Biomarkers - Are we Close? with Dr. Clair Francomano (Ep 118)

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Dr. Linda Bluestein: [00:00:00] Welcome back, Every Bendy Body, to the Bendy Bodies podcast with your host and founder, Dr. Linda Bluestein, the hypermobility MD. Today I'm going to be chatting with Professor Dr. Clair Francomano, Chair of the Medical and Scientific Advisory Board for the Ehlers Danlos Society. I'm so excited to chat with Dr. Francomano. Like many of you, I had an incredibly long diagnostic odyssey to getting my diagnosis of hypermobile Ehlers Danlos Syndrome. We're going to be chatting today about biomarkers, the difference between hypermobile EDS and HSD, if there actually even is one. And genetic testing, when is it indicated and what red flags should we be looking for as clinicians?

[00:01:00] Dr. Clair Francomano is an internist and medical geneticist and is internationally recognized for her work in a hereditary disorders of connective tissue. She has worked in medical genetics at Johns Hopkins, later joining the National Institutes of Health. As an intramural scientist, working as chief of the medical genetics branch and clinical director for the National Human Genome Research Institute, and then as chief of the Human Genetics and Integrative Medicine section in the Laboratory of Genetics at the National Institute on Aging.

She served as director of adult genetics at the Harvey Institute Dr. Francomano has published over 150 articles in the peer reviewed literature and has authored and edited four books. As always, this information is for educational purposes only and is not a substitute for personalized medical advice.

Be sure to stick around until the very end so you don't miss any [00:02:00] hypermobility hacks. Let's get started.

Well, it is so great to finally get to talk with you, Clair. And, um, I've just been wanting to do this for such a long time. 

Dr. Clair Francomano: It's really great to be here, Linda. Thank you so much. 

Dr. Linda Bluestein: Yes, absolutely. Um, and I feel like I, I see, I see you in different meetings and things like that, but, uh, you know, actually getting to talk to you this way is something I, like I said, I've wanted to do for a really long time and, um, I hope everything's going okay in your corner of the world.

Absolutely. Thank you very much. And I hope the same for you. Well, very good. Well, we know that there's actually been a lot, uh, happening lately, so we have more than usual to, to talk about, so I'm really excited about that. Um, I want to start with talking about generalized joint hypermobility, just because I feel like there's so much challenge surrounding things like the Beighton score, and then of course we know that there's more specialized tests like the upper limb assessment [00:03:00] score, the lower limb assessment score, um, and there's also the five point questionnaire, right?

In your clinical practice, um, which of those tools do you feel is most helpful for assessing, um, generalized joint hypermobility? 

Dr. Clair Francomano: So clinically, I'm using the Beighton score still. I mean, that's, that's really the anchor, um, and the one that I'm most familiar with and the one that I, that I use. Um, you know, we are in the midst of a, A fairly large study looking at the diagnostic criteria for, uh, hypermobile Ehlers Danlos syndrome and hypermobility spectrum disorders.

And part of that, uh, study is utilizing some of the measures. from the upper limb and lower limb hypermobility assessments. So, um, I would say stay tuned because it's likely that we will be making some recommendations based on that study to incorporate [00:04:00] those additional measures, uh, to sort of add them in with the Beighton.

Dr. Linda Bluestein: And when I was diagnosed, I had a high Beighton score at that time, but now, actually I guess it's a little over a decade later, my Beighton score is a lot lower through injuries and surgeries and things like that. So I would fall into the category personally of historical generalized joint hypermobility as of course do lots of our patients, right?

So if you have somebody who you feel like. Does fit the current 2017 classification criteria for hypermobile EDS, um, otherwise, you know, they meet the other, um, parts of that criteria, but their joint hypermobility is more historical. How do you usually handle that situation? 

Dr. Clair Francomano: So if, if they tell me that they were able to do the maneuvers that we asked of them in the Beighton, uh, but.

You know, for example, somebody's had surgery or they've had injuries or because of, [00:05:00] uh, progressive osteoarthritis or something like that, that they're not able to do them anymore, then I would include, I would take that historical hypermobility into consideration and I would still make a diagnosis of hypermobile Ehlers Danlos Syndrome.

Dr. Linda Bluestein: That's exactly what I do, so, um, I'm glad that I'm on the right, I'm on the right track there. Just my opinion. Yeah. Yeah. No, right. I mean, we, we are all constantly evolving how we, how we do things and, and I definitely know from, uh, having so many great conversations, uh, with you and with all the, the team for Project ECHO that, um, you know, these situations are complex, right?

And patients are very complex. It's, it's easy. To think that things should be really straightforward, but that's not how bodies work and that's not how science works. Exactly. So, speaking of complex, um, I, I want to jump into also [00:06:00] how we have people who fit the phenotype of hypermobile EDS or hypermobile Ehlers Danlos Syndrome.

And yet we don't yet know the genotype. So if you could explain to us, you know, kind of the difference between those two, and if you have thoughts about why we have not yet found like a single gene for hypermobile EDS. 

Dr. Clair Francomano: So in genetics, we use the word phenotype to describe the person's presentation, what we see clinically or what they experience in their lives.

Um, so their history and their, and their presentation, what we can examine in the examining room. Um, the phenotype is the clinical presentation and the genotype is the genetic sequence that underlies that phenotype. So, um, when we're able, when we have a gene that is identified as underlying a specific genetic disorder.

We can [00:07:00] look at the sequence of that gene and say there is a variant in that gene, which is the cause of the clinical phenotype. But for the hypermobile type of Ehlers Danlos Syndrome, because we don't have a single gene or even a set of genes that we can point to at this point, we're unable to go to the genome.

To make the diagnosis and so for that reason we're really dependent on the clinical diagnostic criteria to, um, to make the diagnosis. And that's why we use those 2017 criteria, uh, that all of us are so familiar with. By this time. So why are we in this situation? You know, there have been so many studies and such a lot of time and effort and money that's gone into trying to identify the genes that cause the hypermobile type of Ehlers Danlos [00:08:00] syndrome.

