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Hereditary haemorrhagic telangiectasia type 1
Also known as Hereditary haemorrhagic telangiectasia (pulmonary AVM) · Hereditary haemorrhagic telangiectasia type 2 · Hereditary haemorrhagic telangiectasia (SMAD4)
HHT is a condition where certain blood vessels, called telangiectasias and arteriovenous malformations, do not form correctly. This can cause nosebleeds, bleeding in other organs, and may affect the lungs, brain, or liver. It is an inherited condition that can affect individuals from birth, though symptoms typically appear later.
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Overview
Hereditary Haemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a genetic disorder that affects how blood vessels develop [PMID:32657158]. Individuals with HHT typically have fragile, dilated blood vessels called telangiectasias, which are often found on the skin, mucous membranes (such as the lining of the nose and mouth), and internal organs. These can bleed easily, leading to symptoms like frequent nosebleeds. More serious complications can arise from larger abnormal connections between arteries and veins, known as arteriovenous malformations (AVMs), which can develop in organs like the lungs, brain, or liver [PMID:32657158].
HHT is an inherited condition, meaning it is passed down through families. It is relatively rare, affecting approximately 1 in 5,000 to 1 in 8,000 people. Although individuals are born with the genetic predisposition, symptoms often develop gradually over time and can vary significantly among affected family members, even those with the same genetic change. The impact of HHT can range from mild, primarily aesthetic concerns to severe, life-threatening complications, depending on the location and size of the blood vessel abnormalities.
In the UK, individuals suspected of having HHT would typically be referred through the NHS for specialist assessment and genetic testing, usually via a clinical genetics service. Management focuses on preventing and treating bleeding, as well as monitoring for and addressing potential complications in major organs. Family members of affected individuals may also be offered genetic counselling and testing.
Symptoms & clinical features
The symptoms of HHT can vary widely, even within the same family. The most common symptom is recurrent nosebleeds (epistaxis), which typically begin in childhood or adolescence and can range from mild to severe, often requiring medical intervention [PMID:32657158]. These nosebleeds are caused by fragile telangiectasias within the nasal lining.
Visible telangiectasias, small red or purple spots, may also appear on the skin, particularly on the lips, tongue, face, and fingertips. While these skin lesions are generally harmless, they can sometimes bleed. Internal telangiectasias can occur in the gastrointestinal (GI) tract, leading to chronic blood loss that may result in iron-deficiency anaemia [PMID:32657158]. Symptoms of GI bleeding can include dark or bloody stools, fatigue, and shortness of breath due to anaemia.
More significant symptoms arise from AVMs in internal organs. Pulmonary AVMs (PAVMs) are common and can allow blood to bypass the normal filtering process in the lungs, potentially leading to reduced oxygen levels, shortness of breath, and an increased risk of stroke or brain abscess [PMID:32657158]. Cerebral AVMs (CAVMs) in the brain carry a risk of haemorrhage, which can cause strokes, seizures, or other neurological problems. Hepatic AVMs (HAVMs) in the liver can sometimes lead to heart failure or liver dysfunction, although many individuals with HAVMs remain asymptomatic. Regular screening and monitoring are important to detect these internal AVMs before they cause severe complications.
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Affected organs
HHT can affect various organs and body systems due to the widespread nature of abnormal blood vessel formation. The most frequently affected areas include the nose and mouth, where telangiectasias cause recurrent nosebleeds and visible lesions on the lips and tongue.
Internally, the lungs are a common site for AVMs (pulmonary AVMs), which can allow deoxygenated blood to pass directly into the systemic circulation, potentially leading to hypoxaemia (low blood oxygen levels) and increasing the risk of paradoxical emboli, which can travel to the brain. The brain can also develop AVMs (cerebral AVMs), which carry a risk of bleeding or seizures. The liver is another organ where AVMs (hepatic AVMs) can occur, sometimes leading to high-output heart failure or biliary complications. The gastrointestinal tract, from the oesophagus to the rectum, can develop telangiectasias that cause chronic blood loss and iron-deficiency anaemia. Less commonly, HHT can affect other organs such as the spine or eyes, though these are rarer manifestations.
Risks & severity
The severity of HHT can vary significantly, even within the same family, making it challenging to predict the course of the condition for any one individual. While most individuals experience recurrent nosebleeds, the risk and severity of internal organ complications differ. For instance, the lifetime risk of developing pulmonary AVMs is approximately 30-50%, while cerebral AVMs are found in about 5-20% of affected individuals [PMID:20301389]. Hepatic AVMs are also common, reported in up to 70% of individuals, though many remain asymptomatic [PMID:20301389].
Complications such as stroke or brain abscess due to pulmonary AVMs can be life-threatening if not identified and treated. Bleeding from cerebral AVMs also carries a significant risk of severe disability or death. The age of onset for symptoms varies; nosebleeds often begin in childhood or adolescence, while complications from internal AVMs may emerge later in life. Regular screening and surveillance are crucial for early detection and management of these risks, helping to mitigate severe outcomes. The variability in symptoms and complications underscores the importance of a comprehensive, personalised approach to care.
