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What is EDS

Posted By Alan Hakim, January 7, 2014

The following document is an article published in the September 2013 HMSA Newsletter. It is aimed at the public and, we hope, also helpful to health professionals.

 

Introduction

Ehlers-Danlos syndrome is a group of conditions that arise from genetic alterations in collagen.

Collagens are proteins found throughout the body. There are a number of different types of collagen in the body, often found together in very particular combinations in different body tissues. We all make the same collagens, distributed throughout the body in the same way.

The collagens give strength and support to, for example, skin, bone, blood vessels, the gut, and tissues in and around joints such as ligaments, tendons and cartilage.

The production of each type of collagen is genetically determined. Alterations to the genes that are responsible for either making collagen or allowing it to function properly can result in weaker or more fragile and stretchy tissues throughout the body.

As a consequence of this certain physical findings and complications arise. It is the recognition of these patterns of physical signs and the identification of specific gene alterations that allow clinicians to separate out the different types of EDS.

The Different types of EDS

There are several forms of EDS. Looking through the list of types might seem a little daunting, but for the majority of individuals the diagnosis is most likely to be the Hypermobility type (estimated at about 1 in 5000 people (but probably more)), followed by the Classical (about 1 in 15000 people), then the Vascular type.

All share common features, such as loose and flexible (hypermobile) joints, abnormal skin, and other fragile body tissues e.g., weak abdominal wall leading to hernias, stretchy blood vessels and varicose veins, and thin heart valves. However, some types have more severe physical signs than others, and some have unique characteristics too.

Apart from the Hypermobility type (for which there is no definitive genetic test at present), genetic abnormalities have been found in most types of EDS but may not be easily identifiable in every case.

Below is a summary of the key features of each type of EDS, with a focus on the Classical and Vascular types.

Classical type.

The diagnostic criteria for Classical EDS are primarily made up of skin and joint findings. There may be a family history of the condition but this is not always the case (see the genetics section later). The gene fault here leads to abnormal production of type 5 collagen.

Typical features of the Classical type are:

  • The skin is smooth and velvety to touch. It is also hyper-elastic – it is stretched easily but it snaps back in to shape when released unlike certain skin conditions like Cutis Laxa, a condition associated with abnormality of the protein Elastin.

Other skin findings that may appear in Classical EDS include: raised and thickened layers of skin termed ‘molluscoid pseudotumours’; small mobile nodules deep in the skin called ‘subcutaneous spheroids’; herniations of underlying fatty tissue through the lower layer of the skin leading to small painful lumps called Piezogenic papules; blue, cold, and sweaty (but not painful) skin due to constriction of blood vessels that return to normal – called Acrocyanosis; and, Chilblains, red and painful swellings after exposure to cold.

  • The skin is also very fragile. Its deep layers can split or shear following relatively minor trauma. Severe bruising then arises. Typical sites where this might occur include pressure points such as the elbows, buttocks, knees, and feet, and at sites commonly prone to blunt injury such as the scalp and forehead, and shins. Wound healing is delayed, and scars will often stretch to a considerable degree, and appear paper thin (papyraceous scars).
  • Joint hypermobility in Classical EDS is typically widespread affecting both large and small joints. It is often noted first when a child starts to walk. Dislocations are common. Other complications of joint hypermobility such sprains and subluxations (partial dislocations) occur. Occasionally joints are painful but this seems far less common than in the Hypermobility type.
  • There may be muscle weakness or low tone (hypotonia) perhaps manifesting in childhood as a delay in development of motor skills (e.g., holding head up, crawling, walking).
  • Other tissues may be fragile: e.g., the diaphragm or abdominal wall leading to a hernia, or prolapse of the rectum (‘back passage’) from early childhood, or weakness of the pelvic floor and support structures of the womb during pregnancy.

Occasionally (found in less than 1 in 20 cases) there may be blood vessel and heart valve abnormalities such as dilation of the aorta or mitral valve or tricuspid valve prolapse. These seem to be mild and unlikely ever to be in need of intervention with medicines or surgical repair.

Vascular type.

The Vascular type of EDS is characterized by thin, translucent skin that bruises easily but is not necessarily particularly stretchy. The problem lies in the production of type 3 collagen.

