POTS, EDS and MCAS: Understanding the Trifecta

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Adam Foster

Director at The Fibro Guy

Adam Foster is the founder of The Fibro Guy and one of the leading voices in hypermobility, EDS, and chronic pain rehabilitation. A former Reconnaissance Soldier, he developed chronic pain after an IED blast in Afghanistan and built his approach from the ground up when the medical system had no answers. Since 2009 he has worked with thousands of people across eight countries, drawing on pain neuroscience, motor learning, and sensorimotor rehabilitation. He co-authored "No Pain, No Pain" with trauma psychologist Dr Mairi Harper, directed the documentary "Invisible Monster," and has been featured in Forbes, BBC Radio 4, ITV News, LiveScience, and The Telegraph.

Latest posts by Adam Foster (see all)

• Which supplements are worth taking when you’re hypermobile - 4 October 2026
• Hypermobile Wrists: Why They Hurt, Which Brace to Use, and How to Build Control - 4 October 2026
• Endometriosis, hypermobility and EDS: where the connective tissue link holds up, and where it doesn’t - 1 October 2026

Most of those with an hEDS or HSD diagnosis have met the word trifecta by now, usually on a forum, occasionally from a cardiologist who said it in passing and then moved straight on to the next thing. It always arrives as a package: hypermobile Ehlers Danlos syndrome, POTS, and mast cell activation syndrome, three conditions that apparently travel as a set, so if you’ve got one you should probably go looking for the other two. The short answer, before any of the detail, is that the set isn’t evenly glued together. The link between hypermobility and orthostatic problems is genuinely solid and has been for a while now, with somewhere around a fifth to a third of those with POTS meeting the full criteria for hEDS ^[1]. The mast cell leg is a different animal though, as once you hold it to the strict diagnostic criteria that allergists actually use, it thins out a great deal ^[2].

None of which means the symptoms are imaginary, of course, or that the flushing and the gut reactions and the sudden sensitivity to half the food in the cupboard are being made up. It just means the label has been getting attached a good deal faster than the evidence has been arriving, and the honest version of that is a lot more useful to you than the tidy one, as the tidy one sends people down testing routes and treatment routes that were never going to pay off.

So, this is the long version: what each of the three actually is, how often they really turn up together, what the proposed mechanisms are and how much weight each one will bear, what helps, and, most importantly, what nobody has managed to show yet.

What Each of the Three Actually Is

Worth doing properly, as a surprising amount of the confusion in this space comes from people meaning slightly different things by the same three acronyms (which honestly happens a lot in this area).

Hypermobile EDS and hypermobility spectrum disorders

The 2017 classification tidied up a long and fairly messy history of overlapping labels, replacing the older terms with hypermobile EDS, and putting those with symptomatic joint hypermobility who don’t meet the full hEDS criteria into the hypermobility spectrum disorders group instead ^[3][4]. That second category matters a great deal more than people realise, as it isn’t a lesser diagnosis or a near miss, it’s a different box on the same shelf, and the symptom burden inside it can be every bit as heavy as the one next door.

hEDS is still, uniquely among the EDS subtypes, a clinical diagnosis with no confirmed molecular test behind it ^[4][5]. Everything else in the family has a gene somebody can point at, whereas this one has a checklist, a tape measure and a clinician’s judgement, and that single fact explains most of the argument that goes on around it, including the people who insist it’s overdiagnosed and the people who insist it’s missed constantly. Both of those can be true at the same time, of course, when the test itself is a judgement call.

Neither hEDS nor HSD is a joint condition in any narrow sense either. Chronic pain, fatigue, gut symptoms, pelvic and bladder symptoms and orthostatic intolerance all sit inside the recognised picture ^[5][6], which is part of why the overlap question comes up in the first place really. If the condition already reaches the gut and the blood vessels and the bladder, nobody should be terribly surprised when a second and a third label get added on top of it.

POTS

POTS is chronic orthostatic intolerance with an excessive heart rate rise on standing, usually taken as at least thirty beats per minute within ten minutes, and in adults it has to happen without the blood pressure dropping in the way it does in orthostatic hypotension ^[7][8]. That last part is the bit clinicians get wrong most often though, as a perfectly normal blood pressure reading gets treated as evidence that nothing is going on.

