EDS, hypermobility, and the link, if any, to ME/CFS

Thinking some more about the hEDS diagnosis.

The main problem is that it attributes a lot of unexplained health complaints to (a supposedly rare) connective tissue disorder without sufficient evidence to back this up.

On the other hand, there are likely a lot of other EDS or other genetic connective tissue disorders whose molecular basis has not yet been discovered yet. And although it seems that most previous cases were found by clustering of cases within families, I can imagine that for researchers looking for these new mutations that it is helpful to have a category of patients where connective tissue disease is highly suspected based on clinical signs.

Perhaps rather than a diagnosis such as hEDS (which is confusing patients and clinicians alike) it would be useful to have a scale that adds up clinical signs that are frequently seen in other connective tissue disorders to a numerical score (one could give multiple points to signs that are more specific).
 
ME/CFS Skeptic said:
Perhaps rather than a diagnosis such as hEDS (which is confusing patients and clinicians alike) it would be useful to have a scale that adds up clinical signs that are frequently seen in other connective tissue disorders to a numerical score (one could give multiple points to signs that are more specific).
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But what would the score tell you and how would you know it was telling you that?

I have only knowingly come across two or three people with actual EDS in the clinic. They already had a diagnosis but just walking up to them ready to be examined I thought 'blimey this does look like real EDS'. Their signs were way beyond anything on Beighton. If anything the Beighton score is a score of the sort of healthy flexibility most of us envy and used to envy in friends at school. It is a bit like meeting people with dystrophia myotonic who have a receding hairline. Once you have recognised one, you never miss another case. No need for scores at all. You don't need a score to recognise a whippet or a German shepherd.
 
Jonathan Edwards said:
But what would the score tell you and how would you know it was telling you that?
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That these people have a lot of clinical signs that physicians associate with known connective tissue diseases.

If researchers wanted to search for new EDS types, new mutations causing a connective tissue disease, wouldn't it be useful to have a group of suspected cases to test your hypothesis in? If I understand correctly EDS diagnosis pre-dated molecular testing and researchers already suspected defects in collagen based on clinical signs alone, which turned out to be true.

Jonathan Edwards said:
They already had a diagnosis but just walking up to them ready to be examined I thought 'blimey this does look like real EDS'. Their signs were way beyond anything on Beighton
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I wonder what those clinical signs were that made the diagnosis so obvious?
 
ME/CFS Skeptic said:
That these people have a lot of clinical signs that physicians associate with known connective tissue diseases.
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But why does the number of signs matter?
The signs only really matter if they are causing pain or distress and I suspect such problems relate to each sign separately.

There is no point in searching for new gene defects unless they are troubling people. One trouble is enough for a search.

ME/CFS Skeptic said:
I wonder what those clinical signs were that made the diagnosis so obvious?
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Things like spontaneous scars, skin pseudo tumours and unusual elbow angulation. Things ordinary people just do not have.
 
Jonathan Edwards said:
But why does the number of signs matter?
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The idea was that people who have several unusual signs might be a better target to search for new gene defects. One could give points based on how unusual or specific a feature is, but the adding up of signs wasn't the main point I wanted to make.

Jonathan Edwards said:
Things like spontaneous scars, skin pseudo tumours and unusual elbow angulation. Things ordinary people just do not have.
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I was mostly concerned with people who have unusual signs such as the ones you list above but who do not have one of the know connective tissue disorders (but probably one that is yet to be identified). If you take away the hEDS category and restrict EDS to only types that have known mutations, those people might be worse of.

If I was in that situation I would very much want to stimulate research into patients similar to me in the hope to find new mutations. I assume the hypermobile type of EDS was originally meant to identify patients in whom such mutations are suspected based on clinical signs but that this got out of hand.

Jonathan Edwards said:
There is no point in searching for new gene defects unless they are troubling people
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Some types like vEDS puts people at higher risk of arterial or organ ruptures. Perhaps other, yet undiscovered, mutations carry similar risks even if the clinical signs do not cause pain or distress?
 
ME/CFS Skeptic said:
Some types like vEDS puts people at higher risk of arterial or organ ruptures. Perhaps other, yet undiscovered, mutations carry similar risks even if the clinical signs do not cause pain or distress?
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But that really is the point. It has nothing to do with pain. The importance of EDS mutations is that they can produce risk of organ failure. So if people have odd connective tissue mechanics one should take an interest. But one odd feature would be as good as three.

ME/CFS Skeptic said:
If you take away the hEDS category and restrict EDS to only types that have known mutations, those people might be worse of.
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I think this is a misconception. The 'hEDS' category at present is simply being flexible and we know that polygenic inheritance commonly results in individuals being very flexible without any obvious problems. 'EDS" as a concept needs to be restricted to monogenic connective tissue structural patterns - as was originally intended. There might be polygenic interactions that produce risky connective tissue problems but I don't think any are actually known. Moreover, if there are there is no particular reason why the hypermobility should be generalised. Most genetic illnesses associated with connective tissue structure problems are actually associated with very specific local things. For instance pseudo-pseudo-hypoparathyroidism, if I remember rightly is associated with a relatively short fourth metacarpal. Osetopetrosis is associated with an odd looking big toe. And so on.

So the idea that 'generalised hypermobility' is an important clinical category has never as far as I know been justified. It isn't the generalisation of hypermobility that matters even in known EDS. Just looking t one or two joints is enough to suggest a diagnosis.
 
I'll try to rephrase.

