Hereditary Hemorrhagic Telangiectasia

rarediseases.org/rare-diseases/hereditary-hemorrhagic-telangiectasia/

NORD gratefully acknowledges Andrew McAsey, NORD Editorial Intern from the University of Notre
Dame, and Reed E. Pyeritz, MD, PhD, William Smilow Professor of Medicine & Professor of Genetics,
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, for
assistance in the preparation of this report.

Synonyms of Hereditary Hemorrhagic Telangiectasia

HHT
Osler-Weber Rendu syndrome
Rendu-Osler-Weber syndrome

Subdivisions of Hereditary Hemorrhagic Telangiectasia

hereditary hemorrhagic telangiectasia type I
hereditary hemorrhagic telangiectasia type II
hereditary hemorrhagic telangiectasia type III
hereditary hemorrhagic telangiectasia type V
hereditary hemorrhagic telangiectasis type IV

General Discussion
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). Chronic nosebleeds are
often the first sign and malformation of various blood vessels may result in
abnormalities affecting the lungs, brain, spinal cord, and liver. A variety of treatments
exist for the various features of HHT to improve quality of life and prevent life-
threatening complications. Individuals with HHT have a near-normal life expectancy.
HHT is inherited as an autosomal dominant trait.

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
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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.

Signs & Symptoms

The symptoms associated with HHT vary from person to person. Differences in disease
expression (phenotype) partially reflect the specific gene that is mutated in HHT. Some
individuals may experience symptoms during infancy or early childhood; others may
show few signs or symptoms until the thirties, forties or later in life.

In many patients, the first apparent symptom of HHT is nosebleeds (epistaxis).

Recurrent nosebleeds occur in most affected individuals. Nosebleeds occur because of
the formation of small red lesions (telangiectases) in the mucous membranes lining the
inside of the nose. Telangiectases occur when capillaries fail to develop between
arterioles and venules and most often affect the skin and the mucous membranes. The
tongue, lips, face, ears, and fingers are the areas most often affected. Telangiectases
may develop at any age including during infancy, but usually become apparent during
adolesence and later.

Telangiectases also occur in the gastrointestinal tract and in additional organs,

including the lungs, brain, spinal cord and liver. While recurrent nosebleeds may be
apparent at any age, they most often begin around puberty. Gastrointestinal bleeding
(hemorrhaging), which affects about 25-30%, does not present until the fourth decade
of life or later. Affected individuals with gastrointestinal bleeding rarely have dark,
bloody stools (melena) or episodes of bloody vomit (hematemesis). Most often, blood
loss is not detected by the patient but leads to anemia.

Because bleeding episodes become more severe with age, they often lead to chronically
low levels of iron in circulating red blood cells (anemia). Anemia may result in chest
pain, shortness of breath, and/or fatigue. Gastrointestinal bleeding can often be slow,
chronic and intermittent, with few noticeable symptoms until the onset of anemia.

Most individuals with HHT develop arteriovenous malformations (AVMs). AVMs, which
are direct connections between blood vessels of larger caliber than in telangiectases,
affect the lungs, brain, spinal cord, and liver.

PAVMs may result in fatigue, difficulty breathing (dyspnea), episodes of coughing up of

blood (hemoptysis), headaches, abnormal bluish discoloration of the skin due to low
levels of circulating oxygen in the blood (cyanosis), and/or abnormally increased levels
of red cells in the blood (polycythemia). Serious neurological complications, including
brain abscesses and stroke, may occur due to passage of blood clots or bacteria
through a PAVM.

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AVMs of the brain exist in a minority of individuals with HHT and may result in
headache, dizziness (vertigo), and seizures. In rare cases, individuals with AVMs of the
brain may experience vision and hearing problems such as double vision (diplopia).
However, usually they are asymptomatic prior to a hemorrhagic event. AVMs affecting
the spinal cord (approximately 1% of those with HHT) are less common and may result
in pain in the back and/or loss of feeling or functions of the arms and legs.

Liver vascular malformations may not cause symptoms or can result in liver or heart
failure. Individuals may experience high blood pressure in the veins carrying blood from
the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension)
and abnormalities of the bile ducts (biliary disease). The bile ducts are narrow tubes
through which bile passes from the liver to the first section of the small intestine.
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).

Heart failure may occur because over time the heart is forced to work extra hard
(hyperdynamic circulation) to compensate for excessive blood flow between the hepatic
vein and the hepatic artery.