It mostly affects adolescent and young adult women, and the symptom list runs well past the racing heart: dizziness, palpitations, fatigue, brain fog, exercise intolerance, gut complaints and pain ^[7][9][10]. Anyone who’s ever been told POTS is “just” a heart rate problem has been told something wrong, and usually by somebody who looked at one number on a monitor for ninety seconds.

Now, it gets mistaken for anxiety on a fairly regular basis too, and the reason is mechanical rather than anybody being deliberately dismissive. Palpitations, dizziness and exercise intolerance in a young woman, read as anxiety from across a consulting room, and the thing that actually separates the two is whether the heart rate reliably climbs on standing and settles again on lying down ^[7][9]. That distinction takes ten minutes and a stand test to make, and it doesn’t get made anywhere near often enough, unfortunately.

MCAS

Mast cell activation syndrome, as it’s actually defined rather than as it gets used online, is quite a narrow thing. It requires recurrent, severe, systemic mast cell activation affecting at least two organ systems, objective evidence that mediators were released during an episode, and improvement on treatment aimed at mast cells ^[11][12][13].

All three of those, by the way, not one of the three!

Tryptase is the main biomarker in the current frameworks, with other mediators playing a supporting role in selected settings ^[11][14]. And the caveat that comes attached to the definition is that an enormous number of chronic nonspecific symptoms overlap with MCAS without proving it ^[11][12]. Flushing, fatigue, gut trouble, headaches and reactivity to apparently random triggers are all real, all pretty miserable, and all compatible with about fifteen other things.

Timing is a large part of why this one is so hard to pin down. The objective evidence the definition asks for has to be captured during an episode rather than a fortnight afterwards, and tryptase is the marker the current frameworks are built around, with other mediators supporting the evaluation in selected settings ^[11][14]. Which means the test only really works if somebody is available to take blood while you’re actually reacting, and in most systems, at most hours of the day, nobody is.

And that gap, between the symptom picture and the confirmed diagnosis, is where most of the trifecta argument actually lives.

How Often They Actually Turn Up Together

Overlap is common in the places where overlap gets counted, which isn’t quite the same claim as overlap being common full stop. Almost all of the numbers come out of specialist services, and the people who end up in specialist services are, by definition, the ones whose symptoms were bad enough and confusing enough to get them referred in the first place. That’s not a reason to throw the numbers away by any means, it’s a reason to read them as what they are.

For hypermobility and POTS, the picture is consistent wherever you look. Roughly a fifth to a third of those with POTS meet hEDS criteria, and hypermobile groups report orthostatic intolerance at high rates going the other way ^[1][15]. Autonomic and cardiovascular abnormalities turn up more often in EDS than in healthy comparison groups, and POTS is the circulatory problem recognised most frequently of the lot ^[15]. Which is about as settled as anything gets in this corner of medicine.

Add the mast cell leg though and the numbers start to wobble, depending entirely on who’s doing the counting and which definition they happened to pick up. In one group of women with a physician diagnosis of HSD or hEDS, getting on for six in ten reported POTS, around a third reported MCAS, and a quarter reported all three ^[16]. Those are big numbers and they get quoted constantly, but they’re self reported diagnoses inside a selected and heavily symptomatic group, which is a long way from a prevalence figure for the hypermobile population generally.

Now, one group of young people was assessed against several competing definitions of MCAS at the same time, and prevalence, overlap, and even how well people appear to respond to treatment all move depending on which definition is applied ^[17]. That’s not a small methodological footnote, it’s more or less the whole problem, as you change the ruler and the thing you’re measuring changes size.

In a POTS service, a little over four in ten had both extra symptoms beyond the orthostatic ones and at least one raised mast cell related laboratory marker, though the caveat attached to that was that a solitary abnormal marker doesn’t make a diagnosis ^[18]. Elsewhere, coded records showed mast cell activation syndrome in about three in ten of those carrying both a POTS and an EDS diagnosis, against something very close to none of those carrying neither, which sounds fairly dramatic until you notice it rests on diagnostic codes rather than on anybody being assessed prospectively against a standard ^[19].

