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  3. Hereditary hemorrhagic telangiectasia type 4
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Hereditary hemorrhagic telangiectasia type 4


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Other Names:
HHT4
Categories:
Blood Diseases; Congenital and Genetic Diseases; Digestive Diseases; Blood Diseases; Congenital and Genetic Diseases; Digestive Diseases; Eye diseases; Nervous System Diseases; Skin Diseases See More
This disease is grouped under:
Hereditary hemorrhagic telangiectasia

Summary Summary


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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 774

Definition
An inherited disorder of angiogenesis characterized by mucocutaneous telangiectases and visceral arteriovenous malformations.

Epidemiology
The prevalence is approximately 1/6,000

Clinical description
The most common clinical signs of hereditary hemorrhagic telangiectasia (HHT) include recurrent epistaxis (nosebleeds), frequently from childhood, and cutaneous or mucosal telangiectases generally presenting later, and increasing with age, where anemia may become an important part of the disease. Visceral arteriovenous malformations (AVMs) are usually asymptomatic but can lead to complications that produce highly variable manifestations. The age of onset of AVM-related complications is variable, ranging from childhood to geriatric age, with a few cases reported during the neonatal period. Pulmonary AVMs may manifest with brain abscesses, strokes, transient ischemic attacks, signs of chronic hypoxaemia or, rarely, haemorrhagic rupture. AVMs of the central nervous system can be haemorrhagic or, rarely, produce signs of slow compression. Hepatic AVMs, which can remain latent for a long time, in a limited proportion of patients become severe leading to high-output cardiac failure, portal hypertension, pulmonary hypertension or ischemic cholangitis. Hemorrhagic digestive telangiectases increase with age and can worsen chronic anemia.

Etiology
This genetic disorder is due to pathogenic variants primarily in ENG (9q34.11) or ACVRL1 (12q13.13), encoding proteins involved in vascular development and angiogenic homeostasis of capillaries. Mutations in SMAD4 (18q21.2) occur in rare cases (1-3%) and result in HHT associated with juvenile polyposis. In a small proportion of HHT families, the pathogenic gene variant has not yet been identified.

Diagnostic methods
The diagnosis is clinical and/or molecular. The clinical diagnosis is based on having at least three of the four Curaçao criteria: recurrent epistaxis, cutaneous/mucosal telangiectases, visceral involvement, and a first line family member with HHT. Genetic testing can be used to screen, to confirm a diagnosis, or to rule out the diagnosis if the pathogenic variant is known in the family.

Differential diagnosis
The differential diagnosis includes limited cutaneous systemic sclerosis, digestive angiodysplasias, isolated sporadic AVMs in the lungs, liver and brain, other vascular anomaly syndromes that cause AVMs; benign hereditary telangiectasia; and other causes of recurrent epistaxis (coagulation disorders or other local nasal factors).

Antenatal diagnosis
Prenatal genetic testing is possible in families where the pathogenic variant has been identified in the family, but is not necessary for proper pregnancy and delivery management. Decisions about prenatal genetic testing are the choice of the parents, but discussion of all related issues is appropriate. The usual antenatal scans will be offered, and sonographers aware of the presence of HHT in the family will detect most major AVMs.

Genetic counseling
Transmission is autosomal dominant. Penetrance is age dependent, the majority having symptoms before 50 years of age. The phenotype is highly variable, even between members of the same family.

Management and treatment
Disease management includes prevention and treatment of epistaxis and anaemia, screening for AVMs, and guidance regarding pregnancy-related issues. The management of pulmonary AVM(s) relies on early detection, occlusion where feasible, and ongoing care in cases of persistent pulmonary AVMs. For severe liver involvement, multidisciplinary patient assessment in a center with expertise in HHT is recommended. Usually, cerebral AVMs that have not bled are not treated, whereas cerebral AVMs that have already bled or have become symptomatic usually require treatment. Gastrointestinal telangiectases may sometimes be the cause of significant anemia, especially in older patients, and need specific management. Awareness of the possibility of AVMs/HHT is important for optimal management of diverse medical states. HHT due to a SMAD4 pathogenic variant requires polyposis screening and aortic follow up.

Prognosis
Life expectancy is reduced in unscreened patients. In patients assessed and treated for pulmonary AVMs in an HHT Center, life expectancy is comparable to the general population. Pregnancy-related death has been reported, and is a particular risk for women with pulmonary arteriovenous malformations.

