Mast Cell Activation Syndrome (MCAS) - discussion thread

[hallmarkOvME]

From the abstract of the review:

This seems like a contradiction. If it is know what causes MCAS, how can it also be true that the underlying mechanism is not yet clearly known?

Can you pick one you think is pivotal or especially robust? That would probably be more productive than asking someone to read thousands of pages. I can make a thread for the paper if we don’t have one already.

If we are to proceed per falsifiability, as someone recommended earlier, and compile a sufficient sample of disconfirmed null hypotheses or reputations, then we must eschew, or at least sacrifice, productivity. Papers to study have been requested. Must I also procvide the next conjecture, or will you do the work and come to know for yourselves? Otherwise we remain hostages to the hearsay feedback loop and learn nothing about individual case complexity, whether by MCAS or some other disease process class.

I picked this one because it's current and comprehensive. Knowing whether a paper is pivotal or not in the medical and social sciences usually takes significant hindsight.

 

[hallmarkOvME]

From the abstract of the review:

This seems like a contradiction. If it is know what causes MCAS, how can it also be true that the underlying mechanism is not yet clearly known?

Could you pick another word than the mostmbuzziest of buzz words in science writing right now than "robust"?. Ick!

Sniffing out contradictions ia what those who Popper critiqued were up to. Let's a stick to Popper's conjecture/refutation dialectic of falsifiability for now.

Also, are you sure you're not conflating causes woth underlying mechamisms? In medical science literature, the former usually refers to symptoms while the latter refers to disease processes l.

As a Feyerabendian, I find most of these terms distasteful and distracting, but I have consented to play the Popper game for the moment. Perhaps when we're done discussing your literature review and analysis, I might have time to revisit these problematics.

 

[Jonathan Edwards]

OK, @hallmarkOvME, I checked PubMed for Maitland-A + mast cell.

I got only 9 papers (below).
6 appear to be reviews or comments on reviews.
2 are reports of committees.
1 is a retrospective diagnostic analysis from an allergy clinic that has serious problems with methodology immediately apparent in the abstract.

Are these the papers you are referring to? Because on this basis Maitland has produced no useful original research on MCAS.

Looking at the brief introductory text given by PubMed in this download there also appear to be ust the sort of confusions we talked about. One includes single organ disease such as asthma and urticaria under MCAS, and so on.

Four of the papers focus on a proposed overlap between MCAS and hypermobile Ehlers Danlos syndrome. 'hEDS' is another unsatisfactory concept that has become popular with private physicians but which makes no real biological sense. This is an area populated by medical pseudoscientists. I know because I trained years ago with one of the main UK protagonists (and worked alongside them for decades), and realised just how bogus it all is.

There is no 'sophistry' here, just a recognition of how much bullshit there is around in medicine.

And yes, I took the trouble to look up the papers. Maybe Maitland has written some stuff I have missed but what I see here is the muddled incompetence I have been familiar with since 1977.

1 Mast cell disorders in Ehlers-Danlos syndrome.
Seneviratne SL, Maitland A, Afrin L.Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):226-236. doi: 10.1002/ajmg.c.31555. Epub 2017 Mar 6.PMID: 28261938 Review.
Well known for their role in allergic disorders, mast cells (MCs) play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury, with an array of chemical mediators. ...This report reviews basic biol …

2 Response to: "In reply to: 'Mast Cell Disorders in Ehlers-Danlos Syndrome' (Jaime Vengoechea, Department of Human Genetics, Emory University)".
Seneviratne SL, Maitland A, Afrin LB.Am J Med Genet A. 2018 Jan;176(1):251-252. doi: 10.1002/ajmg.a.38528. Epub 2017 Nov 21.PMID: 29160015 No abstract available.