So, the overlap is real in the sense that these three labels genuinely do cluster on the same people. Whether they cluster because of a shared biology, or because the same person gets sent to three specialists who each dutifully find something in their own area, is a different question entirely, and it hasn’t been answered.

What Happens When MCAS Is Defined Strictly

The picture has shifted over the last couple of years, and it’s shifted against the version of the trifecta that most of the internet is still running on.

When the question of whether mast cell disorders and hereditary alpha tryptasemia are genuinely related to POTS and EDS was asked properly, with the criteria set in advance, nothing in the published literature met them, not one paper, and the current evidence doesn’t confirm the association ^[2]. That’s a strong statement and it’s worth reading carefully though, as it doesn’t say the association is false, it says nobody has demonstrated it to the standard that was asked for.

The pattern repeats when you look at how often suspected MCAS turns into confirmed MCAS. Of those referred with suspected idiopathic mast cell activation syndrome, only around two in a hundred were confirmed in one real life setting ^[20]. In a much larger group sent to a specialist mast cell service with suspected disorders of various kinds, the figure came out under five in a hundred ^[21].

So, suspicion is common, and confirmation is rare.

The reason for that isn’t complicated. MCAS gets overcalled when nonspecific symptoms, or a response to antihistamines, are used as the evidence in place of a documented rise in mediators during an actual episode ^{[11][12][22][23]}. Feeling better on an antihistamine isn’t a diagnostic test, unfortunately, as plenty of things improve on an antihistamine, including several conditions that have nothing whatsoever to do with mast cells.

None of that makes MCAS a nonsense diagnosis though, and it would be lazy to read it that way. The strict criteria were built to identify a specific and sometimes dangerous disease, and they do that job well. They weren’t built to explain what’s going on in someone who reliably flushes and goes tachycardic twenty minutes after red wine, and a negative result against those criteria doesn’t mean nothing is happening in that person, it means the thing happening in that person hasn’t been characterised yet (which is an uncomfortable place to be left, but it’s where the evidence honestly sits).

If the mast cell label is doing the explaining for every symptom you have, then anything that isn’t a mast cell problem stops getting looked at, and that’s diagnostic overshadowing rather than a diagnosis. It works in the other direction too, as episodic multisystem symptoms in someone already carrying two labels, can get waved through as more of the same.

Why hEDS and POTS Genuinely Do Travel Together

The connective tissue explanation is the oldest one on the table and it still holds up reasonably well. More compliant tissue means more compliant blood vessels, which means more blood pooling in the legs and the abdomen on standing, which means less of it getting back to the heart and a bigger compensatory heart rate to make up the difference. Autonomic testing in women with the hypermobility type of EDS showed raised sympathetic activity at rest with reduced reactivity sitting on top of it, orthostatic intolerance was common, and the most likely reading of the whole picture was that tissue laxity is contributing ^[24]. It’s essentially a plumbing story, and it does fit what these bodies actually do on a hot day, stood in a queue, in a shop with no air conditioning.

Small fibre involvement is the second plausible route, and it’s got rather better support than most people expect. In hEDS, skin biopsy has shown generalised small fibre neuropathy in a clear majority, with around a third of the same group meeting POTS criteria ^[25]. Small fibres carry both the sensory traffic coming in from the skin and the autonomic traffic going out to blood vessels and sweat glands, so if those nerves are in trouble, the pain picture and the orthostatic picture both have somewhere sensible to come from. Take it as one important contributor rather than the whole answer though, as plenty of people have the autonomic problem without it.

So, what doesn’t hold up is the simple autoimmune version. Comparing hEDS against HSD turned up only subtle autonomic differences between the two, and dysautonomia associated autoantibodies were present in well under a fifth ^[26]. A single rogue antibody explaining most cases is off the table, then, whatever you may have read in a Facebook group about a test somebody paid four hundred pounds for.

