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Tuesday 18 December 2018
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International updates and 2017 criteria of the Ehlers-Danlos syndromes

In the last decade, growing attention has been placed on joint hypermobility and related disorders, but the Ehlers-Danlos syndromes (EDS) have fascinated people throughout the ages. The first report of this disorder dates back to Hippocrates (fourth century BC). For many centuries, affected individuals earned their livings as The Elastic Skin Man, The India Rubber Man and The Human Pretzel, amazing their audiences in fairgrounds and circus side shows by exhibiting contortionist tricks and a remarkable ability to stretch their skin.1
 

An international effort

An international effort was initiated to try and address the issues surrounding these disorders. Updated diagnostic criteria were a long time coming, and the issues manifesting as a consequence of this gap in research and progression were becoming apparent. One clinician, who has worked with people with Ehlers-Danlos syndromes since 1965, has referred to Ehlers-Danlos as, ‘the most neglected disorder in modern medicine’. That call resonated with patients who, with their doctors, struggled to find guidelines for diagnosis and care that reflected the emerging manifestations that might have previously seemed unrelated.2
 
Since 1998, two developments led to concerns that the EDS nosology needed to be substantially revised. The first development was the discovery of several new EDS types, which substantially broadened the molecular (gene) basis underlying EDS. The second was the growing concern, in the absence of genetic diagnosis, that the hypermobile type of EDS had expanded characteristics and that the diagnostic criteria currently in use were inadequate. Furthermore, there was a dire need for the development of guidelines for management for each type of EDS to allow medical professionals to care for affected individuals and their families.
 
The First International Meeting on EDS was held in Ghent, Belgium, in September 2012, and an International Consortium on EDS was formed with the objective to convene a group of clinicians, scientists and lay members of the EDS Community to come to grips with the increasingly difficult aspects of definition and management of EDS types, to define research agendas, and to continue EDS meetings. When it became apparent how huge the management and coordination of this global collaboration would be, an intentional charity called The Ehlers-Danlos Society was created to ensure this work would continue, and the consortium grew to over 90 members. 
 

What are the EDS?

The EDS were classically defined as a heterogeneous (varying) group of heritable (genetic) disorders of connective tissue, characterised by joint hypermobility (joints that can move more than usual), skin hyperextensibility (skin that can be stretched further than normal) and tissue fragility affecting skin, ligaments, joints, blood vessels and internal organs3 (Table 1).3
 
Table 1: Types of EDS
 
Classification of Ehlers-Danlos syndromes began in the late 1960s. The most widely spread and used criteria – the Ville Franche criteria – were published in 1998, where a simplified classification was proposed creating six major subtypes, for which major and minor clinical criteria were defined, and substituted the previously used Roman numeral types.
 
In response to the varied needs listed above, new diagnostic criteria and management and care guidelines were published in March 2017 in the American Journal of Medical Genetics. The new criteria classified the EDS into thirteen subtypes. Each EDS subtype has a set of clinical criteria that help define diagnosis; physical signs and symptoms will be matched up to the major and minor criteria to identify the subtype most relevant. For the first time, hypermobility spectrum disorders (HSD) were described.
 
As well as the more known clinical manifestations of EDS affecting the joints and skin, there can also be chronic, early onset, debilitating musculoskeletal pain, chronic fatigue and other comorbidities in other systems in the body such as astrointestinal, autonomic and immune system. There is also clinical evidence of a prevalence of neurological and psychological issues in this patient group, but more research is needed in all these areas.
 
There is substantial symptom overlap between the EDS subtypes and other connective tissue disorders, including HSD. When the gene mutation is known, a definitive diagnosis for all the EDS subtypes also calls for confirmation by genetic testing. The gene is known in all the different EDS forms, apart from hypermobile EDS (hEDS). There is no genetic marker for any of the hypermobility spectrum disorders.
 

What are HSD?

The issue of those with symptomatic hypermoblility who do not full the criteria of hypermobile EDS needed to be addressed. These people still require validation, treatment and management and we could not move forward with EDS, without considering this part of the population. As a response to this, the HSD were developed.
 
HSD are a group of clinically relevant conditions related to joint hypermobility (Table 2). HSD are intended to be diagnosed after other possible answers are excluded. HSD, just like hEDS, can have significant effects on health. Whatever the problems that arise, whatever the diagnosis, it is important that these effects are managed appropriately and that each person is treated as an individual. HSD and hEDS can be equal in severity, but more importantly, both need similar management, validation, and care.
 
