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Disease Profile

Hereditary hemorrhagic telangiectasia type 4

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

HHT4

Categories

Blood Diseases; Congenital and Genetic Diseases; Digestive Diseases;

Summary

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.

Symptoms

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.

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

Organizations

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

    Learn more

    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

      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.