The mast cell case, and how far it actually goes

Mast cells aren’t a silly place to look, by any means. They sit in a perivascular position, close to nerves and to autonomic structures, and they respond to allergens, to stress signalling and to autonomic input by releasing mediators that are vasoactive, inflammatory and capable of sensitising nerves ^[27][28]. Histamine, tryptase, prostaglandins, leukotrienes, platelet activating factor and VEGF all increase vascular permeability and produce vasodilation to varying degrees ^[29] (that list on its own is a decent pub quiz round). So, there’s a perfectly respectable biological route from mast cell activity to flushing, gut symptoms, presyncope and worse venous return, which is precisely the symptom set people keep describing.

The more ambitious models take that a step further and propose a loop, where sympathetic activation sensitises mast cells, and mast cell mediators then worsen the vasodilation and the autonomic instability, feeding back round again ^[30]. It’s an appealing idea and it would explain a great deal if it turned out to be right, but it’s a model rather than a demonstration, and it hasn’t been shown to be what’s actually happening in people carrying all three labels.

Attempts to find a single shared mechanism across the three have come back saying the biological explanations are still limited, still evolving, and not supported by work that applied strict diagnostic criteria ^[31][2]. Current guidance from the gastroenterology side says much the same in more measured language, which is that the associations are observed and the experimental biology explaining them is limited and evolving ^[32]. That’s the honest position, and it’s worth keeping in your pocket for the next time you meet somebody online who is extremely certain about the mechanism.

Telling the Symptoms Apart When They All Overlap

The overlap in symptoms is the central clinical problem. Fatigue, dizziness, gut complaints, headache, pain, flushing and cognitive symptoms can all come from hEDS or HSD, from POTS, or from suspected mast cell activation, which makes attributing any given bad day genuinely difficult and creates a real risk of things being missed ^{[5][7][22][33]}. Once somebody is carrying three labels, every new symptom gets filed under one of them, and the thing that actually needed a scan gets filed with it.

A few rough distinctions are still worth having though, with the caveat that they’re patterns rather than tests, and that on a bad day they’ll all run together anyway.

– Position dependence: An orthostatic episode is tied to being upright and eases off once you get horizontal. If lying down reliably helps within a few minutes, that points towards the autonomic side of things rather than the immune side.

– Skin and gut involvement: Episodes arriving with flushing, itching, hives or gut cramping alongside the cardiovascular symptoms look more mast cell shaped, and the consensus definition itself requires more than one organ system to be involved before the label applies ^[11].

– The trigger pattern: Orthostatic symptoms are provoked by posture, heat, big meals and standing still in a shop. If the reliable trigger is a specific food, a smell or a medication rather than a position, that’s worth logging properly rather than filing under POTS and forgetting about it.

– What the joints contribute: Pain and instability are low level stressors that keep the sympathetic side of the nervous system busy all day, which doesn’t cause the other two, but it doesn’t help either, and it’s the one part of this picture that’s directly trainable.

– Timing against the measurement: Mediator testing is only worth anything close to an episode, so a normal result taken six weeks later on a good day tells you almost nothing ^[11].

Current guidance is explicit that not everybody with hEDS or HSD needs testing for POTS and MCAS as a matter of routine, and that testing should be aimed at those who also have orthostatic intolerance or episodic multisystem symptoms of the mast cell type ^[32]. That’s a sensible position and it does cut both ways, as it stops the unnecessary testing, and it puts an obligation on the clinician to actually ask the questions that would identify who needs it, which is the half of that sentence that keeps getting dropped.

What Actually Helps

An overview rather than a treatment plan, as all three of these need individualising and none of them is well served by a blog post pretending otherwise. So, each strand on its own first, and then the one thing that only becomes visible when you’re dealing with all three at once, which is the order you do them in.

POTS

Now, the consistent first line evidence is the stuff that doesn’t come out of a pharmacy. Education, fluid and salt expansion, exercise training and compression garments are what’s supported, and the drug evidence sits noticeably below all of it ^[1][7][32]. Exercise has also been looked at specifically in young adults with joint hypermobility and related conditions, which is a considerably more relevant group than the general POTS literature ^[34].