Genetic causes
Hereditary Haemorrhagic Telangiectasia is caused by pathogenic variants in specific genes that are involved in the transforming growth factor-beta (TGF-β) signalling pathway, which plays a crucial role in blood vessel development and repair. The most common genetic causes of HHT are variants in the ENG gene, leading to HHT type 1, and the ACVRL1 gene, associated with HHT type 2 [PMID:20301389]. A third, less common cause is linked to variants in the SMAD4 gene.
The ENG gene provides instructions for making endoglin, a protein found on the surface of cells, particularly endothelial cells that line blood vessels. Endoglin helps regulate the TGF-β signalling pathway, which is essential for the formation and maturation of blood vessels. Pathogenic variants in ENG disrupt this process, leading to the formation of fragile and abnormal blood vessels characteristic of HHT.
Similarly, the ACVRL1 gene encodes the activin receptor-like kinase 1 (ALK1) protein, another cell surface receptor involved in the TGF-β signalling pathway. ALK1 is vital for proper blood vessel formation and its interaction with TGF-β influences how new blood vessels differentiate. Pathogenic variants in ACVRL1 impair ALK1 function, contributing to the vascular abnormalities seen in HHT. The SMAD4 gene encodes a protein that acts as a signal transducer, mediating signals from the cell surface to the nucleus within the TGF-β pathway. Variants in SMAD4 can also disrupt this critical pathway, affecting cell proliferation and gene activity, and leading to HHT symptoms.
- ACVRL1 activin A receptor like type 1The ACVRL1 gene provides instructions for a protein essential in blood vessel development and specialisation, particularly for arteries and veins.
- ENG endoglin
- SMAD4 SMAD family member 4The SMAD4 gene provides instructions for a protein crucial in cellular signalling, regulating cell growth and division, and acting as a tumour suppressor.
Inheritance pattern
Hereditary Haemorrhagic Telangiectasia (HHT) has an autosomal dominant inheritance pattern. This means that an individual only needs to inherit one copy of a pathogenic gene variant from either parent to develop the condition. There is no difference in how the condition presents in males or females.
If one parent has HHT, each child they have has a 50% (1 in 2) chance of inheriting the pathogenic variant and therefore developing the condition. This 50% chance applies to each pregnancy. If a child inherits the variant, they will have HHT, though the specific symptoms and their severity can vary greatly, even among family members who have inherited the same genetic change. If a child does not inherit the variant, they will not develop HHT and cannot pass it on to their own children. Genetic counselling is strongly recommended for families with HHT to understand these inheritance patterns and discuss options for genetic testing.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Subtypes & variants
This page covers Hereditary haemorrhagic telangiectasia type 1 as a single condition. Several distinct variants and clinical subtypes are recognised in the literature - they share the underlying biology and broad management approach, but differ in severity, age of onset, or causative gene:
- With pulmonary AVMs OMIM 187300
Pulmonary arteriovenous malformations occur in roughly half of HHT patients and are most strongly associated with HHT type 1. Untreated PAVMs carry stroke and brain abscess risk; embolisation is the standard treatment.
- Type 2 (ACVRL1) ACVRL1 OMIM 600376
ACVRL1-related HHT. Pulmonary AVMs are less common than in type 1, but hepatic AVMs and pulmonary hypertension are more frequent.
- SMAD4 - combined HHT + JPS SMAD4 OMIM 175050
SMAD4 carriers have a combined syndrome of HHT and juvenile polyposis. Colonoscopic surveillance is required from adolescence in addition to standard HHT screening.
Diagnosis & testing
A diagnosis of HHT is typically made based on specific clinical criteria, known as the 'Curaçao criteria', which assess clinical features such as recurrent nosebleeds, visible telangiectasias, internal organ involvement (e.g., AVMs), and a family history of HHT [PMID:32657158]. Meeting three out of four of these criteria suggests a definite diagnosis, while two indicate a suspected diagnosis.
Genetic testing is used to confirm the diagnosis and identify the specific pathogenic variant in genes such as ENG, ACVRL1, or SMAD4. This is often performed as part of an NHS Genomic Medicine Service (GMS) pathway. A referral to a clinical genetics service is typically made by a GP or specialist if HHT is suspected, and a genetic counsellor can explain the testing process, its implications, and the potential impact on family members. The relevant NHS National Genomic Test Directory R-codes for HHT testing include R259 Hereditary haemorrhagic telangiectasia. Genetic testing can also be offered to asymptomatic relatives at risk once a pathogenic variant has been identified in the family, which can aid in early surveillance and management.
