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Connective Tissue

Vascular Ehlers-Danlos syndrome

Vascular Ehlers-Danlos syndrome (vEDS) is an inherited condition that weakens connective tissues throughout the body, most notably affecting arteries and internal organs. It can lead to serious complications such as arterial ruptures or organ perforations, and typically manifests in early to middle adulthood.

Autosomal dominant Connective Tissue Tier A OMIM:130050
1:50,000–200,000
Prevalence
Population estimate
50%
Inheritance
Autosomal dominant - chance of passing to each child
1
Associated genes
COL3A1

Overview

Vascular Ehlers-Danlos syndrome (vEDS) is one of the most serious forms of Ehlers-Danlos syndromes, a group of inherited disorders that affect connective tissues. Connective tissue provides strength and elasticity to various structures in the body, including skin, blood vessels, and internal organs. In vEDS, this tissue is abnormally fragile, making individuals susceptible to potentially life-threatening complications.

vEDS is often recognised in adolescents or young adults, but symptoms can emerge at any age. It is a rare condition, affecting approximately 1 in 50,000 to 200,000 people. Due to its serious nature, early and accurate diagnosis is crucial for appropriate management and to help improve outcomes.

Symptoms & clinical features

The symptoms of vEDS can vary significantly among individuals, even within the same family. However, common features often relate to the fragility of blood vessels, skin, and internal organs. Individuals with vEDS may have thin, translucent skin where blood vessels are easily visible, especially over the chest and abdomen. Easy bruising is also a common sign, sometimes occurring with minimal trauma [PMID:25721871].

Characteristic facial features can include thin lips, a small chin, and prominent eyes, though these are not present in all affected individuals. Joint hypermobility, or 'double-jointedness', is typically limited to the small joints of the fingers and toes, unlike other forms of Ehlers-Danlos syndrome where large joint laxity is more common. Recurring spontaneous pneumothorax (collapsed lung) may also occur. Serious complications, such as arterial ruptures or organ perforations, can be the first indication of vEDS in some individuals, often presenting as acute medical emergencies [PMID:25721871].

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Affected organs

Vascular Ehlers-Danlos syndrome primarily affects organs and tissues rich in type III collagen. The most critical impact is on the arterial system, where medium-sized arteries are particularly vulnerable to aneurysms (bulges), dissections (tears in the vessel wall), and ruptures. These vascular events can be life-threatening and may occur in arteries supplying the brain, heart, kidneys, or intestines.

Internal organs, including the intestines and uterus, are also susceptible to spontaneous rupture or perforation due to weakened connective tissue. The lungs can be affected, leading to spontaneous pneumothorax. In pregnant women with vEDS, there is an increased risk of uterine rupture or major arterial complications during pregnancy and childbirth [PMID:25721871].

Multiple body systems
Multiple body systems
Systemic involvement
Cellular impact
Cellular impact
Mechanism at cellular level

Risks & severity

Vascular Ehlers-Danlos syndrome is considered the most severe type of Ehlers-Danlos syndrome due to the high risk of life-threatening vascular and organ complications. The lifetime risk of a major vascular event, such as an arterial rupture or dissection, is substantial, and these events can lead to sudden death. The median age for the first major complication is typically in the early 30s, but they can occur earlier or later [PMID:19160391].

Complications such as bowel perforation or uterine rupture also contribute significantly to morbidity and mortality. While there is a broad spectrum of severity, even individuals with milder external features can experience severe internal complications. Regular monitoring and proactive management are therefore essential to mitigate these risks.

Genetic causes

Vascular Ehlers-Danlos syndrome is primarily caused by pathogenic variants in the COL3A1 gene. This gene provides instructions for making a component of type III collagen, known as the pro-alpha1(III) chain. Type III collagen is a vital protein that gives strength and elasticity to connective tissues found in blood vessels, skin, intestines, and other organs.

Pathogenic variants in COL3A1 can lead to a deficiency in functional type III collagen or the production of abnormal collagen. This defective collagen weakens the connective tissues, making them fragile and prone to tearing or rupturing. The severity of the condition can depend on the specific type of genetic alteration and its impact on collagen production or structure.

  • COL3A1
    collagen type III alpha 1 chain
    The COL3A1 gene provides instructions for making type III collagen, a crucial component of connective tissues, playing a vital role in the integrity of blood vessels, skin, and internal organs.

Inheritance pattern

Vascular Ehlers-Danlos syndrome is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered COL3A1 gene from either parent to develop the condition. If a parent has vEDS, there is a 50% chance with each pregnancy that their child will inherit the pathogenic variant and also have the condition.