Most researchers suspect there are more EDS types or similar heritable connective tissue disorders that have not yet been explained on a molecular basis. To find these, it would be useful to have a selection tool or category for patients who have abnormal clinical signs suggestive of such a unexplained connective tissue disorder. A bit like EDS descriptions were useful in the past to find the types we currently know.

I have the impression that hEDS currently functions as this category and that this forms one of the main reasons for its existence. However, it seems to do a lousy job at this because the signs it uses such as widespread pain, hypermobility, striae, velvety skin, dental crowding, piezogenic papules etc are not specific at all and quite common in the general population.

The history of EDS and your comment on spontaneous scars, skin pseudo tumours and unusual elbow angulation, however, suggests that useful clinical signs for HCTD likely do exist. So I was wondering how a category or score for 'suspected EDS or HCTD' might look like that might be justified on the basis of furthering the discovery of new mutations.
 
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I think one problem is that there is no particular reason why these signs should be similar for any new genetic mutations. There are a whole lot of other collagen defects that look quite different - like Stickler's syndrome (if I remember rightly). But yes, there are several recognised signs of collagen defects. And if someone has one then looking for a defect makes sense. But I don't see any particular value in a score. We don't use scores of that sort for diagnosing any other sort of condition as far as I can remember. Not for rheumatoid or psoriatic arthritis or gout or anything. Some diagnostic criteria involve numbers of features but there is rarely any real justification for it and it can be seriously misleading in the clinic.
 
Jonathan Edwards said:
I think one problem is that there is no particular reason why these signs should be similar for any new genetic mutations. There are a whole lot of other collagen defects that look quite different - like Stickler's syndrome (if I remember rightly). But yes, there are several recognised signs of collagen defects. And if someone has one then looking for a defect makes sense. But I don't see any particular value in a score. We don't use scores of that sort for diagnosing any other sort of condition as far as I can remember. Not for rheumatoid or psoriatic arthritis or gout or anything. Some diagnostic criteria involve numbers of features but there is rarely any real justification for it and it can be seriously misleading in the clinic.
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But yes, there are several recognised signs of collagen defects

What are these please?
 
Axenfeld rieger has some similarities with stickler syndrome.
In stickler syndrome hyaluronic acid is mentioned,I may try the supplements in capsule form
Alport syndrome kidney,ace inhibitors and (bardoxolone)
Basement membrane in the brain maybe deteriorated with viruses
I seem to have the features of Alport this may be the reason for my kidney problems
 
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Merged thread

UK: Daily Star :Inside painful 'bendy' condition leaving stars like Billie Eilish at risk of long Covid

Certain celebs, including Billie Eilish, Jameela Jamil, and Selma Blair share a condition that may make them more suspectable to the negative effects of COVID-19, including long Covid.

LINK

So it's a risk factor now?
 
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There is a potentially interesting short case series report in an autonomic journal reporting a number of patients with the Mendelian connective tissue disease, Loeys-Dietz syndrome, who were subsequently diagnosed with POTS.

While I wouldn't be surprised if some of these patients had tachycardia as L-D is associated with cardiac defects it may be of potential interest not only because of potential diagnostic conflation between POTS and ME/CFS, but also because L-D arises from mutations in genes associated with the TGFβ signalling pathway, which has cropped up in a few ME/CFS studies. Don't suppose you ever came across any L-D patients exhibiting ME/CFS like symptoms, @Jonathan Edwards? (It isn't something I know much about.)
 
I was not aware of L-D syndrome as a rheumatologist.

The link to TGF beta is very interesting though. I had an interest in aortic involvement in ankylosing spondylitis and TGF beta and L-D syndrome seems to confirm that TGF beta is specially relevant to places like the aortic root.

The relevance to ME/CFS is unclear but it could be an important clue if we knew a bit more what we are looking for. DecodeME ought to tell us whether ME/CFS links to these connective tissue Mendelian disorders in any substantive way.
 
Nightsong said:
There is a potentially interesting short case series report in an autonomic journal reporting a number of patients with the Mendelian connective tissue disease, Loeys-Dietz syndrome, who were subsequently diagnosed with POTS.
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The TGF-β signaling pathway plays a significant role in the normal development of the cardiovascular system and connective tissues. Studies have demonstrated its role in maintaining the homeostatic balance within the structure and composition of the vascular extracellular matrix (11), and its importance in vascular development and reactivity (12). Dysregulation of this pathway may contribute to the development of dysautonomia, and orthostatic intolerance seen in our patients.
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[11] is Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-Beta Signaling | PDF (2014, SpringerLink)

POTS, despite being a well-recognized comorbidity in EDS patients, has never been associated with LDS in the literature. The etiology of this syndrome is multifactorial, and three important mechanisms are commonly reported: hypovolemia, hyperadrenergic state, and excessive venous pooling in the dependant circulation due to partial autonomic neuropathy. […] Recent studies have also described similar associations with Marfan Syndrome (MFS), a condition with significant phenotypical overlap with LDS. A recent nationwide inpatient study of 12079 patients with MFS highlighted a 4.9% rate of occurrence of POTS, which was not previously reported in the literature (15). Although orthostatic intolerance has been previously described in MFS patients, it has been limited to the occurrence of dizziness and the drop of systemic blood pressure upon standing (15,16).
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[15] is Frequency of Arrhythmias and Postural Orthostatic Tachycardia Syndrome in Patients With Marfan Syndrome: A Nationwide Inpatient Study (2022, Journal of the American Heart Association)
 
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