Causes
HHT is inherited as an autosomal dominant trait. In rare cases, the disorder occurs
randomly as the result of a spontaneous genetic change (i.e., new mutation). 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 600 different
mutations found within the four genes known to cause HHT.

Human traits, including the classic genetic diseases, are the product of the interaction of
two copies of a gene for that condition, one received from the father and one from the
mother. In dominant disorders, only a single copy of the disease gene (received from
either the mother or father) is required to cause the disease. The risk of transmitting
the disorder from affected parent to offspring is 50 percent for each pregnancy,
regardless of the gender of the resulting child.

Researchers have identified four genes that cause HHT. At least one and perhaps more
genes are yet to be discovered.

One gene that causes HHT (ENG), and the protein it produces (encodes), is called
endoglin. Endoglin is found on the surface of the cells that line the inside of the blood
vessels. Scientists believe that endoglin binds to transforming growth factor-beta (TGF-
ß). In mice that are deficient in endogolin, the blood vessels do not mature and there is
a failure in vascular smooth muscle development.

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Another gene that causes HHT is activin receptor-like kinase 1 (ACVRL1) gene. People
with mutations in this gene are somewhat more prone to liver AVMs and to elevated
pressure on the right side of the heart (pulmonary hypertension).

Mutations in another gene that primarily causes familial pulmonary hypertension,

BMPR9, is occasionally associated with the vascular features of HHT.

A distinct type of HHT is a rare combination of HHT and juvenile polyposis, a disorder
involving polyps in the gastrointestinal tract. This type of HHT is caused by mutations in
SMAD4.

The genes that cause HHT all code for proteins involved in the TGF-ß/BMP (for bone
morphogenic protein) superfamily of signaling. This group of proteins helps regulate
many cellular functions such as cell survival, proliferation, and differentiation. With
malfunctioning signaling, the cells of blood vessels cannot form correctly (angiogenesis),
causing the features of HHT.

Affected Populations
HHT affects males and females in equal numbers. Symptoms can occur at any age. The
disorder is estimated to occur in at least 1 per 5,000 people. However, because some
affected individuals develop few obvious symptoms and findings, the disorder often
remains unrecognized. HHT is known to be underdiagnosed. This makes it difficult to
determine the true frequency of HHT in the general population.

Related Disorders
Symptoms of the following disorders can be similar to those of hereditary hemorrhagic
telangiectasia. Comparisons may be useful for a differential diagnosis:

Von Willebrand disease (VWD) is a common inherited bleeding disorder in the general
population affecting males and females equally. There are three main types of VWD
each with differing degrees of severity and inheritance patterns. Von Willebrand
disease has occurred in individuals who also haveHHT. (For more information on this
disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)

Calcinosis-Raynaud’s-Sclerodactyly-Esophageal dysfunction-Telangiectasia syndrome

(CREST syndrome) is a combination of various symptoms, and is related to scleroderma.
Scleroderma is a rare disorder characterized by thickening and hardening of the skin.
Telangiectases are also present is this disorder. (For more information, choose
“Scleroderma” as your search terms in the Rare Disease Database.)

Ataxia telangiectasia (AT) is a complex genetic neurodegenerative disorder that may

become apparent during infancy or early childhood. The disorder is characterized by
progressively impaired coordination of voluntary movements (ataxia); the development
of reddish lesions of the skin and mucous membranes due to permanent widening of
groups of blood vessels (telangiectasia); and impaired functioning of the immune
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system (i.e., cellular and humoral immunodeficiency), resulting in increased
susceptibility to upper and lower respiratory infections (sinopulmonary infections).
Individuals with AT also have an increased risk of developing certain malignancies,
particularly of the lymphatic system (lymphomas), the blood-forming organs (e.g.,
leukemia), and the brain. (For more information, choose “Ataxia-Telangiectasia” as your
search terms in the Rare Disease Database.

Diagnosis
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 nosebleeds; the presence of multiple
telangiectases in characteristic locations; the presence of internal (visceral)
telangiectases or AVMs; and a family history of HHT. A diagnosis is confirmed if three of
the four criteria are present.

Molecular genetic testing is available to determine if a mutation is present in ENG,

ACVR1, SMAD4, or BMPR9. This testing is particularly important for children of an
affected parent whose mutation is known because an offspring 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 diagnostic criteria.