3 AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.
Weiler CR, Austen KF, Akin C, Barkoff MS, Bernstein JA, Bonadonna P, Butterfield JH, Carter M, Fox CC, Maitland A, Pongdee T, Mustafa SS, Ravi A, Tobin MC, Vliagoftis H, Schwartz LB.J Allergy Clin Immunol. 2019 Oct;144(4):883-896. doi: 10.1016/j.jaci.2019.08.023. Epub 2019 Aug 30.PMID: 31476322
Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other …

4 Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference.
Gotlib J, George TI, Carter MC, Austen KF, Bochner B, Dwyer DF, Lyons JJ, Hamilton MJ, Butterfield J, Bonadonna P, Weiler C, Galli SJ, Schwartz LB, Elberink HO, Maitland A, Theoharides T, Ustun C, Horny HP, Orfao A, Deininger M, Radia D, Jawhar M, Kluin-Nelemans H, Metcalfe DD, Arock M, Sperr WR, Valent P, Castells M, Akin C.J Allergy Clin Immunol. 2021 Jun;147(6):2043-2052. doi: 10.1016/j.jaci.2021.03.008. Epub 2021 Mar 11.PMID: 33745886 Free PMC article.
The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. ...In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy a …

5 Mast cell activation disease and immunoglobulin deficiency in patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder.
Brock I, Prendergast W, Maitland A.Am J Med Genet C Semin Med Genet. 2021 Dec;187(4):473-481. doi: 10.1002/ajmg.c.31940. Epub 2021 Nov 7.PMID: 34747107
Mast cell activation disease (MCAD) includes single organ disease such as asthma, urticaria, and gastroenteritis, as well as multiorgan system involvement such as mast cell activation syndrome and anaphylaxis. ...

6 Adult-onset mast cell activation syndrome following scombroid poisoning: a case report and review of the literature.
Brock I, Eng N, Maitland A.J Med Case Rep. 2021 Dec 18;15(1):620. doi: 10.1186/s13256-021-03190-w.PMID: 34920756 Free PMC article. Review.
This led to proposed diagnostic criteria of mast cell activation syndrome. Mast cell activation syndrome is a heterogeneous disorder, defined by a combination of (1) recurrent symptoms typical of mast cell activation, (2) an increase of v …

7 Association of mast-cell-related conditions with hypermobile syndromes: a review of the literature.
Monaco A, Choi D, Uzun S, Maitland A, Riley B.Immunol Res. 2022 Aug;70(4):419-431. doi: 10.1007/s12026-022-09280-1. Epub 2022 Apr 21.PMID: 35449490 Free PMC article. Review.
Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/HSD may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Abe …

8 Mast cell activation syndrome: Current understanding and research needs.
Castells M, Giannetti MP, Hamilton MJ, Novak P, Pozdnyakova O, Nicoloro-SantaBarbara J, Jennings SV, Francomano C, Kim B, Glover SC, Galli SJ, Maitland A, White A, Abonia JP, Slee V, Valent P, Butterfield JH, Carter M, Metcalfe DD, Akin C, Lyons JJ, Togias A, Wheatley L, Milner JD.J Allergy Clin Immunol. 2024 Aug;154(2):255-263. doi: 10.1016/j.jaci.2024.05.025. Epub 2024 Jun 6.PMID: 38851398 Free PMC article. Review.
Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. ...Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known infla …

9 Environmental exposures, epithelial barrier dysfunction, and the evolving landscape of allergic disorders and asthma.
Fenner R, Norris RA, Maitland A.Curr Opin Allergy Clin Immunol. 2026 Feb 1;26(1):29-36. doi: 10.1097/ACI.0000000000001136. Epub 2025 Dec 5.PMID: 41355466 Review.
To prevent chronic inflammation and aberrant tissue remodeling, tight regulation of mast cells is essential in response to microorganisms, autoantigens, and environmental changes. RECENT FINDINGS: The surge in mast cell-mediated disorders and evidence …

 

[SNT Gatchaman]

Here are two papers previously posted in our threads with Anne Maitland in the author list: both on hEDS and both referencing mast cells.

Proteomic discoveries in hypermobile Ehlers–Danlos syndrome reveal insights into disease pathophysiology (2025, ImmunoHorizons)

KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome (2025, iScience)

 

[Hutan]

Sorry if I asked already.... What's the difference between diagnostic consensus criteria and "good clinical guidelines"?

