Vascular Ehlers-Danlos syndrome (vascular EDS, vEDS, or VEDS, previously known as Ehlers-Danlos type IV) is a life threatening uncommon genetic disorders characterised by arterial aneurysm, dissection and rupture, bowel rupture, and rupture of the gravid uterus.
It is a dominantly inherited disorder that results from mutations in COL3A1, the gene that encodes the chains of type III collagen.
The initial diagnosis is usually suspected on the basis of family history, or a clinical history of arterial rupture, dissection or aneurysm, rupture of the large intestine, or pregnancy complications at young ages.
Because of clinical overlap with some forms of Loeys-Dietz syndrome, Marfans syndrome and dissection syndromes, the diagnosis should be confirmed by identification of pathogenic variants in COL3A1 to allow for appropriate surveillance, treatment, and family studies.
Type III collagen is a major protein in the walls of blood vessels and hollow organs, which explains increased bruising, arterial and bowel fragility, and uterine, cervical and vaginal fragility during pregnancy and delivery.
At present, the life span for affected individuals is a median age of about 51 years (49 for males and 53 for females) but with a very large range from 10 years to 80 years.
The major cause of death is arterial dissection or rupture with organ failure. The nature of the underlying mutation in COL3A1 influences life expectancy.
The prevalence is estimated as 1/50,000 to 1/200,000.
Patient concerns should be taken seriously and any reports of pain need full and immediate investigation.
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Fortunately vascular EDS is an uncommon genetic disorder and it is estimated to account for less than 5% of the EDS community, it is considered the most severe due to the risk of life threatening vascular ruptures.
In some reports, up to 70% of cases are diagnosed due to vascular rupture or dissection, gastrointestinal perforation, or organ rupture is a presenting sign.
The clinical features are variable but a number of characteristics can be identified to enable a diagnosis.
Although thin skin with readily visible venous patterning is one of the typical features described in individuals with vascular EDS, it is often a subtle finding and bruising that is not explained by trauma is more common.
The skin is thinned to about a half to one third of normal thickness resulting in being translucent. This results in the underlying blood vessels being clearly visible, especially over the chest and extremities. In some individuals these changes are more pronounced over the hands and feet, giving the appearance of premature ageing (acrogeria).
In addition, wounds heal abnormally slowly resulting in thin scars. The scars may become deeply pigmented giving rise to brown discolouration.
The most common presentation in childhood is easy bruising that may be accompanied by striking skin lucency and vascular visibility. There may be excessive bleeding with circumcision.
In some instances, childhood bruising has been sufficient to raise the question of abuse. Child protection agencies may have been or could be involved due to this prominent feature.
Elastosis perforans serpiginosa (EPS), which presents as a red circular rash usually around the face, neck and upper body, is more common in vascular EDS than other types. It is not harmful and consists of microscopic fragments of elastic fibres which are 'extruded' through the skin. It is not fully understood why this happens but it also occurs in other inherited connective tissue disorders. Treatment is, in general, unsatisfactory.
Some individuals have the typical facial appearance (facies) which is characterised by a thin pinched nose, thin lips, prominent protruding eyes, hollow cheeks, small chin, lobeless ears and thinning of scalp hair. Some of these features can be rather subtle, particularly in children.
In vascular EDS this is usually limited to the small joints of the hands and feet.
Laxity, double-jointedness is not very marked in vascular EDS. If present, if joint laxity affects the ankles some babies may be born with club feet.
Varicose veins may appear in early adult life and can be an early clue to the diagnosis.
Vascular EDS in Children
In children, the features most commonly identified as the reason for testing are family history, easy bruising, thin skin and club foot.
Infants with the condition may be born with;
In childhood, also may see inguinal hernia, pneumothorax, and recurrent joint subluxation or dislocation can occur.
Complications in children with vascular EDS
It is the same as adults, but less common;
Internal organ involvement
The most important complication in vascular EDS is rupture of internal organs. This most commonly affects arterial blood vessels, which are fragile and prone to aneurysms (dilatations). Arterial rupture accounts for the majority of deaths in vascular EDS and any artery may be affected, although 50% occur in the chest and abdomen, 25% in the head and neck and the rest in the extremities.
The bowel is another site prone to rupture (occurs in 25% of individuals) and involves predominantly the lower bowel (colon). Catastrophic events can potentially occur at any age but are rare before puberty.
