Ehlers-Danlos syndromes

·      The term Ehlers-Danlos syndrome refers to a group of inherited connective tissue disorders

·      Each type is separate and distinct, having a different genetic basis

·      Accurate diagnosis of the type of Ehlers-Danlos syndrome allows targeted management

The Ehlers-Danlos syndromes (EDS) are a group of inherited conditions that fit into a larger group known as heritable disorders of connective tissue. Connective tissues are present in many areas of the body including the walls of blood vessels, organs, skin, bones and tendons. Collagen proteins are the main component of connective tissues and there are a number of different types.

The different types of EDS are separate conditions with different causes, but they can have some characteristics in common.¹ Key features include: joint hypermobility, hyperextensible skin and tissue fragility. The diagnosis is currently based on the Villefranche classification written in 1997.² Although there are currently no particularly good prevalence figures, the most frequent type is hypermobile EDS, followed by classical EDS and vascular EDS. The other types of EDS are exceptionally rare. Since 1997 there have been advances in the understanding of EDS and a number of new subtypes have been described. 

Each type of EDS has a genetic basis, caused by mutations affecting the production of a particular collagen, or a protein that interacts with collagen (see Table 1). Each gene codes for a different protein. Our genes come in pairs with one inherited from each parent. A change in a gene that affects the protein produced is known as a mutation. The inheritance pattern depends on the type of EDS. Autosomal dominant conditions are due to a mutation in just one copy of a particular gene. An affected person may have inherited the causative mutation from a parent, or may be the first person in the family to be affected, due to a new mutation. Autosomal recessive conditions are due to mutations in both copies of a particular gene, one being inherited from each parent. The parents will not have the same condition if their other copy of the gene is normal. 

Each type of EDS has different management requirements, hence the need for accurate diagnoses.³ Each person’s care is based on the type of EDS and their symptoms.

Table 1 – EDS subtype, genetic cause and inheritance pattern; autosomal dominant (AD) or autosomal recessive (AR).

Hypermobile EDS 

By far the most frequently diagnosed type of EDS is hypermobile EDS. The diagnosis is made clinically on the basis of hypermobile joints with associated symptoms including joint pain and subluxations/dislocations. There are currently no tests that can confirm a diagnosis of hypermobile EDS and a clinical distinction is not currently recognised between the terms hypermobile EDS and joint hypermobility syndrome.⁴

There are a number of co-morbidities that are recognised to occur more frequently in patients with hypermobile EDS, including postural tachycardia syndrome (PoTS), autonomic and gastrointestinal dysfunction. PoTS can be diagnosed with a tilt table test in specialist cardiology clinics. Regular gentle exercise such as pilates, swimming, walking or cycling is important for managing pain and fatigue associated with hypermobility. There are a number of useful books on managing hypermobility.^5-7 Patients with chronic pain and/or recurrent joint dislocations or subluxations may benefit from physiotherapy. Occupational therapy enables patients to learn about pacing and sleep hygiene. A multidisciplinary approach to pain management is needed, as pain medications are often not helpful for hypermobile EDS patients. Psychology input to explore coping strategies through cognitive behavioural therapy (CBT) and/or mindfulness can make a big difference to patients.

Classical EDS

Classical EDS is characterised by the triad of hyperextensible skin, atrophic scarring and joint hypermobility. Bruising is often the first feature noted in young childhood. The skin is both hyperextensible and extremely fragile, and can split leaving gaping wounds with only minor trauma. Scars tend to stretch, for the best outcome any skin lacerations should be sutured in layers by a plastic surgeon. As children are particularly prone to injury, the skin can be protected with shin pads and bandages. Custom made shin pads can be obtained from local appliance departments. Contact sports should be avoided due to the risk of skin splitting and damage to hypermobile joints. The condition is caused by faulty type V collagen. The diagnosis may be confirmed by skin biopsy or genetic testing. Individuals with a diagnosis of classical EDS should have an echocardiogram to look for aortic root dilation and mitral valve prolapse. If surgery is being considered the surgeon must be aware of the diagnosis of classical EDS because of the tissue fragility. In pregnancy, the obstetrician and midwife should be made aware of the diagnosis if either the mother or father has classical EDS because of the potential for early rupture of the membranes.

Vascular EDS 

Although vascular EDS is a rare condition, it is one that medial professionals should be aware of as there are potentially life saving management implications. Patients with vascular EDS have major risks due to connective tissue fragility. Vascular EDS is caused by faulty type 3 collagen and the diagnosis must be confirmed by genetic testing to identify a causative mutation in the COL3A1 gene.