Diagnostic criteria are for diagnosing someone with a disease/disorder. Clinical guidelines are to help health care professionals care for people with a disease/disorder e.g. how to diagnose, how to treat and support.

Mast cell activation syndrome: An up-to-date review of literature - PMC

Mast cells are a subtype of white blood cells and are involved in the immune system. These cells contain many chemical substances called mediators, which are involved in the allergic response. The fact that mast cells play a role in many events that ...

pmc.ncbi.nlm.nih.gov

The content's typical. The meat's in it's references. Follow and read them.

That 2024 review is a mishmash of trendy speculations, poorly put together and revealing a very superficial knowledge. See for example the section on 'Long Covid and MCAS'. The authors haven't quite understood Long Covid and it is instead 'Long-Term Coronavirus Disease 2019', with the authors seemingly being certain that the issue is prolonged or severe Covid-19 causing mast cell activation. Of course, Long Covid can, and often does occur after a very mild Covid-19 illness.

THE RELATIONSHIP BETWEEN PEOPLE WITH LONG-TERM CORONAVIRUS DISEASE 2019 AND MCAS

Long-term coronavirus disease 2019 (COVID-19) is an outcome of immune dysregulation. T and B cell deficiency, hyperactivity of innate immune cells, and an increase in proinflammatory cytokines are observed[7]. This dysfunction leads to a constant inflammatory reaction, pathogen reactivation, endothelial damage, host-microbiome dysfunction, and autoimmunity. Risk factors for the development of long-term COVID-19 include female gender, type 2 diabetes, autoimmune diseases, connective tissue, and allergic disorders[51,52].

People with long-term COVID-19 disease have major cardiac, neuropsychiatric, and pulmonary complaints. Multi-system disorders such as myocardial inflammation, POTS, dystonia, and myalgic encephalomyelitis/chronic fatigue syndrome can develop. Immune system effects include recurrent infection, autoimmunity, urticaria, allergic rhinitis, and asthma. MCAS is thought to be the possible mechanism underlying these effects[26,53].

Mast cells are the key producers of the inflammatory cytokines of COVID-19. A persistent inflammatory state with prolonged COVID-19 causes abnormal mast cell activation. One of the reasons for this is the maturation of mast cells in the pulmonary perivascular space[54]. Another cause is the discharge of substance P from immune cells due to severe acute respiratory syndrome coronavirus 2 infection. The secretion of this substance increases the stimulation of the G-protein X2 receptor and predisposes to MCAS formation[55,56].

It is thought that symptomatic improvement will be achieved with the treatment of MCAS in long-term COVID-19 cases. It is thought that stabilization of mast cells and reduction in related symptoms will be achieved by histamine blockade[57,58].

 

[Jonathan Edwards]

Here are two papers previously posted in our threads with Anne Maitland in the author list: both on hEDS and both referencing mast cells.

Interesting that these did not come up on a PubMed search for Maitland-A and mast cell. The second paper I remember as being of interest but Maitland is 54th author out of 57 and it is not primarily about mast cells as far as I can see. Kallikrein15 is a secreted serine protease from various cells.

 

[Jonathan Edwards]

I think the other paper is from the same group with Maitland probably as a provider of patients in both cases. It looks less impressive,

 

[Jonathan Edwards]

That 2024 review is a mishmash of trendy speculations, poorly put together and revealing a very superficial knowledge.

Yes, this seems to be a group with little understanding of basic inflammatory biology. I had not got as far as the Long Covid bit but much of it is wrong.

If this is the best review of MCAS to cite, the situation is dire indeed. I suspect at least there are some better written ones.

 

[hallmarkOvME]

Yes, this seems to be a group with little understanding of basic inflammatory biology. I had not got as far as the Long Covid bit but much of it is wrong.

If this is the best review of MCAS to cite, the situation is dire indeed. I suspect at least there are some better written ones.

I explained above I why I chose it ("The meat is in the references.). I don't know where you and @Hutan got the idea to look at it as whether it's the best, but it wasn't my idea.

 

[hallmarkOvME]

Interesting that these did not come up on a PubMed search for Maitland-A and mast cell. The second paper I remember as being of interest but Maitland is 54th author out of 57 and it is not primarily about mast cells as far as I can see. Kallikrein15 is a secreted serine protease from various cells.