In some cases, vEDS can result from a new (de novo) pathogenic variant in the COL3A1 gene that occurs for the first time in an individual and is not inherited from either parent. In such situations, the affected person is the first in their family to have the condition, but they can then pass it on to their children in an autosomal dominant manner.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

Diagnosis & testing

Diagnosis of vEDS typically begins with a clinical evaluation, where a doctor assesses an individual's symptoms and family history. Confirmation of a vEDS diagnosis usually relies on genetic testing for pathogenic variants in the COL3A1 gene. This testing can be performed through a blood test and is crucial given the condition's serious implications.

In the UK, genetic testing for vEDS falls under the NHS Genomic Medicine Service (GMS) pathways. Referrals for genetic testing are often made by a clinical geneticist or other specialist, particularly when there is a strong suspicion based on clinical features or family history. The relevant R-code for testing COL3A1 for vEDS is R43 (Inherited Connective Tissue Disorders). Genetic counselling is an integral part of the diagnostic process, helping individuals and families understand the condition, its inheritance, and implications.

Management & lifestyle

Managing vEDS focuses on surveillance to detect potential complications early and implementing strategies to minimise risks. Regular imaging of arteries, such as MRI or CT angiography, is often recommended to monitor for aneurysms or dissections. Blood pressure control is also important, with some research suggesting that certain beta-blocker medications may help reduce arterial complications, though treatment decisions are individualised [PMID:28751512].

Individuals with vEDS are advised to avoid activities that could cause trauma or put excessive strain on their arteries, such as contact sports or heavy lifting. Lifestyle modifications and careful planning are encouraged, especially during pregnancy for women with vEDS. Multidisciplinary care involving cardiologists, vascular surgeons, and geneticists, often coordinated through clinical genetics services, is typical for individuals with this condition in the UK. This coordinated approach ensures comprehensive support and access to specialist advice.

UK care pathway

In the UK, individuals suspected of having vEDS will typically be referred to a clinical geneticist or a specialist service for connective tissue disorders within the NHS. These services are part of the NHS Genomic Medicine Service (GMS) network, which provides access to specialised diagnostic and management pathways.

Following a referral, a clinical geneticist will assess symptoms, family history, and determine the appropriateness of genetic testing. Genetic counselling is offered as a standard part of this pathway, providing essential information and support. For confirmed diagnoses, ongoing care is often managed by a multidisciplinary team to address the complex needs associated with vEDS, following established clinical guidelines and utilising relevant NHS R-codes for genetic testing, such as R43 for Inherited Connective Tissue Disorders.

Frequently asked questions

What is the life expectancy for someone with vEDS?

Life expectancy for individuals with vEDS can be reduced due to the risk of life-threatening vascular and organ complications. However, with early diagnosis, careful monitoring, and proactive management, many individuals can live into their 50s or beyond. Outcomes are highly variable.

Can vEDS be diagnosed before birth?

Yes, prenatal diagnosis is possible if a specific pathogenic variant in COL3A1 has been identified in a parent. This involves genetic testing of foetal cells obtained through chorionic villus sampling or amniocentesis. Genetic counselling is essential to discuss the risks and benefits of such testing.

Is there a cure for vEDS?

Currently, there is no cure for vEDS. Management focuses on preventing complications, monitoring for signs of issues, and treating symptoms as they arise. Research is ongoing to better understand the condition and explore potential new therapies.

How does vEDS affect pregnancy?

Pregnancy in individuals with vEDS carries significant risks due to the fragile nature of blood vessels and the uterus. There is an increased risk of arterial dissection or rupture and uterine rupture during pregnancy and childbirth. Specialist medical care and careful planning are crucial for pregnant individuals with vEDS.

What precautions should someone with vEDS take?

Individuals with vEDS are generally advised to avoid activities that can cause physical trauma or put stress on their blood vessels, such as contact sports, heavy lifting, and activities that involve sudden pressure changes. Regular medical follow-ups and adherence to prescribed medications are also important precautions.

References

  1. Byers PH, Belmont J, Black J. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2017. PMID: 28306228
  2. Pepin MG, Schwarze U, Rice KM. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genetics in medicine : official journal of the American College of Medical Genetics. 2014. PMID: 24922459
  3. Bowen JM, Hernandez M, Johnson DS. Diagnosis and management of vascular Ehlers-Danlos syndrome: Experience of the UK national diagnostic service, Sheffield. European journal of human genetics : EJHG. 2023. PMID: 36977837
  4. Frank M, Albuisson J, Ranque B. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. European journal of human genetics : EJHG. 2015. PMID: 25758994
  5. Adam MP, Bick S, Mirzaa GM. Vascular Ehlers-Danlos Syndrome. 1993. PMID: 20301667
  6. Senser EM, Misra S, Henkin S. Thoracic Aortic Aneurysm: A Clinical Review. Cardiology clinics. 2021. PMID: 34686263
  7. Germain DP, Herrera-Guzman Y. Vascular Ehlers-Danlos syndrome. Annales de genetique. 2004. PMID: 15127738
  8. Marques M. Vascular Ehlers-Danlos syndrome. Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology. 2022. PMID: 36062645
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.