Drug evidence, to be straight about it, is thin. What exists is small and heterogeneous, beta blockers, midodrine and ivabradine all look reasonable for selected people, and long term comparative evidence barely exists ^[35][36][37]. There’s still no drug approved specifically for POTS ^[32]. None of which is a reason to avoid medication, it’s a reason to treat any particular drug as a trial with an honest review date attached, rather than as the answer.

MCAS

Where a mast cell diagnosis is genuinely established, the approach is stepwise and mediator directed: H1 and H2 antihistamines, leukotriene blockade, cromolyn, and in selected refractory cases anti IgE therapy or combination regimens, with the subtype and the underlying trigger clarified first wherever that’s possible ^{[11][38][22][32]}.

The evidence underneath that is limited though. H1 antihistamines in primary mast cell activation syndromes rest on a handful of small pieces of work, all carrying moderate or high risk of bias ^[39]. So, the standard treatment is standard because it’s sensible, cheap and low risk, rather than because anybody has tested it hard, which is a perfectly reasonable basis for trying something and a pretty poor basis for building a whole management plan around it and then blaming yourself when it doesn’t deliver.

The hypermobility side

For the joints, the clearest signal points at rehab rather than at a purely structural framing of the problem. Therapeutic exercise, motor training and multidisciplinary care all come out favourably, with the honest rider that the literature is still limited and pretty heterogeneous ^[40][41][42].

Worth being clear about what that work is and isn’t, though. It isn’t stretching, and it isn’t generic gym strength bolted onto a body that can’t yet feel reliably where its own joints are. What comes out favourably is therapeutic exercise and motor training ^[40][41], which is a rather different job: giving the brain a clearer signal from the joint first, then a better movement strategy, and only then adding load on top of that.

Two specifics are worth having. In hEDS and HSD with multidirectional shoulder instability, a home exercise programme produced significant improvement in shoulder function measures across twenty four weeks ^[43]. And a structured rehabilitation programme in hEDS produced gains in exercise capacity, fatigue and quality of life that were still there at six months ^[44]. Both are small pieces of evidence, and both point the same direction, which is that the nervous system’s control of a joint is trainable even when the tissue itself is never going to change.

This is the part of the picture we spend our working lives on, and it’s the part that gets dropped most often, as it’s slower and a good deal less interesting than a medication list. It’s also the only one of the three strands where the thing you do at home on a Tuesday morning, is the treatment.

The sequencing question

Order matters, and it’s the practical bit most people get wrong. Pushing hard into an exercise programme while the reactive symptoms are all over the place tends to produce flares rather than progress, and expecting standard POTS conditioning to stick while somebody is repeatedly crashing is unrealistic. Getting the reactive side reasonably settled, then building the orthostatic conditioning, while the strength and control work runs alongside at a level you can actually sustain, is a more sensible sequence than attempting all three at full intensity at the same time.

It isn’t linear and you will have setbacks along the way. The aim isn’t a symptom free baseline before you’re allowed to start moving, as that baseline may never arrive, it’s a level you can repeat next week without paying for it for four days afterwards.

Getting Diagnosed, and Why It Takes So Long

All three are criteria based, they share a symptom pool, and only one of them has a biomarker worth much, so the diagnostic process is slow by construction, rather than by accident or by anybody’s incompetence.

hEDS requires generalised joint hypermobility, the systemic and musculoskeletal features, and the exclusion of alternative diagnoses, and that last step isn’t a formality. Among those who initially met the 2017 criteria, just over a quarter turned out to have an alternative or an additional diagnosis once somebody looked properly ^[5]. That’s a quarter of people who’d have been left with the wrong answer, or with half of the right one, if the exclusion step had been skipped to save twenty minutes.

Now, MCAS is the one most vulnerable to being called wrongly in either direction. It gets overcalled when nonspecific symptoms or a treatment response get used as the evidence ^[11][12][23], and it gets undercalled when nobody thinks to measure mediators during an actual episode, which is the only moment the measurement is worth taking.