There is also very characteristic facial appearance:

  • Protruding eyes,
  • Thin nose and lips,
  • Sunken cheeks, and
  • Small chin.

Hypermobility is typically found in the small joints of the hands. Other (non skin) features akin to other forms of EDS may also be found such as hip dislocation and clubfoot.

The major causes for concern in this condition arise because of fragility of the blood vessels, gut wall, and uterus.  There is a risk for rupture of any of these structures, which may be life threatening.

About a quarter of individuals with Vascular EDS experience significant medical problems by the time they are 20 years of age. More than 80% of individuals experience major problems by the age of 40. Because of this life expectancy is shortened in Vascular EDS.

Hypermobility type.

This is the most common form of EDS. There is currently no known genetic cause for the vast majority of cases. In less than 10% of cases an abnormality in the production of a protein called Tenascin X that interacts with collagen, is found. However, this is not a routine test.

The skin and joint features may be the same as those of Classical EDS but much less severe. Joint pain and fatigue also appear to be more common in this form of EDS. Other signs of tissue fragility such as hernias and varicose veins may also be found. Importantly, this type of EDS is not associated with weakness or rupture of major blood vessels or bowel wall, or with the more severe forms of scoliosis.

Many experts consider EDS Hypermobility type (EDS-HM) to be clinically the same as the Joint Hypermobility Syndrome (JHS). More about JHS and the terminology used in the diagnosis of JHS and EDS-HM can be found in the ‘Help and Advice’ section of the HMSA website by clicking Here.

Arthrochalasia type.

Arthrochalasia is a rare condition associated with short stature, fragile skin, and dislocation of the hips from birth. The gene alteration leads to abnormal production of type 1 collagen.

Two other rather forms of type 1 collagen abnormalities can lead to heart valve defects and a condition similar to Classical EDS but with a tendency to rupture major blood vessels. These are very rare.

 

Some forms of EDS arise because of non or underproduction of specific enzymes. These are biochemical structures that assist in the production or the bundling up of collagen fibres. Below is a list of some of these. All of them are very rare.

Kyphoscoliotic type.  

This is a rare condition in which the spine is severely curved from childhood. There is also joint laxity, low muscle tone, and, in some cases fragility of the ball of the eye. Also, some individuals are at risk of rupture of medium-sized arteries, and some experience difficulty with breathing because the chest wall feels squashed with the curve of the spine.

Dermatospraxis type.

Here the skin is doughy, wrinkly, and sags. It is an exceptionally rare condition. Some cases also have a delayed coming together and fusion of the skull bones (fontanels), puffiness of the eyelids due to fluid retention, a blue tinge rather than ‘white’ to the eyes, short stature, and short fingers.

Periodontal type.

This form is similar in presentation to Classical EDS, but is also associated with fragile and severe bleeding of the gums.

Progeroid type.  

This is a very rare disorder characterized by a very wrinkled face, fine curly hair, and thin or scanty eyebrows and eyelashes. Periodontitis and the typical signs of Classical EDS are also found. It is caused by a fault in a very specific gene responsible for a particular enzyme, one of several proteins that are needed to make collagen.

Musculocontractural type.

The musculocontractual type is characterized by abnormal shape of the skull and facial bones, skin signs like those of Classical type, hypermobility in the small joints e.g. hands and feet, finely wrinkled palms, tapered fingers, stiffening (contractures) of joints, scoliosis of the spine, and progressive loss of muscle tone.

Spondylocheirodyplastic type.

Similar to the musculocontractual type but without the facial features, this type of EDS is associated with particular features on x-rays of the joints and mild stunting of growth.

 

Tests for Classical and Vascular EDS

Both are determined primarily by the medical history and clinical examination but there are certain tests that may help establish the diagnosis.

Collagen Gene, Skin biopsy, and Biochemical tests

In over half of cases of Classical EDS there is an identifiable gene abnormality. The gene is responsible for producing type 5 collagen. Although this gene defect may run in families it can also appear spontaneously for the first time in an individual and be carried forward to future generations. It is always important that genetic counseling is given along side genetic testing. Although a gene may be strongly inherited the problems that might arise can be highly variable between members of the same family.