Fragile blood vessels are at risk of rupture, dissections and aneurysms. Hollow organs, such as the bowel and lungs, or the uterus in pregnancy, are also at risk of rupture. Surgical risks are higher for patients with vascular EDS and the fragility of all tissues means that invasive procedures should be avoided where possible. The diagnosis can be difficult to make in advance of a major complication. Easy bruising, talipes, small joint hypermobility and characteristic features including small facial features with large eyes, premature aging of hands and feet, thin hair and lobeless ears can be present.Surgeons have described attempting to suture patients internal tissues as like handling wet blotting paper. Patients with vascular EDS are advised to avoid surgical procedures where possible and should carry a medical alert inscribed ‘vascular EDS’. Given the risks, patients need to take unusual symptoms seriously and seek medical advice in the event of sudden pain, swelling, bruising increasing in size, or other unusual symptoms.

Patient concerns should be taken seriously and investigated by magnetic resonance imaging(MRI) ora computerised tomography(CT)scan. The risks of tissue fragility can cause significant anxiety for patients and families with vascular EDS. However, many patients with the diagnosis have relatively few problems day to day. All patients should be under a cardiologist with knowledge of the condition to discuss the options of drug therapies and screening. Women should be advised about the life-threatening risks associated with pregnancy and all pregnancies need careful management by an obstetrician who has knowledge of the condition.⁸

Rare types of EDS

There are a number of other rare types of EDS. Kyphoscoliotic EDS can present similarly to classical EDS, but patients usually have a kyphoscoliosis from a young age and are at risk of glaucoma. A number of other genes have now been reported to have a similar phenotype to kyphoscoliotic EDS, including FKBP14 and CHST14. Tenascin X deficient EDS causes the hyperextensible skin of classical EDS, but without atrophic scarring. Another rare type is dermatosparaxis EDS which can be confused with cutis laxa. These conditions all follow an autosomal recessive pattern of inheritance. Arthrochalasia EDS is a rare type that follows an autosomal dominant pattern of inheritance. The EDS National Diagnostic Service is a highly specialised service for the diagnosis of rare and complex EDS in the UK.

Table 2 – Overview of management for the three main types of EDS

The role of the nurse

The conditions falling under the umbrella term of Ehlers-Danlos Syndrome are life-long conditions and patients may need care and assistance from community nursing teams at various stages through life. For patients with significant mobility issues, the input of the community team is essential to ensure that they can reach their full potential and live as independently as possible. Patients with bowel and bladder issues may similarly need support to manage this sensitive aspect of their condition. Quick recognition of signs regarding delayed early development, like late walking, could be the first step towards making a diagnosis in this group of conditions.

Conclusion

EDS is an important group of conditions to recognise. For many patients the time taken to reach a diagnosis can be long and challenging. Accurate diagnosis ensures that patients get the appropriate management (see Table 2). For hypermobile EDS advice on exercise and pacing can bring about a significant improvement in quality of life. Vascular EDS patients are proven to have a better medical outcome when the diagnosis is known. For conditions where the genetic cause is known, genetic counselling can also help identify relatives at risk and ensure that patients have the correct information about inheritance patterns.

The British and American support groups, EDS Support-UK and EDNF, are funding an international symposium in 2016, with the aim of updating the diagnostic criteria and management guidelines.

Resources

• GeneReviews(expert-authored, peer-reviewed descriptions of inherited conditions) –  genetests.org
• Ehlers-Danlos Support UK– ehlers-danlos.org
• Annabelle’s challenge(UK charity raising awareness of vascular EDS)- annabelleschallenge.org

References

1. Sobey G. Ehlers-Danlos syndrome – a commonly misunderstood group of conditions. Clinical Medicine 2014;14(4):432-6.

2. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997. American Journal of Medical Genetics Part A 1998;77:31-37.

3. Sobey G. Ehlers-Danlos syndrome: how to diagnose and when to perform genetic tests. Archives of Disease in Childhood 2015;100:57-61.

4. Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence D. The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). American Journal of Medical Genetics Part A 2009 Nov;149A(11):2368-70.

5. Keer R, Graham R. Hypermobility Syndrome; Recognition and Management for Physiotherapists. London: Butterworth Heinemann; 2003.

6. Beighton P, Graham R, Bird H. Hypermobility of Joints, Fourth edition. London: Springer; 2012.

7. Tinkle B. Issues and Management of Joint Hypermobility; A Guide for the Ehlers-Danlos Syndrome Hypermobility Type and the Hypermobility Syndrome. Left Paw Press; 2008.

8. Murray M, Pepin M, Peterson S, Byers P. Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. Genetics in Medicine 2014;16:874-880.