Did you use Maitland-A? I used "Anne Maitland" and got 17ish?

 

[hallmarkOvME]

Diagnostic criteria are for diagnosing someone with a disease/disorder. Clinical guidelines are to help health care professionals care for people with a disease/disorder e.g. how to diagnose, how to treat and support.




That 2024 review is a mishmash of trendy speculations, poorly put together and revealing a very superficial knowledge. See for example the section on 'Long Covid and MCAS'. The authors haven't quite understood Long Covid and it is instead 'Long-Term Coronavirus Disease 2019', with the authors seemingly being certain that the issue is prolonged or severe Covid-19 causing mast cell activation. Of course, Long Covid can, and often does occur after a very mild Covid-19 illness.

Mishmashing and speculating have their place in science, especially with in these early phases of data gathering, and which the "poor" organization is reflective and artificial of.

Point some core examples of this "superficial knowledge" and take us to the depth you think ought to be at with your own knowledge.

I'll address your Covid points after.

 

[hallmarkOvME]

Please bring us up to speed on basic inflammatory biology. Use examples from as contrast.

 

[hallmarkOvME]

OK, @hallmarkOvME, I checked PubMed for Maitland-A + mast cell.

I got only 9 papers (below).
6 appear to be reviews or comments on reviews.
2 are reports of committees.
1 is a retrospective diagnostic analysis from an allergy clinic that has serious problems with methodology immediately apparent in the abstract.

Are these the papers you are referring to?

I didn't refer to papers. I said "her work." You didn't need to all this. Regardless, did you have time read all nine. Carefully?" Maybe you noticed she and Afrin are in different dx Consensus camps?

Got to go. I'll read the rest of this later.

 

[Hutan]

Mishmashing and speculating have their place in science, especially with in these early phases of data gathering, and which the "poor" organization is reflective and artificial of.

Point some core examples of this "superficial knowledge" and take us to the depth you think ought to be at with your own knowledge.

I'll address your Covid points after.

HOM, I'm sorry. I'm sure it hasn't been a comfortable experience, you mentioning that you have an MCAS diagnosis in passing and then reading that many of us here have doubts about the utility of the MCAS label, and getting drawn in to a debate about it. That is not an ideal start to being on the forum.

I am by no means an expert on the MCAS literature. I had a look at it a bit, because, like all of us with ME/CFS, I'd love for there to be an easy answer like anti-histamines. My comments about what I found are upthread. I can't recall them exactly, but what disturbed me the most was that proponents of MCAS seemed to be creating all sorts of outs, making it impossible to prove that someone didn't have MCAS. It seems that there are many different molecules that might be present at wrong levels, so a normal level of one doesn't rule out MCAS. Also, it seems that there are lots of reasons why a specific treatment or diet might not help, and so lack of a response to those doesn't mean that a person doesn't have MCAS either.

Any theory that isn't falsifiable rings alarm bells. Also, importantly, I couldn't see evidence of a whole lot of people being cured or improved by the MCAS treatments. So, I have rather lost interest in the idea and, unless someone offered up some compelling evidence, I guess I'd rather spend time looking at other things.

For the Long Covid +MCAS excerpt, I have already said what my biggest concern is. The authors seem to be suggesting that the MCAS reaction is due to a severe or prolonged Covid-19 infection, but we know that ME/CFS-like Long Covid can and often does happen after a mild infection.

There are also other problems, for example the confident assertion that a whole range of possible pathologies are definitely involved. There isn't evidence to warrant such certainty. I haven't seen good evidence that treatment of MCAS and specifically histamine blockade helps Long Covid, but the authors state that 'it is thought' that it does. People can think all sorts of things, but I think a review needs to offer up a bit more rigour than simply saying that people have suggested something.

 

[ChronicallyOverIt]

Been loosely following this thread, my questions and maybe it has already been answered in the early pages of this thread, is what does MCAS as a model need to do to get some foundational basis? I can see from lightly browsing that a big complaint is they ascribe many symptoms, does there need to be a strict criteria similar to CCC for ME/CFS? Are current doctors skipping the research phase and going right to treatment?