A quarter of individuals experience a significant medical complication by age 20 years and more than 80% by age 40 years.
During the latter stages of pregnancy severe complications such as rupture of the uterus (womb) may occur, but this is fortunately relatively uncommon. Premature births due to cervical insufficiency (weakness) and foetal membrane fragility are seen in vascular EDS, as well as in the other EDS types.
Partial collapse of the lungs (pneumothorax) is more frequent in individuals with vascular EDS and affects about 15%. It may present with sudden shortness of breath or chest pain.
What causes vascular EDS?
Vascular EDS is a genetic condition caused by an alteration, also known as a mutation, in a gene called COL3A1. This gene is the instruction for making collagen type III. When this gene is altered it causes a lack or deficiency of this collagen. This leads to disordered packing of collagen fibres making the connective tissue less effective, particularly in blood vessels, hollow organs and the skin.
How is vascular EDS inherited?
Our bodies are made up of millions of cells and inside almost every cell is a complete set of our genetic material. Genes are the unique instructions which make us each individual. There are many thousands of genes, each carrying a different instruction. We have two copies of each gene. One copy of each pair is inherited from our mother, in the egg, and the other from our father, in the sperm.
People diagnosed with vascular EDS will have an alteration in one copy of the COL3A1 gene. The inheritance pattern for this is called autosomal dominant inheritance, because the altered copy of the gene is dominant over the other copy. Autosomal means it can affect, and be passed on by, both males and females.
When someone with this condition has children, they will pass on one copy of their COL3A1 gene to each child, either their altered or unaltered gene. So in each pregnancy, there is a 50% (1 in 2) chance of a child inheriting the altered copy of the gene and having vascular EDS. Equally, there is a 50% (1 in 2) chance of a child getting the unaltered copy of the gene and not inheriting the condition.
The gene alteration can happen for the first time in an individual, so there may be no previously affected family members.
How can family members find out if this is relevant to them?
If family members would like further information about the implications for them, they should talk to their GP about the possibility of being referred to their local genetics service.
What advice is given to both men and women with vascular EDS who are considering a pregnancy?
Before planning a family it is important to discuss the implications of pregnancy with your family doctor (GP) who can refer you to your local genetics department. The geneticist or genetic counsellor will discuss the options available to you. It is also useful to speak to an obstetrician (a doctor who specialises in the care of pregnant women), who has experience with vascular EDS, before planning a pregnancy. There may be an increased risk of early rupture of membranes and premature delivery when either the mother or the father has vascular EDS.
Is there particular advice for women with vascular EDS who are pregnant?
Any pregnancy puts the cardiovascular system (heart and blood vessels) under exceptional pressure. There are additional risks for women with vascular EDS in pregnancy, due to blood vessel fragility. It is essential that the obstetrician and midwives are aware of the diagnosis of vascular EDS as soon as the pregnancy is confirmed.
It is recommend starting maternity leave and resting from 30 weeks of pregnancy, or possibly earlier if recommended by the obstetrician. As pregnancy progresses pregnant women with vascular EDS have a higher chance of blood vessel or uterine rupture. The timing of delivery of the baby will be decided by the obstetrician.
A planned Caesarean delivery, in a hospital with access to specialist vascular surgery may be suggested. The baby may be born prematurely because the cervix and membranes surrounding the baby can be weak or fragile.
We know that women with vascular EDS have an increased chance of dying during pregnancy, or in the weeks following birth. It is difficult to estimate the chance of this happening, but studies suggest it may be as high as 10% of pregnancies. Many women still choose to become pregnant, while others may choose surrogacy or adoption.
Villefranche diagnostic criteria
The criteria for diagnosis were updated and published by 'Beighton et al' in the American Journal of Medical Genetics 1998. The presence of two or more major criteria is highly indicative of the diagnosis.
Major diagnostic criteria
Minor diagnostic criteria
Type III collagen predominates in blood vessels, uterus and bowel. It is also present in skin and tendons. Mutations (faults) in the COL3A1 gene responsible for collagen III causes reduced, or abnormal, production of collagen which in turn leads to the clinical features of vascular EDS.
Two methods of identifying abnormalities of collagen III are generally used:
1. Biochemical Analysis
This requires culture of dermal fibroblasts (cells in the skin that produce collagen) that are obtained by a small skin biopsy, under local anaesthetic.