Table 2: HSDs types
 
There may be a scenario where the diagnosis of HSD is given to an individual with a family history of hEDS (that is, relatives with an independent diagnosis of hEDS).4
 

When does hypermobility become a problem?

A good place to start when it comes to understanding EDS and HSDs is to ask the question – what is joint hypermobility? Joint hypermobility is a term to describe the capability of joints to move beyond normal limits. It can exist by itself or be a part of a more complex diagnosis. There are some who have extreme hypermobility, and have no reports of symptoms – for example, dancers and athletes – but there are those who experience chronic pain and complications as a result of their hypermobile joints. 
 
Hypermobility can either be localised (in a single joint) or generalised (across the body). Joint hypermobility depends on age, gender, family and ethnic background.
 
A tool that it used to measure hypermobility is the Beighton Score. This is an assessment that is done in clinic and measures the hypermobile range and helps to define a diagnosis. 
 

The Beighton Score

A score of 5/9 or greater defines hypermobility. The total score is obtained by:
  1.  Forward flexion of the trunk with knees fully extended so that the palms of the hand rest flat on the floor – one point
  2. Hyperextension of the elbows beyond degrees – one point for each elbow
  3. Hyperextension of the knees beyond 10 degrees – one point for each knee
  4. Passive apposition of the thumbs to the flexor aspect of the forearm – one point for each hand
  5. Passive dorsiflexion of the little fingers beyond 90 degrees – one point for each hand.5
 
Joint hypermobility can be symptomless other than the increased mobility, but there are a series of other symptoms that can result from that mobility. Trauma can occur and either be macro-trauma, including dislocations, subluxations, and soft tissue damage (ligaments, tendons, muscles). This can cause acute pain and loss of joint function. There can also be micro-trauma when injuries are too small to be noticed in situ, but over time they can lead to recurrent or persistent pain – and possibly early joint degeneration like osteoarthritis.
 
Another consequence can be pain. Occasional, recurring pain is a natural result of the trauma, but chronic pain can develop – perhaps because of unusual sensitivity to pain (hyperalgesia), or impaired connective tissue function (as suggested by the discovery of small fibre neuropathy in adults with classical, hypermobile, and vascular EDS).
 
There can also be a disturbance in proprioception, which is the sense of the relative position of parts of the body and how much effort is needed for movement. Not understanding where joints are and how much muscle strength it takes to use them can lead to a cycle that increasingly limits the ability to manage everyday life (www.ehlers-danlos.com).
 

Conclusions

The future is brighter for hypermobility and specifically within EDS and HSD. Now there is a proactive international consortium tasked with the research and advancement of the Ehlers-Danlossyndromes and hypermobility spectrum disorders, there might well be revisions as early as the next symposium in 2018. What cannot be questioned is that hypermobility in itself is highly prevalent in society, and it is important to consider these diagnoses when it is present. EDS and HSDs remain disorders that are both under- and mis-diagnosed in the medical world, and education and more importantly, re-education is essential to prevent this community suffering any further neglect. 
 
With 2018 seeing the Ehlers-Danlos Society launching the first EDS global registry, and being awarded a million dollars to find the genetic causations for hypermobile EDS – it is an exciting time that promises progression and advancement in this important disorder. 
 
For more information and the latest updates please visit: ehlers-danlos.com
 

References

1 Bloom L et al, on behalf of the Steering Committee of The International Consortium on the Ehlers-Danlos Syndromes. The International consortium on the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet 2017;175C:5–7.
2 https://www.ehlers-danlos.com/classification-update/ (accessed June 2018)
3 Steinman B, Superti-Furga A,  Royce PM. Ehlers-Danlos syndrome. In: Fernandes J, Saudubray JM, Tada K (eds). Inborn metabolic diseases, diagnosis and treatment. Berlin: Springer;2017:525–61.
4 Castori M et al. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet Part C Semin Med Genet 2017;175C:148–57.
5 Juul-Kristensen B et al. Measurement properties of clinical assessment methods for classifying generalized joint hypermobility – A systematic review. Am J Med Genet Part C Semin Med Genet 2017;175C:116–47.

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