Just wondering if someone could wave a wand what would you fix with the current line of research? I’m not well read on MCAS at all so I’m just trying to understand

 

[ChronicallyOverIt]

That looks unhelpful. It fails to quote the study that showed no overlap with ME/CFS. It also fails to point out that MCAS remains a fringe concept in general medicine that has no clear definition. Moreover, Bateman Horne are not a reliable source on things like this.

We now have DecodeME and some other genetic studies that have found nothing to suggest a link.

What would expect to see if MCAS was implicated in decodeME? What in the current decodeME data is suggesting it’s not? Wanting to understand how decodeME could show a positive or negative correlation to the connection

 

[Jonathan Edwards]

Maybe you noticed she and Afrin are in different dx Consensus camps?

I think I had previously, which simply underlines the confusion about the concept.

I think you have made it clear that you have no explanation to give us as to why we should take this category seriously. We have wasted enough time on such things over thousands of hours of discussions of the literature.

 

[EndME]

To me, a layman, the main difference between MCAS and ME/CFS as concepts is that one of them is concept that is more free of belief or implications. All you need to have, to have ME/CFS, are certain symptoms for a certain duration, nothing more. The concept isn't married to a certain pathology that is automatically implied. For MCAS the definition implies that certain symptoms are caused by something for which there is no substantial evidence, that is pathology is implied without evidence. In that sense MCAS is more similar to "priori ME/CFS definitions" that for example implied that the thing which used to be called "ME" implied brain inflammation and other things, which many on S4ME argue can now be assumed was a description of illness that was a bad concept.

To me it is arguably not quite correct that the nowadays "PEM focused ME/CFS concept" is entirely free from belief either. For example there isn't research to show what exactly PEM is supposed to be or entail or why it can be used as distinguishing factor from other illnesses, why exactly PEM is good to distinguish ME/CFS from other illnesses rather than say a certain cognitive defect or something to do with OI or what the delay is about and whether it should or shouldn't be part of the concept. But in general the concept feels to imply much less, PEM is based on what people report as symptoms. People can be given a diagnosis of ME/CFS on the basis of how they present, having other things ruled out and nothing more is implied.

If I've understood @hallmarkOvME correctly they think that MCAS as concept is still more towards the beginning and that things will still change, whilst ME/CFS is further along (and at least on S4ME it is argued that the brain inflammation "ME", rather than "ME/CFS", was a bad concept as well). One author argues it's about trytase levels, for which there aren't high quality studies tying them to MCAS, then in the next criteria these aren't as important anymore. Then it's tied to symptoms. Then it's tied to certain treatments being effective but these have never shown effectivity in any well-run trial and others argue that they needn't be effective because of x,y,z. In the one study MCAS is supposed to have a prevalence of 1% and in the next it is supposed to be as high as 20%, which just suggests that the people running these studies can't quite agree yet by what MCAS is supposed to mean. Then there is still the combination of it all being explained by immunology that seemingly a lot of immunologists think is not proper immunology.

The problems I mention above are not unique to MCAS. For example we've seen some pretty horrid prevalence estimates for ME/CFS as well and for Long-Covid things are even far worse. Some doctors diagnose ME/CFS in every other patient whilst others have never diagnose it once. You can't automatically blame a concept just because epidemiologists or doctors don't know what they are doing.

As a layman, MCAS as concept, is perhaps similar to what a Long-Covid concept would be if you added into the Long-Covid concept that it was also caused by some viral persistence explanation for which there is no hard evidence. And of course you will find many people arguing that from a pathological standpoint of untangling Long-Covid in itself (rather than say a public health definition), without any implied viral persistence cause, it is already not a useful concept due to it compromising many different things that have nothing to do with each other.

As others have said nobody disbelieves the symptoms people are experiencing and nobody is suggesting them to be made up or that they can thought away. The question is just whether the current MCAS concept describes this group of people well enough. If it does it should be very easy to show that with a well-run RCT and mast-cell studies. But time has shown that there is a lack of willingness to do exactly that. The review states a diagnostic criterium that is in parts based on treatment efficacy (the citation on offer is one by Afrin which doesn't back this up). How can that be useful when precisely that has not been shown in well-run studies? Surely a concept based on treatment needs at least a study to back this up?