And, um, I think there, there are a number of possible reasons why we don't have an answer still. Um, the HEDGE study is ongoing and the analysis of that data is still in progress. And I think it's still possible that we may find something that will contribute to our understanding of the hypermobile type of Ehlers Danlos syndrome.

Um, it's possible that there are just many, many genes. That, uh, that underlie it and there's an example in genetics, um, of hypertrophic cardiomyopathy, which uh, hereditary hypertrophic cardiomyopathy has something like 24 or 26 different genes that cause it. And so that's another phenotype that took a long time for people to.

Dissect, because, um, you know, they're, they're [00:09:00] conflicting signals when you look at the genome, when you look at the gene, the genetic sequences, when there are that many different genes that are contributing. So that's one possibility. Um, and. Uh, another possibility is that the, the underlying mechanism is a mechanism that is something that outside of the realm that we're thinking and we're thinking about hereditary disorders that involve the connective tissue and are structural proteins.

of the connective tissue, and maybe it's more of an inflammatory, uh, issue, um, and we're, we're looking, we're looking under the lamppost, and if the lamppost, if you can sort of say that's our, uh, the light that we're shining on it to look at the specific genes that we're interrogating. We're looking under a set of genes for structural [00:10:00] proteins and maybe we're not looking in the right place.

So that's one of the things that the team that's involved with the hedge analysis is really looking at. You know, they want to make sure we have the whole genome there. We sequence the whole genome. So, we have all those other genes, we just have to interrogate them, and of course you've got 3 billion base pairs for each participant, so it's a lot to look through.

I think those are the two really major possibilities. Another option, another possibility, a reason why we may not have an answer right at this moment, is that, um, It's not a monogenic phenomenon, but that there are multiple genes that, and the interplay of those multiple genes are contributing to the phenotype.

And we have several examples of that in genetics also, where we know [00:11:00] that it's, you have to have a variant in two different genes in order to express. The phenotype. So if that's the case, it's going to take us a little longer to figure this out. You know, so we just have to not give up hope because we know that we know the condition runs in families.

It looks for all the world like a Mendelian disorder. Um, it looks like, uh, an autosomal dominant condition. So I just think we have to keep looking. We're not 

Dr. Linda Bluestein: giving 

Dr. Clair Francomano: up hope. 

Dr. Linda Bluestein: Well, I think it's actually really exciting that there is obviously this massive amount of data to be looked through, and I think it's great that, uh, you know, you're looking under all of these different lampposts, as you said, because, right, it could be that You know, what we thought is very different than what actually is, is the case.

[00:12:00] So, um, that's really, it's really exciting, actually. 

Dr. Clair Francomano: Yeah, it's a very exciting time, really, because we've, we have never been in the situation to really. We have the tools and the means to just go after it and, and, and there's a lot of interest and enthusiasm to do that right now. 

Dr. Linda Bluestein: Mm hmm. Yeah, that's, that's really, really exciting.

So the 2017 classification criteria for hypermobile EDS we know are, are being revisited, but of course all of these things take a considerable amount of time, right? There's a lot of work that happens behind the scenes that I think. A lot of people are not aware of, in the meantime, that's the set of criteria that we are, you know, generally going by when we're looking at somebody clinically, do they or do they not have hypermobile EDS, or would they fit more into the category of HSD, and we know that the third part of that diagnostic criteria [00:13:00] is Exclusion of other conditions.

How do you approach satisfying that criterion 3? 

Dr. Clair Francomano: Well, I have a list of what I consider to be red flags or signs in the family history or the person's personal history. That make me wonder whether there might be either another type of Ehlers Danlos syndrome that's causing the person's hypermobility or a different hereditary disorder of connective tissue altogether.

So, um, I go through those red flags, uh, when we take the family history and also when I'm collecting the information about the person's personal history. And then there are certain things that I look for on my clinical exam that also are red flags to me that say, this is a little unusual for hypermobile Ehlers Danlos Syndrome.

It's [00:14:00] not our garden variety, hypermobile EDS, and that whenever, if there's anything that comes up in the family history or the personal history or on the exam. It seems out of the ordinary or is on that red flag list for me, then we do genetic testing. 

Dr. Linda Bluestein: And that was going to be my next question about when you do genetic testing.

So it's when you have one of those red flags? Yes. Yeah. Normally? Okay. Yeah. Okay. And is that something that maybe we could put in the show notes? Cause probably a lot of people just heard that and they're going to think, Oh my gosh, I would like to know what those red flags are because of course we know that there's also confirmation bias, right?

So, you know, a lot of people, and we're going to talk later about direct to consumer testing and all the challenges with that. We know a lot of people are resorting to tools like that because it is so hard. To get in to see a geneticist and sometimes you know they get back like a variant of uncertain [00:15:00] significance or something like that and then they they look up what's the closest condition that that might be associated with and then you can see what are some of the different features and then You know, you think, oh, well, I have that.

I have that. I have that. And so it's very easy to be led down a path that is more scary, I think. Yes. Yeah. 

Dr. Clair Francomano: Yeah. I have, there's a table of the red flags that we published in the book Symptomatic. Um, which came out in, in January of 20, uh, 2024. Yeah, just this last year. So, uh, it's a great book. Thank you.

Thank you. So I can, I can send you that table. And, uh, happy to share it with your 

Dr. Linda Bluestein: listeners. That would be wonderful. So if somebody does not have, uh, those red flags, then generally speaking, um, you, you usually do not do genetic testing. Is that, [00:16:00] is that that 

Dr. Clair Francomano: has been my practice. Um, because for, for, for, for, for, for, for, for, for, for, for, for, for, for, for, For some time I did do genetic testing and we've done genetic testing as part of a number of different research projects for several years now, many years, starting back when I was at the National Institutes on Aging, and we just don't find anything.

You know, we find variants of uncertain significance, but, uh, like if you, if you look at the hedge data, um, with the whole Genome sequencing, uh, those are people, the people who were diagnosed clinically as part of HEDG. We did not find any, any variants, pathogenic variants in any of the genes that cause other types of EDS or other hereditary disorders of connective tissue.[00:17:00] 

There were a few people who were enrolled in HEDG after COVID hit, and so those are people that we didn't have an opportunity to see clinically, and so in some of those people, it's just a handful, really less than a handful of people where we found pathogenic variants. But, um, Yeah, for the most part, if we saw and, and clinically we, we came to the conclusion that this was hypermobile EDS, we haven't found any variants in other genes.