Clinical Testing and Work-Up

After a diagnosis of HHT has been made from a clinical assessment and detailed family
history, an individual with HHT will begin the process of screening for asymptomatic
manifestations for the disease and treatment of existing problems. Current symptoms
will be identified and severity assessed for best possible treatment (for example
nosebleeds). Then, patients will be referred to organ specialists for the various systems
affected by HHT (lungs, liver, gastrointestinal tract, brain). Those specialists will consult
with the patient, using their current symptoms and family history to determine
frequency of screening of AVMs in the lungs and brain, and liver. If the brain has no
vascular malformations as a child, then the imaging should be repeated in late
adolescence. If the brain is unaffected in late adolescence, then it does not need to be
screened again. Similarly, if the lungs are either treated in early adulthood or
unaffected, further screening is not needed.

Standard Therapies
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 (www.hht.org) that include brain MRI procedures to
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screen for cerebral AVM upon diagnosis. For patients with confirmed diagnosis, starting
at 10 years of age, a contrast echocardiogram should be performed. If more than a few
bubbles of contrast show late passage through the lungs, then a chest CT scan should
be performed to determine if an AVM large enough to be treated is present. Once an
adult, no further regular screening for PAVMs is required.

Nosebleeds can often be temporarily relieved with lubrication or the application of

pressure to the affected areas. If conservative measures are insufficient, then the
patient should be seen by a specialist (rhinologist) experienced with HHT. Ablation,
using a laser of telangiectases in the nasal mucosa can provide temporary relief. More
aggressive surgical therapies are possible when the patient is severely anemic from
nasal blood loss. Several experimental medical therapies are being studied.

Transcatheter embolization is currently the recommended treatment for lung AVMs

that have a feeder artery that can be entered by a catheter.

AVMs of the brain are usually treated by surgical removal, embolization, or treatment of
the affected area with radiation. Specific therapy for AVMs affecting the brain varies
from person to person.

Because of the risk of complications, treatment of AVMs affecting the liver is only
undertaken if an affected individual is in liver or heart failure. Screening for liver AVMs
will only take place if the patient is symptomatic. Liver transplants offer a more long
term treatment for liver failure, but with greater risk.

Treatment of telangiectases of the gastrointestinal tract is usually pointless, either

because there are so many mucosal telangiectases or they are in the small bowel,
which cannot be examined by an endoscope. In older adults, persistent anemia may
occur. There have been some experimental treatments to treat gastrointestinal
bleeding with hormone treatments or antifibrinolytic treatments, but the effectiveness
and safety of these techniques are still unknown.

Iron replacement therapy, either orally or by transfusing iron dextran, are used to treat
anemia secondary to the nose or GI bleeding associated with HHT. Blood transfusions
are a last resort.

Investigational Therapies
Antifibrinolyic drugs such as tranexamic acid have been found to have mixed results in
treating nosebleeds in individuals and carry a risk of developing blood clots elsewhere.

Bevacizumab (Avastin) has been used experimentally to reduce the number and
severity of nosebleeds in persons with HHT. While results are promising in reducing
nosebleeds, the proper dosing, route of administration and treatment frequency for
individuals with HHT has yet to be determined.

Estrogen and progesterone therapy, either alone in combination, have been used
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experimentally to prevent recurrent bleeding associated with HHT. Reports of the
effectiveness of these treatments have varied in the medical literature. Further research
is needed to determine the long-term safety and effectiveness of these treatments for
HHT.

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]

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/

NORD Member Organizations

Cure HHT Foundation
P.O. Box 329
Monkton, MD 21111 USA
Phone: (410) 357-9932
Email: [email protected]
Website: http://www.curehht.org/

Other Organizations
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/
March of Dimes
1550 Crystal Dr, Suite 1300
Arlington, VA 22202 USA
Phone: (888) 663-4637
Website: http://www.marchofdimes.org

References
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Emery and Rimoin’s Essential Medical Genetics. Oxford: Academic Press, 2013;192-5.

JOURNAL ARTICLES
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

Faughnan, M. E., et al. International guidelines for the diagnosis and management of
hereditary haemorrhagic telangiectasia. Journal of medical genetics. 2011:48.2:73-87.

Karnezis, Tom T., and Terence M. Davidson. 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, 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, Fatima S., and Claire L. Shovlin. Hereditary haemorrhagic telangiectasia: a

clinical and scientific review. European Journal of Human Genetics. 2009:17.7: 860-871.

Jameson, John J., and David R. Cave. Hormonal and antihormonal therapy for epistaxis
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Sabbà, Carlo, Mauro Gallitelli, and Giuseppe Palasciano. Efficacy of unusually high doses
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