. These women may benefit from cut. People with HHT bleed from parts of conceptual map of the abnormal vessels in additional monitoring and specialized care the body where they have abnormal blood someone with HHT, including everything during pregnancy and delivery, to reduce vessels (AVMs and telangiectasia). The uterus from telangiectasia in the nose to AVMs in the risk of complications. This can be also is not a typical place for AVMs to occur in the organs. The HHT footprint is person- very reassuring for the mother and the HHT, so there is no reason to expect women alized, different in each woman with HHT, family, when there is higher risk. with HHT to bleed with delivery. and can change over her lifetime. Knowing the specific HHT footprint in a woman As typical for rare diseases, there are not Myth #2: Women with HHT can’t should help guide pregnancy planning and many studies published about pregnancy and have an epidural. care. For example, if a woman’s HHT foot- delivery in HHT. As such, there are no clear print includes only telangiectasia in the nose guidelines for physicians to follow for care of NO, this is not the case. In fact most www.hht.org 17 women with HHT decide to have an The first concern is that women with HHT for pregnancy and delivery, and the pregnan- epidural, or at least to have the option might be likely to bleed during or after cy need not be considered high risk, though of having one. There is no evidence of delivery. This is addressed in Myth #1. some precautions should be followed. If a increased risk of complications. pregnant woman has untreated lung AVMs, The second concern is that a brain AVM treatment during Trimester 2 or Trimester 3, Why is there concern? Many anesthetists might be more likely to rupture when “push- with embolization should be considered, but and other doctors are worried about the ing” at delivery. There is no evidence that only at an expert HHT center. Once treat- risks of epidural anesthesia in women with this is the case, or that cesarean section is ed, the lung AVMs are no longer a significant HHT. Specifically, they are worried about a safer alternative to normal vaginal delivery concern for pregnancy and delivery. If lung puncturing a spinal AVM when they insert in people with brain AVMs. This situation AVMs are present but not treated, then the the epidural needle into the women’s lower needs to be handled on an individual basis. pregnancy should be considered high-risk. spine. This worry stems from the knowledge Screening for brain AVMs can be performed that approximately 1% of HHT patients can in early third trimester with an unenhanced Summary have AVMs in the spinal canal. BUT, the vast MRI of the brain. If the MRI is negative (i.e. majority of spinal AVMs in HHT are much no brain AVMs), then this is no longer a con- For most women with HHT, the main higher in the spinal canal than where the epi- cern (90% of women with HHT will have problem is nosebleeds, and though dural needle is usually inserted. ALSO, com- a negative MRI of the brain). If the woman bothersome, this is not often a major plications of spinal AVMs are exceedingly does have a brain AVM then her case needs concern during pregnancy. Some women rare in adults (most have come to attention to be discussed in detail with a brain AVM with HHT have a more extensive HHT during childhood). In fact screening for spinal expert and an obstetrician, and likely should footprint, with AVMs in the brain or lungs, AVMs hasn’t been routinely recommended be considered a high risk pregnancy and de- which may be more concerning. However, in adults with HHT (unlike screening for lung livery. There may be some discussion about with the right screening, treatment and and brain AVMs) given how very rare they assisting the delivery to reduced pushing or surveillance, most women with HHT can are in adults. FINALLY, no case has ever about a cesarean section, though there is no have normal pregnancy and delivery, with been reported in the medical literature of an good evidence that this is the safer approach. no more risk than women without HHT. epidural causing spinal bleeding in HHT. In These decisions will need to be made on Any patient with lung AVMs (treated or other words, if there is a risk, it is so low that a case by case basis, with all the experts untreated) should follow pulmonary AVM no one has been able to document a case or involved. If a brain AVM is diagnosed, the precautions, including antibiotics before any quantify the risk. On the other hand, there usual recommendation is to treat within two procedures that can cause bacteria in the is no study that has “ruled out” any risk of or three months after delivery. As such, since blood as well as an air filter (bubble trap) epidural in HHT. For all of these reasons, we treatment will be delayed anyway, some any time they have an intravenous access. call it a “theoretical” risk. women opt to postpone the brain MRI till after delivery. This is not unreasonable, but If a pregnant woman with HHT wants the may leave the woman and her physicians References 1. Faughnan, M.E., et al., International guidelines for option of an epidural, she should meet with un-necessarily worrying about the possibil- the diagnosis and management of hereditary haem- the anesthetist prior to delivery and have a ity of brain AVMs, and therefore considering orrhagic telangiectasia. J Med Genet. 48(2): p. 73-87. discussion about all the risks, including the it a “high-risk” pregnancy, whereas an MRI 2. De Gussem, E.M., et al., Outcomes of Pregnancy “theoretical” risk related to HHT. Many would dispel this worry in 90% of women. in HHT(Abstract). Hematology Meeting Reports, anesthetists will agree to proceed if the 2009. 3(4): p. 10. 3. Gershon, A.S., et al., Transcatheter embolotherapy woman understands the risks. The third concern is that lung AVMs might of maternal pulmonary arteriovenous malformations be more likely to rupture and bleed when during pregnancy. Chest, 2001. 119(2): p. 470-7. Myth #3: Women with HHT should “pushing” at delivery. There is no evidence 4. Shovlin, C.L., et al., Medical complications of have a cesarean section to avoid of this. However, lung AVMs do seem to be pregnancy in hereditary haemorrhagic telangiectasia. QJM, 1995. 88(12): p. 879-87. bleeding and other HHT-related more likely to rupture during pregnancy if untreated. Screening and preventative treat- 5. Shovlin, C.L., et al., Estimates of maternal risks of complications with labor and pregnancy for women with hereditary haemorrhagic ment for lung AVMs should be done prior delivery. telangiectasia (Osler-Weber-Rendu syndrome): to pregnancy, when possible. If lung screen- suggested approach for obstetric services. BJOG, There is no evidence to support this as a ing is negative, then lung AVMs are no lon- 2008. 115(9): p. 1108-15. 6. Wain, K., et al., Hereditary hemorrhagic telangiecta- routine approach. There are three main ger a concern for pregnancy and delivery. If the woman has lung AVMs and these have sia and risks for adverse pregnancy outcomes. Am J concerns that have led some doctors to Med Genet A, 2012. been successfully treated (and recently reas- recommend cesarean section for women 7. http://www.nichd.nih.gov/health/topics/high_risk_ sessed), then lung AVMs are not a concern with HHT. pregnancy.cfm