That's, 

Dr. Linda Bluestein: that's really important and hopefully reassuring for people who are being assessed in person by somebody who is knowledgeable enough about these conditions and feels quite confident that they fit into the hypermobile EDS phenotype, but at least per the hedge group out of that group, none of them tested positive for a [00:18:00] different type of EDS or a Hereditary disorder of connective tissue, if I, if I heard you correctly.

Absolutely. On the topic of genetic testing, we know that cost has changed dramatically over the past five years, probably three years even. If somebody is going to be tested, if you're going to test them, do you How do you normally order a connective tissue panel or do you do whole genome sequencing, whole exome sequencing?

How do you normally approach that? 

Dr. Clair Francomano: Well, there's been a little bit of a shift in the landscape of the hereditary disorders of connective tissue panels just in the last month, I would say. You know, my practice for the last, well, since I've been here at Indiana, which is the last five years. We've been sending, um, panel testing for the hereditary disorders of connective tissue panel, either to GeneDx or Invitae.[00:19:00] 

And, um, All that time up until just August of this year, uh, both of those companies had an option for self pay where you could get that panel done for 250 even if your insurance was not covering it. So within the same month, Invitae was acquired by LabCorp and that self pay option went away and GeneDx has now, um, Eliminated the hereditary disorder of connective tissue panel from their menu, from their offerings, so we don't have that option anymore.

Now, LabCorp is in network for most insurance companies, so, um, the people from Invitae have been pretty reassuring. That the testing is going to be covered to a greater degree even than they were able to [00:20:00] offer it before. So we, we just don't know. We don't have enough experience yet in this new environment with Invitae rolled into LabCorp to know what the costs are going to be for the, for the patients in this setting.

But I still prefer, I mean, if it's an option to do the Hereditary Disorders of Connective Tissue Panel, I prefer to do that rather than the exome because we have so much greater chance of finding variants of uncertain significance when we do the exome. I mean, we know that, um, people vary from one to the other when we look at the genetic sequence.

The variant, variation is about. 0. 1 percent. That's one in a thousand base pairs. So for every thousand base pairs that we sequence, we're going to find a variant that we have to explain somehow. It's either going to be a likely benign or benign or a variant of uncertain [00:21:00] significance or likely pathogenic or pathogenic.

And, um, so I prefer to narrow the number of genes that we interrogate just because it gives us less of a chance of finding those variants of uncertain significance, which are, they're unnerving to people, even if, 

Dr. Linda Bluestein: you know, 

Dr. Clair Francomano: we can say that we just don't know till the cows come home, but it just raises questions in people's minds, you know, and it's difficult.

So, if we can minimize the numbers of those that people have to. Navigate. I think it's better. 

Dr. Linda Bluestein: Yeah, that's interesting because I, I encountered that when it was recommended that I have a cancer panel done because I have a very small family and had had some things happen and so they recommended that I do this panel and they, they asked me, it was going to be done through Invitae, you know, how many did I want?

Did I want the smallest or the largest that they offered me, which I think was around a hundred genes? And I said, I [00:22:00] wanted the largest and I thought, well, I can handle it if I get back a variant of uncertain significance. Yeah. Which of course I did, um, luckily, nothing that was pathogenic, but, um, you're right.

It kind of is in the back of your mind and, uh, people, it, it, it is hard. People can find that stressful. And um, so you're saying that until we have more data, cause of course people can always get tested again. Um, but for, but for now doing the connective tissue panel is the most helpful because then it can rule out these.

Uh, you know, genes that we know cause vascular EDS or, you know, some of these other, uh, more rare subtypes. And we're not then confusing the picture or making a person anxious over these variants of uncertain significance. Did I understand that correctly? That's exactly it. Yeah. And we know that stress plays a role in symptoms, for sure.

For sure. 

Dr. Clair Francomano: Yes, [00:23:00] absolutely. And, you know, and for people with EDS. The dysautonomia symptoms, the mast cell symptoms, all of those things are really exacerbated by stress. You don't sleep well when you're stressed, and that makes pain worse, and so, yeah, all the things, we definitely want to minimize stress.

Dr. Linda Bluestein: Yeah, yeah, I remember when my pain was at its worst, and my doctor was telling me to take some deep breaths, and you know, it definitely was like, Uh, I think, I think she definitely could have done a better job of explaining that it does not matter what is causing the pain, but that stress will make the pain worse.

Um, I felt like instead, like she was making me think that there was no actual cause of the pain other than what I was generating in my own head. You know what I mean? Right. Yeah. Yeah. But, um, I, yeah, I think that's a helpful concept for people to understand and like you said, it makes the dysautonomia symptoms worse, mast cell activation syndrome, um, et cetera.[00:24:00] 

Okay. So, uh, I bet you won't be surprised at this next question, hypermobile EDS versus HSD. Is it possible that the same condition and we are going to talk in a little bit about the fibronectin? Okay. Paper that, that recently came out, but, um, more from a, a, maybe genetics, uh, standpoint. What are your thoughts on that?

Dr. Clair Francomano: I do think there's a very good chance that when we separated those things out, we, we didn't do a service, a good service to our. Our patients. Um, I really, I mean, I was there when it happened. I wasn't on the subcommittee that was dealing with hypermobility, and I completely understand we needed a more rigorous subcommittee.

So, that's the first diagnostic set of criteria for hypermobile Ehlers Danlos Syndrome. But the information that we've gained over the last, well, it's [00:25:00] seven years now, right? Since 2017. So, um, we recognize that, um, The prevalence of the comorbidities is very comparable between people who are diagnosed with hypermobile Ehlers Danlos syndrome and hypermobility spectrum disorder, generalized hypermobility spectrum disorder.