The gene responsible for Vascular EDS encodes the production of type 3 collagen. Like that of Classical EDS the gene is strongly or ‘dominantly’ inherited.

Analysis of the skin by taking a biopsy and looking in detail at its structure under an electron microscope may also assist in a diagnosis. Changes in the way collagen fibrils are bundled together may be seen. Assessment of these changes requires very specialist expertise. Often findings are non-specific and must take account of the clinical picture.

Collagen proteins can also be tested for their biochemical properties. The collagen is extracted from cells taken from a skin sample. Abnormal responses to specific laboratory tests can pick out certain collagen defects. Such tests (called protein electrophoresis) may in particular identify type 3 (Vascular EDS) and type 1 collagen abnormalities, but for technical reasons are less sensitive in picking up problems with type 5 (Classical EDS) collagen.

Imaging Tests

Several tests may be requested to help determine the nature of problems in EDS.

These include:

  • Echocardiogram – to look at the anatomy and function of the heart, heart valves, and the size and shape of the aorta as it leaves the heart.
  • Ultrasound – of other large blood vessels (particularly in the bowel and pelvis), and of gut and pelvic organs.
  • Magnetic Resonance Angiography – using MRI technologies to look at blood vessels in all parts of the body including those of the neck and brain.
  • Plain x-rays of the bones and bowel.

Blood Clotting Tests

Although the bruising is assumed to be due to easy rupture of fine capillaries that break due to the frailty and elasticity of the skin, it is important to ensure there is no clotting disorder. The general tests for this are accessible to doctors in general practice. If abnormalities in these tests are found then the advice of a haematologist should be sought. Occasionally individuals with EDS are found to have slow clotting due to a defect in platelets (cells in the blood that encourage clot to form). Again, a Haematologist can assess this in more detail if the clotting tests are abnormal.

 

Managing Classical and Vascular EDS

This article will not focus on pain, fatigue, or physical rehabilitation as these are covered elsewhere with advice available, for example, on the HMSA website. The principles of pain and physical management are similar for all forms of EDS.

There are some important points to make with regard to Classical and Vascular EDS. First, there is no current way of manipulating the gene defects to correct the problem. Neither is there any way to replace faulty collagen.

The skin problems can be difficult to manage. Prevention of trauma is key. This might include for example padding or bandages over vulnerable sites, keeping the body clothed, and using high-factor sun blocks. It is best to avoid strong and skin drying soaps and deodorants may help maintain suppleness and avoid drying and splitting.

If the skin has split it is best that the wound is closed without tension (pulling too tight) and if stitches are used then probably best placed in two layers (deep tissues and superficial tissues). In general stitches should be left in place for twice as long as usual. Stretching of scars may be less likely to occur if the skin is carefully taped.

Surgery is very challenging because of the fragile tissues. Prevention of rupture of tissues is difficult. In the case of the bowel for example vulnerable dilated bowel at risk of perforation may need to be repaired or removed. It may also be possible to repair dilated blood vessels but the risks are high.

If no abnormality is found on imagining after the age of 40 years then it is unlikely that an abnormality will occur later in life due to the EDS per se. The difficulty with this statement is that there are no studies over time in EDS to inform doctors of how often something like an echocardiogram should be repeated in these circumstances. For those who remain concerned about risk of developing a problem a compromise might be to rescan every 5 years and only increase the frequency of this if a problem arose.

If a problem has been identified on images but is not in need of immediate intervention then it is sensible to re-image every 12 months in the first instance for up to 5 years and then reduce the frequency dependent on the changes observed over this time.

 

Dr Alan J Hakim MA FRCP

Consultant Physician and Rheumatologist, Barts Health NHS Trust, & Chief Medical Advisor and Trustee, HMSA

Published in HMSA newsletter November 2013. On line Jan 2014. Revised March 2015 V.3. Date of review Jan 2017

 

Bibliography

Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7.

Malfait F, De Paepe A. Molecular genetics in classic Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2005;139C:17–23.

Malfait F, Wenstrup RJ, De Paepe A. Ehlers Danlos Syndrome. GeneReviews August 2011: available at  http://www.ncbi.nlm.nih.gov/books/NBK1244/

 

 


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