Visit the Orphanet disease page for more resources.
Last updated: 1/1/2019

Symptoms Symptoms


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This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 48 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Epistaxis
Bloody nose
Frequent nosebleeds
Nose bleed
Nose bleeding
Nosebleed
[ more ]
0000421
Telangiectasia of the skin 0100585
30%-79% of people have these symptoms
Cavernous hemangioma
Collection of dilated blood vessels that forms mass
0001048
Cholecystitis
Gallbladder inflammation
0001082
Microcytic anemia 0001935
Migraine
Intermittent migraine headaches
Migraine headache
Migraine headaches
[ more ]
0002076
Portal hypertension 0001409
Spontaneous hematomas 0007420
Visceral angiomatosis 0100761
5%-29% of people have these symptoms
Amblyopia
Lazy eye
Wandering eye
[ more ]
0000646
Cerebral hemorrhage
Bleeding in brain
0001342
Cholelithiasis
Gallstones
0001081
Cirrhosis
Scar tissue replaces healthy tissue in the liver
0001394
Congestive heart failure
Cardiac failure
Cardiac failures
Heart failure
[ more ]
0001635
Conjunctival telangiectasia
Small dilated blood vessels near membrane covering front of eye and eyelids
0000524
Esophageal varix
Enlarged vein in esophagus
0002040
Gastrointestinal hemorrhage
Gastrointestinal bleeding
0002239
Hematuria
Blood in urine
0000790
Hemoptysis
Coughing up blood
0002105
Hepatic failure
Liver failure
0001399
Intestinal polyposis 0200008
Nephrolithiasis
Kidney stones
0000787
Peripheral arteriovenous fistula 0100784
Pulmonary arterial hypertension
Increased blood pressure in blood vessels of lungs
0002092
Pulmonary embolism
Blood clot in artery of lung
0002204
Retinal telangiectasia 0007763
Seizure 0001250
Subarachnoid hemorrhage 0002138
Transient ischemic attack
Mini stroke
0002326
Venous thrombosis
Blood clot in vein
0004936
Percent of people who have these symptoms is not available through HPO
Arteriovenous fistulas of celiac and mesenteric vessels 0002642
Autosomal dominant inheritance 0000006
Cerebral arteriovenous malformation 0002408
Cyanosis
Blue discoloration of the skin
0000961
Dilatation of celiac artery 0100858
Dilatation of mesenteric artery 0011934
Dyspnea
Trouble breathing
0002094
High-output congestive heart failure 0001722
Ischemic stroke 0002140
Lip telangiectasia 0000214
Nasal mucosa telangiectasia
Spider veins of mucosa of nose
Spider veins of mucous membrane of nose
Spider veins of nasal mucous membrane
[ more ]
0000434
Palate telangiectasia
Telangiectasia of the roof of the mouth
0002707
Pulmonary arteriovenous malformation 0006548
Right-to-left shunt 0001694
Spinal arteriovenous malformation 0002390
Spontaneous, recurrent epistaxis
Recurring nosebleed
Spontaneous, recurrent nosebleed
[ more ]
0004406
Tongue telangiectasia 0000227
Venous varicosities of celiac and mesenteric vessels 0002626
Showing of 48 |
Do you have more information about symptoms of this disease? We want to hear from you.
Last updated: 2/1/2021
Do you have updated information on this disease? We want to hear from you.

Find a Specialist Find a Specialist


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If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

  • To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Research Research


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Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • The Centers for Mendelian Genomics program is working to discover the causes of rare genetic disorders. For more information about applying to the research study, please visit their website.

Patient Registry

  • The Brain Vascular Malformation Consortium is a team of doctors, nurses, research coordinators, and research labs throughout the U.S., working together to improve the lives of people with familial cavernous malformations, Sturge-Weber syndrome, hereditary hemorrhagic telangiectasia through research. The Brain Vascular Malformation Consortium has a list of studies for patients who wish to learn more.

    For more information: https://www.rarediseasesnetwork.org/cms/bvmc/Get-Involved/Studies

Organizations Organizations


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Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Providing General Support

  • The Aneurysm and AVM Foundation (TAAF)
    182 Howard St.
    Box 715
    San Francisco, CA 94105
    Telephone: (510) 464-4540
    Fax: (510) 464-4540
    E-mail: info@taafonline.org
    Website: https://taafonline.org/
Do you know of an organization? We want to hear from you.

Learn More Learn More


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These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
  • The Brain Vascular Malformation Consortium has information and frequently asked questions about Hereditary hemorrhagic telangiectasia type 4 for patients and their families.
    Learn More About Hereditary Hemorrhagic Telangiectasia (HHT)
    Frequently Asked Questions about HHT

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Hereditary hemorrhagic telangiectasia type 4. Click on the link to view a sample search on this topic.

News & Events News & Events


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News

  • Rare Disease Day at NIH 2021
    March 1, 2021

GARD Answers GARD Answers


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Have a question? Contact a GARD Information Specialist.
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