And um, I have families where we have one person who meets the diagnostic criteria for hypermobile Ehlers Danlos syndrome, and then there are other people who don't meet the diagnostic criteria and by the, by the rigid criteria, we would have to say that one of them has HSD and the other one has hypermobile Ehlers Danlos.

So, um, and then this fibronectin paper that you're mentioning now suggests that the biomarkers are very similar, uh, from one to the other. So, this is another thing that I [00:26:00] think we're, we're really going to have to look at very closely in the diagnostic criteria study. And, um, It's one of the things we're going to be focusing on when we do the analysis of that data.

Dr. Linda Bluestein: And on the opposite side, I guess, sort of, um, do you think that it's possible within a family for one person to meet the criteria for hypermobile EDS, but for another member of the family to have vascular EDS, for example, or have crossover types within a, within a person even? 

Dr. Clair Francomano: So, it's theoretically possible, right?

We know that people, um, it's possible for vascular Ehlers Danlos Syndrome to occur as the result of a new variation in the DNA of the gene which causes vascular EDS, which is called COLT3A1. So, If a mom, for example, has hypermobile Ehlers [00:27:00] Danlos Syndrome, it doesn't protect her from, uh, having an egg that would have a new variant in COLT3A1.

That could happen. Another thing that could happen is she may have a partner who has vascular Ehlers Danlos Syndrome. So a mom with hypermobile EDS and a dad with vascular EDS could have a child. with either one or both of those conditions. There is kind of, people tend to think about vascular phenotypes.

In hypermobile Ehlers Danlos Syndrome, and I think sometimes that's a source of some confusion, because, um, we think about POTS as a, as a vascular phenomenon in some ways, the cardiovascular phenomenon, and, um, the bruising is a result of, uh, you know, the [00:28:00] subcutaneous blood vessels are particularly fragile, and so they bleed.

And so people People who are not familiar with the type of vascular complications that we see in the vascular type of EDS think that they have some vascular manifestations even though what they really have is hypermobile Ehlers Danlos Syndrome. So I think it's important to make that distinction and for people to know.

But the kinds of vascular phenomena that we see in vascular EDS are the ruptures of the arteries, those medium sized arteries in the abdominal cavity. So Things like the hepatic artery and the splenic artery and the artery that goes to the stomach, you know, those. I mean, we can see dissections and ruptures in the carotid arteries and vascular EDS, but the POTS type symptoms [00:29:00] and the easy bruising and things like that are not things that make us worry about vascular EDS.

Dr. Linda Bluestein: Mm hmm. Okay. I think that's, that's really important. I, a couple of times when I did post about vascular EDS, I had so many comments from people that were so concerned about that. And yes, it did seem like a lot of the things that, that they were sharing, right, didn't fit into those red flags that we talked about that I think are going to be really important for people to, to be aware of so that they can understand that, that distinction because that's so important.

Yeah. Okay. 

Dr. Clair Francomano: The, um, there's also, I think people have the same kind of confusion with the classical type of EDS also because, you know, the hypermobility is a feature in both in classical and hypermobile EDS. And, um, and the skin, uh, soft skin, stretchy skin is something that's seen in both. So, um, it's, it's [00:30:00] really a matter of degree for the stretchiness of the skin.

And that those really, uh, extreme scars that people see on the shins to me are really the, that's the big giveaway for the classical type when I'm looking at somebody in the office. I always look at their shins 

Dr. Linda Bluestein: first. Interesting. Okay. And when you look at their shins, what are you looking for specifically?

Dr. Clair Francomano: So often, um, people with classical EDS will just have tremendous bruising up and down their shins. And they often have these scars that are described as Fish mouth scars, they're kind of like a V shaped or U shaped scar. Um, the children often get them if they're, when they start toddling around and walking into, uh, furniture and things, the skin just splits.

And then it doesn't heal very well and you get, you get really, uh, prominent scars that are [00:31:00] sometimes described as hemo siderotic. It looks like there was blood there and then the bruising just never goes away. So they kind of dark in color. And um, Um, they're, they're quite characteristic, like these, these very, uh, very scarred shins are a real giveaway for the classical type of EDS.

And then of course the stretchiness also of the skin, which is usually, uh, much more pronounced than what we see in the hypermobile type. 

Dr. Linda Bluestein: Mm hmm. And, and definitely. Yeah. That is a point to the benefits of having an in person evaluation, especially for that first visit where you can actually feel someone's skin and feel, you know, not just having them show you on camera.

So I feel like that's so important. I always, if I'm having a new patient, that first visit is always in person. 

Dr. Clair Francomano: I [00:32:00] agree completely. I mean, we were really handicapped, I think, during, uh, the COVID years when we weren't seeing patients in person. Um, I still have a few people that I saw for their first appointments, um, by telemedicine and we're trying now to bring them in to make sure that we've got a really good in person evaluation.

Dr. Linda Bluestein: Okay. We are going to take a quick break and when we come back, we are going to touch on TNXB. the calocrine variant, this is my wishlist, fibronectin, the skin biopsy paper, what to do if you can't get in to see a geneticist, and then we'll chit chat if we have more time. So we'll be right back.

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We are back with Dr. Francomano and have so many So, other fantastic topics to dig into. First thing I want to ask about is TNX B and what your thoughts are on if this has a contribution with the hypermobile EDS phenotype. Is this something that, you know, we are, needing testing for or what are your [00:34:00] thoughts on that?

Dr. Clair Francomano: I think this is something we really need more information about. Um, the, the hedge team has been looking at the TNXB, uh, gene and look, really interrogating the sequence that we have for TNXB and they are not really coming up with much. It's been a little bit of a surprise to me. Um, we know that there is a phenotype associated with bi allelic variants, so two copies.

Two copies of a TNXB variant causes an autosomal recessive phenotype that looks comparable to, more comparable to the classical type. It's what we call classic like. Um, and some of the children of people who have two copies of a TNXB [00:35:00] variant. have a phenotype that looks more like the hypermobile type of Ehlers Danlos Syndrome.

Um, so, we've been kind of, I mean, in my mind, I had been thinking that it's possible that heterozygous variants are single copies of those TNXB variants. Could be one cause of hypermobile Ehlers Danlos Syndrome, but based on the data that we have so far from Hedge, it's really not that promising. 