POTS is the most straightforward of the three to confirm, and it’s still missed constantly, largely because a stand test takes ten minutes that nobody has, and because a normal blood pressure reading gets read as reassurance ^[7][8].

The practical problem sitting underneath all of it, is that finding a clinician comfortable with all three at once is genuinely difficult. Rheumatology, cardiology or neurology, and allergy or immunology each hold a piece of it, and coordinating those three usually falls to the person least well placed to do it, which is the person who’s ill and exhausted and has already told the story eleven times.

The Long COVID Question

Now, interest in this cluster went up sharply after 2020 and it’s easy enough to see why. Somewhere between two and fourteen in a hundred of those who have had COVID go on to develop POTS, with a good many more reporting POTS like symptoms without ever getting the formal diagnosis ^[45]. The mechanistic work since has pointed at autonomic dysfunction, small fibre neuropathy, immune dysregulation and possible mast cell involvement ^[46][47], which will be a fairly familiar list if you’ve read this far.

What hasn’t happened is the confirmation. It’s still unclear whether POTS arriving after COVID is biologically the same condition as the POTS that existed before the pandemic ^[48][49], and the evidence tying long COVID to rigorously defined mast cell activation syndrome, or to hEDS, doesn’t reach a consensus standard ^[2][22]. So, the post viral route is an important clinical reality and a promising research direction, and it’s not yet proof that the trifecta has one underlying biology.

It does change one practical thing though. A lot of people came into this picture through an infection rather than through a lifetime of hypermobile joints, and they’re frequently told their hypermobility must have been there all along and simply gone unnoticed. Maybe it was, but that’s an assumption rather than a finding, and it’s being made in an area where the basic question of whether these are even the same condition is still open.

What Nobody Knows Yet

The biggest shift over the last few years is that the hypermobility and POTS connection has hardened into something everybody recognises, while the three way trifecta has gone the other way and become more contested the more strictly mast cell activation gets defined ^[1][2][17].

The open question, and it’s a big one, is whether there’s a real biologically confirmed subgroup in which connective tissue fragility, autonomic dysfunction and mast cell activation are genuinely linked, or whether the clustering everybody keeps seeing is mostly a product of referral patterns, overlapping symptoms and case definitions nobody can agree on. Both are live possibilities at the moment, and anybody telling you which one it is has got out ahead of the evidence, and in our opinion that includes a fair number of people selling tests for it.

For you, practically, that leaves a handful of things. If you’ve got one of the three, the other two are worth knowing about and worth asking about, particularly if your symptoms don’t fit the diagnosis you’ve already got. And if somebody has given you a mast cell label on the strength of symptoms alone, that isn’t necessarily wrong, but it’s worth knowing it hasn’t been established to the standard the criteria ask for, as it changes how much weight to put on treatments aimed at it and how long to persist with them before asking a different question.

If you’re managing all three, the sequencing matters more than the individual interventions do, and the rehab side runs on the same principle whichever combination you’ve ended up with, which is that the nervous system’s control of the body is trainable even when the tissue underneath it isn’t.

The Fibro Guy

References

[1] Vernino, S., Bourne, K.M., Stiles, L.E., Grubb, B.P., Fedorowski, A., Stewart, J.M. et al. (2021) ‘Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting – Part 1’, Autonomic Neuroscience. https://doi.org/10.1016/j.autneu.2021.102828

[2] Farley, M., Estrada-Mendizabal, R.J., Gansert, E.A., Voelker, D., Marks, L.A. and Gonzalez-Estrada, A. (2025) ‘Prevalence of mast cell activation disorders and hereditary alpha tryptasemia among patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: A systematic review’, Annals of Allergy, Asthma & Immunology. https://doi.org/10.1016/j.anai.2025.03.022

[3] Castori, M., Tinkle, B., Levy, H., Grahame, R., Malfait, F. and Hakim, A. (2017) ‘A framework for the classification of joint hypermobility and related conditions’, American Journal of Medical Genetics Part C: Seminars in Medical Genetics. https://doi.org/10.1002/ajmg.c.31539