Management & lifestyle
Management of Hereditary Haemorrhagic Telangiectasia (HHT) is multidisciplinary and focuses on preventing and treating symptoms, as well as monitoring for and managing complications. There is no cure for HHT, so treatment aims to alleviate symptoms and reduce the risk of serious events. Regular surveillance is key, particularly for internal AVMs in the lungs and brain, as early detection allows for timely intervention before complications arise [PMID:32657158].
Common management strategies for nosebleeds include nasal humidification, topical treatments to promote clotting, and sometimes cauterisation or laser therapy. For significant gastrointestinal bleeding leading to anaemia, iron supplements are often prescribed, and in some cases, endoscopic treatments or medications that can help reduce bleeding may be considered. Pulmonary AVMs are often treated with embolisation, a procedure to block the abnormal blood vessels, which significantly reduces the risk of stroke or brain abscess [PMID:20301389]. Cerebral AVMs may be managed through surgical removal, embolisation, or stereotactic radiosurgery, depending on their size and location. Hepatic AVMs are usually monitored, and treatment is reserved for those causing severe symptoms like heart failure.
Individuals with HHT are typically managed through specialist NHS centres with expertise in the condition, often involving a team of specialists including respiratory physicians, neurologists, gastroenterologists, interventional radiologists, and clinical geneticists. Genetic counsellors play a vital role in providing information and support to individuals and families. Lifestyle considerations, such as avoiding activities that increase the risk of nosebleeds (e.g., certain sports or medications that thin the blood), may also be discussed.
UK care pathway
In the UK, individuals suspected of having Hereditary Haemorrhagic Telangiectasia (HHT) are typically referred through their General Practitioner (GP) or a specialist to a clinical genetics service or a specialised HHT centre within the NHS. These centres offer a multidisciplinary approach to diagnosis and management. The diagnostic process often involves clinical assessment and genetic testing, which is available via the NHS Genomic Medicine Service (GMS). Genetic tests for HHT are listed in the National Genomic Test Directory under specific R-codes, such as R259 for Hereditary haemorrhagic telangiectasia.
Upon diagnosis, individuals and their families are usually offered genetic counselling. This service provides detailed information about the condition, its inheritance pattern, and the implications for family planning and cascade screening of at-risk relatives. Ongoing care involves regular monitoring and management by a team of specialists, tailored to the individual's specific symptoms and organ involvement, following established national guidelines and care pathways.
Frequently asked questions
What are the most common symptoms of HHT?
The most common symptoms of HHT are frequent and sometimes severe nosebleeds, which often begin in childhood or adolescence. Many individuals also develop small red spots called telangiectasias on their skin or mucous membranes, especially on the lips and fingertips.
Can HHT affect internal organs?
Yes, HHT can affect internal organs, especially the lungs, brain, and liver, where it can cause larger abnormal blood vessels called arteriovenous malformations (AVMs). These AVMs can lead to serious complications like stroke, brain abscess, or heart problems.
How is HHT inherited?
HHT is inherited in an autosomal dominant pattern. This means if one parent has HHT, there is a 50% chance with each pregnancy that their child will inherit the condition. It affects males and females equally.
Is there a cure for HHT?
Currently, there is no cure for HHT. However, treatments are available to manage symptoms, prevent complications, and improve quality of life. This often involves regular monitoring and specific interventions for bleeding or AVMs in internal organs.
How is HHT diagnosed in the UK?
Diagnosis in the UK typically involves a clinical assessment based on specific criteria, followed by genetic testing through the NHS Genomic Medicine Service. A referral to a clinical genetics service is usually the first step, often arranged by your GP or a specialist.
References
- Giordano P, Francavilla M, Buonamico P. Hepatic angiodynamic profile in paediatric patients with hereditary haemorrhagic telangiectasia type 1 and type 2. VASA. Zeitschrift fur Gefasskrankheiten. 2017. PMID: 28248153
- Abdalla SA, Geisthoff UW, Bonneau D. Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. Journal of medical genetics. 2003. PMID: 12843319
- Jerkic M, Kabir MG, Davies A. Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress. Cardiovascular research. 2011. PMID: 21859819
- Tracy EP, Adereti I, Chu J. Hereditary haemorrhagic telangiectasia type 1 complicated by recurrent deep-seated MSSA infections necessitating lifelong antibiotic suppression. BMJ case reports. 2024. PMID: 39375159
- Raab U, Velasco B, Lastres P. Expression of normal and truncated forms of human endoglin. The Biochemical journal. 1999. PMID: 10215596
- Hume AN, John A, Akawi NA. Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations. Molecular and cellular biochemistry. 2013. PMID: 23124896
- Johnson DW, Berg JN, Baldwin MA. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nature genetics. 1996. PMID: 8640225
- Chan NL, Bourdeau A, Vera S. Umbilical vein and placental vessels from newborns with hereditary haemorrhagic telangiectasia type 1 genotype are normal despite reduced expression of endoglin. Placenta. 2004. PMID: 14972453