Dr. Linda Bluestein: That's so interesting.

When it comes to, we talked a little bit about variance of uncertain significance before the break. For all the people out there who have had some kind of testing and have had a variant of uncertain significance, you mentioned that it could be, fall into the category of likely benign. Benign, like, you know, there's different categories, right?

So, um, can you maybe just explain that a [00:36:00] little bit more and, and basically how people should view that if they do get testing and it does come back with some variants of uncertain significance or VUSs? 

Dr. Clair Francomano: Absolutely. So the American College of Medical Genetics, um, came up with a set of algorithms basically that allow us to assign.

Variants into one of five categories, they're either going to be pathogenic or disease causing, likely pathogenic, a variant of uncertain significance, likely benign or benign. And some of the things that the, these algorithms use. These are, um, well, one, one example, one thing that we look at is the frequency of the variant in population databases.

So, there are a couple of different [00:37:00] databases that are out there now that tell us how common are specific variants in population databases. particular genes. So if the variant is present with a frequency of like 10 or 15 percent in the general population, it's not likely to be causing a rare condition.

Um, so that's one thing that we, it makes it more likely to be a benign variant if it's got a high frequency in a general population database. There are also these programs that we can run that say what the likely effect of the variant is on the protein structure and function. So if it's likely to be, to not really change the structure or function of the protein that is encoded by that gene, then then it's not likely to be a pathogenic variant, it's more likely to be benign.[00:38:00] 

So, these kinds of things, there's a long, long list of the different factors that are taken into consideration, but the diagnostic laboratories run each variant that they find through these algorithms and then they come up with The assignment based on the probability generated by the diagnostic algorithms that they use.

So, um, if it's a pathogenic variant, it's probably either been seen before, or it's a type of variant that is known in that gene to cause disease, uh, in, in other people. Um, If it's a variant that's been seen frequently in unaffected individuals, that will be classified as benign and so on. So the variants of unknowns of uncertain significance are the ones that we just, we just don't [00:39:00] have enough information.

You know, it might, maybe the in silico, you know, the computer models say that it possibly might change the structure, but we don't really know. Or, um. It might be in the population databases, not very common, but not absent either, you know, so there just isn't enough information and it can't be classified one way or the other.

And sometimes we can do family studies. You know, for example, if a person has, um, classical Ehlers Danlos Syndrome, and they've inherited that from their mom, and we find a variant in one of the type 5 collagen genes that's a variant of uncertain significance, we can test the mother and see if the mother also has it, then it's possible that that's a little bit of additional evidence that it [00:40:00] could be a pathogenic variant.

But if, if that variant was inherited from the dad who's not affected with the type, with classical EDS, then that's unlikely to be explaining the phenotype in the patient. So the family studies can be helpful. They're not always helpful, but they can be helpful. Um, and then if we don't have any additional information from family studies or for whatever reason we can't get family studies, we just recommend to people that they come back and let's look at it again in a year or two, because We're getting more and more information all the time, the variant databases are growing by leaps and bounds and the information we have about the variants is growing by leaps and bounds.

So, in two years, we may be able to say one way or the other, where we're not able to say now. 

Dr. Linda Bluestein: That makes sense. And when you were talking about, you know, doing the family studies, I don't [00:41:00] know if you've made this observation, but I feel like we've talked about this maybe a little bit in the, in the echo groups as, you know, not something that's been studied necessarily per se, at least at this point in time, but that, that over the generations, that it does maybe seem like.

People are being more affected. Is that something that you've observed in your, in your patients? You know that the younger patients seem to maybe have a greater impact of the hypermobile EDS than older generations or is that not something that you've really seen? 

Dr. Clair Francomano: So I've heard people say that, but it's not something that I've really, um, I can't say that I've personally witnessed it or could testify to it, you know, if you put my hand on a Bible.

There is, that's a phenomenon that we recognize in genetics. It's called anticipation, where the, uh, the children and subsequent generations are more, uh, [00:42:00] Profoundly affected by the condition than the previous generations were. And typically, um, that phenomenon is caused by variance in a gene that has multiple triplet repeats.

And so we know that as, as those variants are passed down from generation to generation, they're more likely to expand. So the numbers of repeats of those triplet repeats gets larger as in subsequent generations and the phenotype is more profound when the variants are, when they are more. So, that process of anticipation is something that's recognized in genetics, but, um, we haven't found any triplet repeats in underlying the hypermobile type of Ehlers Danlos Syndrome [00:43:00] yet and, uh, I, I just don't, I, I don't know.

It does seem like some of the, um, comorbid conditions. These are definitely, uh, more, they're more recognized now. Like I never thought about mast cell activation or allergies or, um, even, even the dysautonomia kinds of things didn't really seem to be part of the clinical picture when I was first learning about Ehlers Danlos Syndrome, which was in the 80s.

So, 50 years ago. Wow. 30 years. But, I don't know if that's because we didn't know enough to look. We're because they weren't there, right, you know, right. It's really hard to know. 

Dr. Linda Bluestein: Yeah. Yeah. It just seems like there's a not insignificant number of people in [00:44:00] their twenties, late teens that are, you know, quite significantly impacted and have, their quality of life is quite poor.

And I just don't remember when I was that age having, you know, any friends or, I mean, obviously, you know, if you're talking about, uh, the prevalence would be, you know, pretty Potentially low enough that you wouldn't necessarily know somebody, but it just, and maybe now that, you know, being in this world, it just seems like there's more people than there really are because you're, you know, you're biased by who you see, but it just, uh, it just, I don't know, maybe that's part of the COVID effect of, you know, people having activation of their immune system from this, you know, novel virus and that having impacts.

I was just curious. Yeah. 

Dr. Clair Francomano: Yeah. I don't know. I really, I do think the, there's more awareness now, and that's a good thing. Um, it's definitely a good thing. I credit the Ehlers Danlos Society, who has done a huge amount [00:45:00] to bring awareness about EDS to the general population. And so, I think people are being diagnosed, uh, more readily now than they were 10 years ago because of those efforts.