18 HEREDITARY HEMORRHAGIC TELANGIECTASIA THANK YOU FOR YOUR CONTRIBUTION TO THE LEARN ABOUT HHT BROCHURE

The HHT Foundation International would BARBARA BERNHARDT, MS, CGC SCOTT OLITSKY, MD like to acknowledge the individuals who Hospital of the University of Pennsylvania HHT Board Director Children’s Mercy Hospital and Clinic contributed to the medical information MARIE FAUGHNAN, MD, MSc presented in this brochure. Although University of Toronto / St. Michael’s Hospital REED PYERITZ, MD, PhD Hospital of the University of Pennsylvania the HHT Treatment Centers and the HHT JAMES GOSSAGE, MD Foundation are independent institutions, it Georgia Regents University LYNNE SEKARSKI, MSN, RN, CPN Washington University / St. Louis Children’s Hospital is through partnerships like this that RAJ KASTHURI, MD extraordinary outcomes are accomplished. University of North Carolina at Chapel Hill CLAIRE SHOVLIN, PhD, MA, FRCP Imperial College of London / Hammersmith Hospital JAMIE MCDONALD, MS, CGC University of Utah LORI SPANGENBERG, BSN, RN Washington University / St. Louis Children’s Hospital Join Our Community! We hope that you find this information Your donation to the HHT Foundation Your contribution will ensure that the HHT helpful and we encourage you to share it will fund important HHT specific Foundation continues to provide you with with your extended family members. initiatives: the most current information.

• Research The HHT Foundation International, Inc. Please consider making a contribution provides the primary source of informa- • International Guidelines Conference or becoming a member of the HHT tion about HHT throughout the world. • Physician’s Registry Foundation. As the only HHT patient advocacy • HHT Outcomes Project Your support is greatly appreciated. organization, we strive to find a cure for • Patient and Physician Education this disease while funding HHT research • National Awareness Campaign Your personal information is private and is not shared and educating patients and healthcare with a third party outside of the HHT Foundation. professionals.

“I think of the Foundation as the power plant ERIC CORNELL for HHT families - creating knowledge through Staff Scientist, National Institute of Science research, collating the knowledge through and Technology sponsored conferences, and spreading that Physics Professor, University of Colorado knowledge around through outreach. The HHT 2001 Nobel Prize Recipient HHT Foundation Member Foundation is the source of power we need to hold this troublesome condition at bay while we all go on to do the stuff in life we care about.”

Enclosed is my gift of $______. The HHT Foundation is a 501(c)(3) non-profit Please charge $ ______to my: organization. Donations are tax deductible as allowed 1 My company will match this gift by law. Tax ID: 22-311504 (circle one) Visa Mastercard 1 I pledge $ ______American Express Discover 1 I am donating securities and have asked my broker to contact the HHT Foundation International Card # ______Office at 410-357-9932 Signature ______

Name ______Expiration Date ______CVV Code ______Street ______1 Single installment 1 Multiple installments City, State, Zip ______Please charge $ ______for ___ months. Home Phone, Work Phone ______My gift is: In honor of ______Email______In memory of ______1 I prefer my gift remain anonymous www.hht.org 19 RESEARCH IS OUR FUTURE. . . “HHT is an inherited disease that affects over 1 million people worldwide. It is caused by defective blood vessels in the brain, lungs, liver, nose, skin, and intestines, and typically begins with nosebleeds during childhood. HHT is highly treatable but can result in serious health problems if not promptly diagnosed and treated”

HHT Foundation International P.O. Box 329, Monkton, MD 21111 phone (410) 357-9932 CureHHT.org