The fibroblasts are then analysed to determine the amount and type of collagen produced. This test usually takes several months to get a result but has the advantage that it will also pick up abnormalities in other collagens, particularly type I and V collagens.
Furthermore a small part of the skin sample can be sent for electron microscopic analysis, if required, to look at the shape of the collagen fibres. If an abnormality is detected this is confirmed by genetic analysis.
2. DNA Analysis
If the diagnosis of vascular EDS is very likely then genetic analysis of DNA from a blood or saliva sample to look specifically at the COL3A1 gene can be undertaken.
Both methods have roughly the same pick up rate (sensitivity) and the method used will be determined on an individual basis. As the cost of genetic analysis comes down DNA analysis is becoming the first test of choice in individuals in whom the diagnosis of vascular EDS is very likely.
This subtype is so rare that many in the medical profession will never have seen a case. It is, therefore, important that affected individuals are aware of their diagnosis so that they can alert the attending physician.
Individuals should be encouraged to wear a Medic Alert bracelet and carry a card (available from the EDS UK support group) which informs of the diagnosis.
Internal bleeding must be considered as a possible cause of any unexplained symptoms and patients should present to their GP (or Accident and Emergency Department if acute symptoms), for appropriate investigations.
Currently, no consensus exists as to the required investigations at the time of initial diagnosis. Any imaging of the vascular tree (arteries) should be non-invasive as arterial tears may result from catheterisation during an angiogram.
Blood pressure should be monitored in adult patients and any heavy physical exercise in which a sudden increase of blood pressure is likely, must be avoided. Contact sports must be discouraged.
A clinical trial in France has been undertaken to determine whether a blood pressure lowering drug (Beta blocker) can protect affected individuals from the risk of vascular complications.
Aspirin and non-steroidal anti-inﬂammatory drugs e.g. ibuprofen should be avoided, if possible, as they may aggravate any bleeding/bruising tendency.
Vitamin C has been advocated for patients with EDS, since it is essential for the correct function of lysyl oxidase, an enzyme involved in collagen formation. However, formal studies to prove its effect are lacking.
As a general rule varicose vein surgery should be avoided. However the less invasive procedures using endogenous laser, radioblation or foam sclerotherapy may reduce the risk of poor wound healing and bleeding following surgery.
Pregnant women with vascular EDS should be considered as high risk and closely supervised during pregnancy, particularly in the later stages and delivery. It is still unclear whether elective caesarean section is the best option for delivery.
Genetic counsellors provide an opportunity for sufferers to assimilate all the facts including the risk of occurrence of the disorder within the family.
About 50% of affected individuals have inherited the fault from an affected parent and the other 50% have developed the mutation as a first event (de novo). Prenatal diagnosis is possible if one parent is affected but the invasive techniques required during pregnancy can be extremely hazardous for the affected mother.
Newer techniques, such as pre-implantation genetic diagnosis (PGD) may be safer. PGD is a technique that involves checking the genes of embryos created through IVF for COL3A1 gene abnormalities.
The life span of individuals with vascular EDS is shortened and the ultimate quest, therefore, is for gene therapy. However major technical difficulties still have to be overcome, meaning that gene therapy for this type of disorder is still some way off.
What follow up is recommended for people with Vascular EDS?
Individuals should be referred to a cardiologist to discuss the available options for heart and blood vessel monitoring and whether medication is indicated.
Blood pressure should be checked regularly by the GP. Treatment can be used to lower the blood pressure, if necessary.
Any unusual signs or symptoms should be investigated thoroughly because of the possibility of internal bleeding.
If any surgery or invasive procedures are being considered, the surgeon must be made aware of the diagnosis of Vascular EDS and should be encouraged to seek specialist advice.
Good dental hygiene with regular visits to the dentist can help to prevent teeth and gum problems.
Is there anything an individual with Vascular EDS should avoid doing?
It is recommended that people with Vascular EDS avoid contact sports, such as team games, boxing or martial arts. However, it is important to maintain a healthy lifestyle so gentle exercise, such as walking, cycling or swimming may be beneficial. Individuals with Vascular EDS should avoid sudden changes of load e.g. lifting very heavy weights, sudden changes of acceleration (sprinting), or isometric exercises such as weight training.
Strenuous household tasks involving lifting or pushing large or heavy objects should be avoided. Brass and woodwind musical instruments also involve physical exertion, so alternative instruments may be more suitable.
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