So, um, I don't know. It's hard to say. It's very hard to say. 

Dr. Linda Bluestein: Sure. Sure. Okay. And let's talk about biomarkers a minute. So we know that there have been a lot of different things that probably have been looked at over the years. And I mentioned briefly, you know, the fibronectin paper. We know that there was the MUSC study where they looked at the calocrine variants.

They also talked about, you know, is the complement system perhaps. And you had mentioned earlier, you know, is it possible that the, that the immune system or that there's, you know, more inflammatory conditions than we, than we realized involved in these processes? How close do you think we are to having biomarkers?[00:46:00] 

Dr. Clair Francomano: So the paper from Marina Columbi that was just published in the last couple of weeks is very promising, I think, uh, you know, this, um, she's found these markers at the That's the amino terminal, uh, end of, uh, fibronectin, um, as being, um, pretty prevalent among patients with the hypermobile type of EDS and NHSD, which is interesting.

Um, but not in some of the other types of Valler syndrome and not in, um, uh, some, she looked at a couple of different rheumatologic conditions. Uh, as well. So, uh, it seemed to be both, uh, sensitive and specific for hypermobile EDS and HSD. So that's, that's a very promising, uh, line of inquiry. And I think, uh, people are [00:47:00] very, very interested in seeing some replication studies.

To try to, um, try to, uh, verify that that is a useful biomarker and it would be so helpful, I think, uh, to have a concrete test to offer people to make a diagnosis, uh, rather than being entirely dependent on the clinical criteria. So I, I think that would be really, really helpful. And then it also, uh, might.

lead us to be thinking down the lines of what kind of rational therapies, um, might that lead, that bring us to, uh, with a little bit more understanding about the underlying, um, connective tissue physiology or pathology. And, um, the Calocrin study, uh, from MUSC is also extremely interesting. And I know a number of people are working on trying to [00:48:00] replicate that Uh, right now, um, unfortunately it still has not been published in the peer reviewed literature.

And, uh, so we, we're still kind of, it's kind of up in the air. I, I think we, we still just need more information about that, uh, in order to know whether it's going to be a pan out as a, as a marker or not. 

Dr. Linda Bluestein: That makes sense. Okay. Uh, one of the listeners submitted a question about the, whether we want to call it the triad of MCAS, EDS, and POTS, or the pentad, you know, you add in autoimmune and GI septet.

I mean, you know, we see a lot of these things, right, that travel together. Um, do you think that, The comorbidities are, you know, truly separate conditions, or do you think that this is perhaps all part of one multisystemic condition? 

Dr. Clair Francomano: I've been thinking about it as, [00:49:00] as part of all one multisystemic condition.

And I think that the, You know, as I said earlier, we have been thinking about HSD as disorders fundamentally of the connective tissue. Um, and we know that the connective tissue plays a really important role in, if you can call it, the education of the mast cells. Um, and we also know that it, the, um, autonomic nervous system.

Can be profoundly impacted by, not only by the mast cells, but also, uh, by disruption of the craniocervical junction and we can get venous pooling as a result of the, uh, uh, venous insufficiency from the legs. So, We can think of ways that the underlying connective tissue issues may be [00:50:00] contributing to some of these phenotypes.

The GI issues are related to the dysautonomia and they can also be related to the mast cells. It is just one huge big Venn diagram with overlaps everywhere you look, right? Right. And so, and you can imagine, I mean, we could create a story that tells, explains how the connective tissue is contributing to all of these various things.

But as I, as I said earlier, it's possible that we're thinking about it in the entirely upside down way and that when we, when we understand more about the pathology, we will recognize that the connective tissue involvement was the secondary. Issue. So, um, I think we have to keep an open mind about it at this point.

Um, but and well, and take care of each symptom and problem for the [00:51:00] patients in the very best way that we can while we're sort of operating in the dark. 

Dr. Linda Bluestein: Right, right. And I think that's one of the challenges that people face, right? Because so frequently we see people that have so many different. Symptoms, and they might be in so many different bodily systems, and you and I are used to that, and other people who, you know, are in this space, but a lot of other physicians are looking for things within one system, and if you start talking about problems in other systems, that becomes, I think, problematic from the standpoint of, you know, getting good care.

We know that there's a lot of Challenges with our health care right now, uh, currently for sure. Do you think there's a way that patients can approach that in a way that might help them be understood a little bit better or, you know, we know medical trauma is, is so prevalent and you've written some great papers about this.

It's so, so important. Do you think there's a way [00:52:00] that a patient can present this that would be where they gaslit, I guess is what I'm asking. 

Dr. Clair Francomano: I think one of the most important things is finding a primary care doctor who's going to be in your corner, you know, and, um, someone who really understands the multifaceted nature of this condition.

Uh, and then it helps to have the referral coming from the primary care doctor and, and I think it gives validity, uh, to that referral if it's from, from a PCP and a knowledgeable. Um, if people are going to specialists, I think it serves them well to just try to deal with the one issue that they're going in to talk about because, uh, it is really, really challenging.

You know, I don't know about you, Linda, but when I was in medical school, I was [00:53:00] taught that if everything is wrong, probably nothing is wrong. 

Dr. Linda Bluestein: Yes. Yes. 

Dr. Clair Francomano: And I think there are still a lot of doctors out there that have this mindset that if you have a pan positive review of systems, if you ask about every system and there's a problem in every system, likely it's not, it's not real.

And we know that is not the case for our patients. They have very, very real issues in almost every organ system. So, um, Um, it's important if, if you're dealing with a new physician or new, new, uh, practitioner to just really focus on that one thing that you know they'll be able to help you with and not get into the whole nine yards.

Dr. Linda Bluestein: so, right. So if you're seeing a neurologist to focus more on your neurologic symptoms and not necessarily expect them to address your gastrointestinal symptoms, [00:54:00] right. 

Dr. Clair Francomano: Or your mast cells and things like, yes. 

Dr. Linda Bluestein: Right, right. Even though they, 

Dr. Clair Francomano: they may, they might all be relevant, they may be playing a role.