None of this is unique to MCAS. For example there is much criticism on S4ME that the concept of POTS to charactise orthostatic problems in ME/CFS is not justified because research seems to suggest that the problems reported by patients cannot be classified by POT. So members on S4ME argue that it is more meaningful to just give them the OI name, rather than a name that implies a certain pathology that doesn't actually classify the problem.

Naturally I'm very biased, the information I've gotten on MCAS is that from S4ME, where it is argued that the concept doesn't make much sense. I don't doubt that there is information out there that can persuade me of the opposite. That's why it would be nice to discuss one well done study, rather than a review where even a layman can tell that parts of it are nonsense and can't judge other parts in the first place (but some parts being nonsense doesn't yield trust in parts that can't be understood in the first place). Naturally it isn't anybodies responsibility to do this. Especially not after they have had to engage in a very lengthy argument after all they did was mention a diagnosis given to them by a doctor.

 

[Jonathan Edwards]

what does MCAS as a model need to do to get some foundational basis?

It needs to be a clear concept. There is a hidden problem. You can define an illness in symptom terms, as a syndrome, on the basis that those symptoms occur together in a sufficiently regular way to suggest that there is some common causal step (whether presence of bacterium X or activation of macrophages by small immune complexes or whatever). There does not need to be one single cause, just a common step that is likely to hve useful implications for care.

Atopy is a syndrome, involving the co-occurrence of very typical features like asthma and eczema. We think there is a common causal step involving mast cell activation, although there are a wide range of causal triggers and pathways may be varied, maybe involving IgE, maybe not.

You can also define an illness in terms of a causal step. TB is defined by the causal step of the presence of live Mycobateria. Membranous glonerulonephritis is defined by a particular pattern of immune complex deposition in kidney basement membrane (sometimes other proteins).

And syndrome concepts often migrate completely or partially to causal step concepts. Marfan syndrome started as a cluster of signs. It is now defined as an inherited abnormality in a fibrillin gene. Ehlers-Danlos syndrome is problematic because it was originally defined as not only having certain features but having a family pedigree consistent with a monogenic dominant or sex-lined recessive gene defect. It is now formally defined in those genetic terms. However, about fifty years ago the pedigree requirement got fudged and 'type III' was expanded to include clinical features without a clear pedigree. The situation got worse with the coining of 'hEDS' which means no more than relative hypermobility, which will mostly be polygenic.

The problem with MCAS is that it seems half the time to be defined as a clinical syndrome and half the time as a putative causal step. That causal step is implied in the name - something to do with too much mast cell activation. We already have a syndrome for that - atopy - but this is claimed to be different. And as has been pointed out nobody can agree what this new concept actually is. Is it any old other cause of mast cell activation (excluding clonal mastocytosis) in which case it probably isn't homogeneous enough to be useful, or is it something specific like a tryptase abnormality. (That seems to have been binned now.)

So in answer to the question, what does MCAS need to be useful, it needs to be a real concept rather than whatever a private physician likes to use it for.

And that is a major problem because as it stands MCAS is supposed to include just about any symptom you can think of so physicians can diagnose it in just about anyone feeling lousy and wanting a diagnosis. Which is what is happening all over the world and why so many people with ME/CFS think they have 'MCAS' as well. A good proportion get told they have hEDS and 'POTS' as well, which makes the whole thing ridiculous.

 

[Jonathan Edwards]

What would expect to see if MCAS was implicated in decodeME? What in the current decodeME data is suggesting it’s not? Wanting to understand how decodeME could show a positive or negative correlation to the connection

If abnormal mast cell activation was genuinely associated with ME/CFS I think we could expect some sort of clue to turn up in terms of a linked gene involved in a mast cell specific pathway. It might be an IgE receptor gene or tryptase gene. The absence of any gene being found on DecodeME may not exclude mast cell involvement but it is another negative.