They definitely might. Yeah. Yeah. I mean, and the other thing is to try to find the people who are, who are knowledgeable, and that's one of the things, you know, the. The Ehlers Danlos Society Centers and Networks of Excellence, we're really working to try to put out there where, where people can get care, um, from knowledgeable clinicians who are aware of what's multi, multifaceted nature of the problem.

So I, I hope that eventually, I mean, right now we have like 37 centers and networks around the globe, but, and it's not nearly enough. But it's a start. And the, um, the other place people can look is the, uh, healthcare professional directory at the Ehlers Danlos Society webpage, uh, to try to find people who have [00:55:00] experience with these multiple different issues in EDS.

Dr. Linda Bluestein: The group that, uh, we are a network, not a center, but I am part of the Colorado Network of Excellence, which is very exciting. That was just something that I think was that prior to the last couple of months that that next group was awarded from the Ehlers Danlos Society. So I'm very excited to be a part of the Colorado Network of Excellence, um, based mostly out of the Denver area.

So. Yeah, those kind of resources I think are really, really important for patients to have. So what about patients who really want to see a geneticist and or they're told you need to see a geneticist for a diagnosis, but there's, you know, obviously we know long wait lists. What do you recommend that they do?

I

Dr. Clair Francomano: think that to get on those wait lists, the time is going to go by, [00:56:00] um, and, uh, look for, there, there are genetic specialists. Practitioners, uh, all over and we had, I guess they need to try to find one that's accepting patients. Unfortunately, we, we are in this situation where there are a number of genetic practices in, in academic medical institutions where they're not seeing patients with hypermobile Ehlers Danlos Syndrome anymore.

So this is really, this is really difficult. And, um, I think we're going to have to get away from the idea that it has to be a geneticist who makes this diagnosis. Because, uh, really those criteria are very straightforward, a primary care doctor who's knowledgeable about the criteria can easily make the diagnosis.

The most important thing is for them to be able to recognize those red flags and to [00:57:00] know to look for them. So, uh, if we can make those available and, um, you know, have, find. Primary care doctors, rheumatologists, uh, neurologists, physiatrists, um, they're even, you know, we had a really great discussion on the, uh, ECHO program a couple of weeks ago about physical therapists making the diagnosis and it can be done.

It's just, uh, we, the geneticists are a limited resource. There aren't enough of them. Um, and I don't think that should be a barrier to getting a diagnosis for hypermobile EDS. We should be able to have the diagnosis made by other, uh, specialists, other practitioners and, you know, move forward in the care of the symptoms, um, without having to wait three years to get a diagnosis.

Dr. Linda Bluestein: Yeah, [00:58:00] definitely. And if someone is being evaluated by a physical therapist, of course they're doing their own assessment of, you know, movement and they're used to doing an assessment and making an evaluation. I don't know exactly how it works in terms of their diagnosis, but is it? Is it processed from the standpoint of insurance and or, you know, being listed as one of their ICD 10 codes in the same way as if you or I make the diagnosis or do you know about that?

I don't really know. I don't 

Dr. Clair Francomano: know. But I think that a physical therapist could certainly Raise the question of possible Ehlers Danlos syndrome and send that person back to their primary care doctor and, um, and then the primary care doctor could establish the diagnosis and put it in the, in the diagnostic, uh, ICD 10.

Dr. Linda Bluestein: Yeah, it was, yeah, it was my physical therapist who first said to me, you know, you have very hypermobile joints and I honestly had no idea [00:59:00] what that meant even though looking back I realized that I had so many doctors that told me I had extremely, um, you know, excessive range of motion of multiple different parts of my body and, but they never said anything about what that might mean.

And I didn't actually really think about it until I started having a lot of problems, you know, and then you start to really, you know, try to get more information. So, um, I think that's an excellent thought that somebody could talk to their physical therapist and ask them to provide some kind of documentation that they can then take to their patient.

PCP and or the PCP if they're in the same system, they can look at the physical therapist note and see that the physical therapist commented that they had numerous hypermobile joints and had this concern. So, that's a good idea. Okay, I want to make sure to talk about direct to consumer testing before we wrap up because I feel like that's something that, is, is really challenging, you know, when people, they can't get in to see a geneticist, they may or may not [01:00:00] be able to get their primary care doctor to really, you know, listen to their concerns, validate their concerns, order the kind of tests that they feel like they need.

Um, so, so a lot of people are resorting to that kind of thing. What are your thoughts on direct to consumer testing? Are there times that it is appropriate? Is it? More harmful than good. What do you think? 

Dr. Clair Francomano: So, I'm not a big fan, I have to say, um, there, the direct to consumer testing does come in different flavors, though, so one thing, um, it's very important for people to know is that 23andMe, for example, is not going to give them any information that's relevant to making a diagnosis of EDS of any type.

So, the 23andMe technology is looking at something we call single nucleotide polymorphisms. It's not sequencing the DNA. It's just looking for the presence of variants that are [01:01:00] known to be more common in certain diagnoses than others. So, uh, I've had people who've come through who've been told that they have vascular Ehlers Danlos Syndrome based on 23andMe, uh, and this is just not, not accurate and not good.

So don't rely on those, on those Ancestry and 23andMe. They're great for looking into, um, you know, ethnicity and finding relatives and things like that. Uh, but not for making genetic diagnoses, but there is directed to consumer testing that's available through Invitae, for example, which is a very reputable company and they are doing sequencing and they require that you meet with a genetic counselor.

Uh, before you have the testing and that genetic counselor will explain the possible outcomes of the [01:02:00] genetic testing. So that is an entirely different thing. And I think much more, um, much more likely to come up with, uh, valid information. But also, you know, we come back to those variants of uncertain significance, which are inevitable whenever we look at DNA sequencing.

And so just important for people to know that that's a possible outcome and to be prepared to deal with that uncertainty. 

Dr. Linda Bluestein: Mm hmm. Okay. And if somebody does want to obtain testing themselves through a company like Invitae, and you may not know this, but is it possible to get their insurance to cover that?

Or because they're doing it kind of on their own, they're, they're probably going to be self pay. 

Dr. Clair Francomano: Yeah. I think, I think if you're, if, if the test has not been ordered by a physician, it's unlikely that an insurance company is going to pay [01:03:00] for it. I really don't know, since Invitae has been acquired by LabCorp, what the implications of that for that self referral are either.

I don't know if there's been a change in that or not. 

Dr. Linda Bluestein: Mm hmm. Okay. And another company that I've heard of is, it's either sequence. com or sequencing. com, something like that. Do you know if that falls more on the 23andMe side or more like a medical, are you familiar with them at all? I've, 

Dr. Clair Francomano: I've seen them advertised, but I don't really know, uh, I don't know whether they're working with genetic counselors or, um, I, I really don't, I don't know very much, 

Dr. Linda Bluestein: anything about it really.

Sure. I, I heard someone describe this the other day and I think, I think it's, uh, very, um, accurate, uh, in a way of that in some ways this is kind of like the gold rush that, you know, you see a lot of these companies, they put, you know, Ehlers Danlos on their [01:04:00] website. They're trying to attract, uh, you know, this population of people who's concerned about it.

And, Thinks that they might have it and Mm-Hmm. it has become, in, in some ways kind of the, you know, the, the much more popular thing to put on your website or discuss and, and of course it's, it's great in, in most every way, but we also wanna make sure that people are not being taken advantage of by charlatan's.

So that's word. Absolutely. 

Dr. Clair Francomano: Absolutely. Yeah. And there's one of those companies that may be that sequencing.com that's advertising the sequencing for the Crin genes. Which, um, both, uh, the MUSC folks and the Ehlers Danlos Society We have put out a joint statement saying that it's premature to be testing for those.

So um, I think we have to be aware of that and it speaks 100 percent to what you're saying is we just don't want people to be taken advantage of. [01:05:00] 

Dr. Linda Bluestein: Yeah, it's definitely a vulnerable population and, uh, well, we want people to get information and obviously we want them to get better care, but we also want to be careful of where people are looking because, yeah, it's amazing.

I'm sure you see the same thing. Some of the things that people have tried or some of the places that they've gone. So, yes, often spending a lot of money and, uh, you know, yeah, so, correct, correct. Yes. Uh, are there Yes. Are there red flags that you would want to share with people that, you know, uh, if you see these things that might be assigned to run, like I always say the word cure, if you see the word cure, you know, we can cure Ehlers Danlos, like that's, we don't, we can't do that yet.

Dr. Clair Francomano: Right. And certainly if they're advertising to diagnose hypermobile Ehlers Danlos syndrome that, you know, at this point in time, nobody can do that, uh, with molecular [01:06:00] testing. So, I would say that would be a big red flag. 

Dr. Linda Bluestein: All right. Um, I like to finish every episode with a hypermobility hack, um, a quick win for listeners.

Um, do you have one that you can share with us? 

Dr. Clair Francomano: You know, I've, I've done so much work with the Ehlers Danlos Society, Linda, and I really think that their website is the biggest hypermobility hack out there because there is so much information There, uh, that people can find in terms of making a diagnosis of, of, uh, of Ehlers Danlos Syndrome, all the diagnostic criteria on there, everything from the 2017 publications, uh, all the information about the centers and networks of excellence and the healthcare professions, uh, professionals, uh, directory.

So, I would just really encourage people to seek out that Ehlers Danlos Society website for a lot of really good information. [01:07:00] 

Dr. Linda Bluestein: Yes, the work that the society has done has been just incredible in this space. The advances and everything that they're responsible for is really amazing and the website is ehlers danlos.

com, correct? Yes. Yeah, there's lots and lots of resources there, so definitely check it out. So Well, thank you so much for joining me today. I really have just had such a great time chatting with you. I've really enjoyed it. Thank you, Linda. Before we go, I just have one other quick question. I would love to know if you have any special projects that you're involved in or research that you're doing and then also where we can find more about you.

Dr. Clair Francomano: Well, I mean, there are a number of projects that I'm working on at this time. Um, the HEDGE study is ongoing and that's a, that's a really big one that I've been working on for several years. Uh, with, uh, Dr. Woody Gandy and the Ehlers Danlos Society, [01:08:00] and, um, the analysis right now is under the direction of Joel Hirshhorn and Christina Likaitis.

Um, I'm working with Dr. Alan Hakim on the clinical criteria study. And, um, we have a study that's looking at, uh, the role of sex hormones in the phenotype of, uh, of hypermobile Ehlers Danlos syndrome. And, um, we have a study that we just launched this year looking at the natural history. of hypermobile Ehlers Danlos Syndrome and HSD.

So, there's lots and lots going on. Um, my website, uh, I think I sent you the URL from Indiana University. And I also, I have a YouTube channel that I just really have started up and running with some videos talking about just 10 minute videos talking about the various [01:09:00] comorbidities and Resources that are available to people and, um, we've been pulling some Instagram reels from those YouTube videos.

So there's an Instagram, uh, site as well, um, which is Dr. Clair Francomano.

Dr. Linda Bluestein: Okay, fantastic. And we will have those links in the show notes so people can definitely access those sites as well. So, all right, well, thank you so much again. I've been wanting to do this as I said already for such a long time and we finally did it. 

Dr. Clair Francomano: It's a great, great, great pleasure and thank you so much.

Dr. Linda Bluestein: Well, that was such a fascinating conversation with Dr. Clair Francomano, who is chair of the Medical and Scientific Board of the Ehlers Danlos Society. So, she really has the insight into [01:10:00] everything that's going on in this space. It's really great to get this, just, this insight. Incredibly current and up to date scientific information from her.

And I want to just thank you for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. You can really help us spread the word about joint hypermobility and related disorders by leaving a review and sharing the podcast. This helps raise awareness about these complex and misunderstood conditions.

You can find me, Dr. Linda Blustein on Instagram, Facebook, Twitter, or LinkedIn at HypermobilityMD. You can find Human Content, my producing team, at Human Content Pods on TikTok and Instagram. You can also find full video episodes up every week on YouTube at Bendy Bodies Podcast. If you would like to dig deeper, you can meet with me one on one by visiting the services page of my website at hypermobilitymd.

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