Hi. Welcome, everyone, to the ACMG Genomics Case Conference. This series has been planned by the ACMG Education Committee. Each month, the conference will rotate among laboratories that perform genome-scale testing and the clinicians involved in the cases. Use of all case materials that will be presented have been formally consented for use with the patient or the guardians. This session involves the professional practice and guidelines committee and is on Ehlers-Danlos Syndrome hypermobile type in children, differential diagnosis, and recommendations for management. Before we get started, I do want to mention that this activity is supported by an unrestricted educational grant from QIAGEN Bioinformatics and the Ingenuity Clinical Decision Support Platform. This session is intended for educational purposes only. If you read through this language, basically the idea is that this session should not take the place of your individual medical judgment in specific clinical scenarios. My name is Scott Hickey. I'm Assistant Professor of Clinical Pediatrics at The Ohio State University College of Medicine. Nationwide Children's Hospital is the academic tertiary care facility associated with Ohio State. And I'm joined today with Dr. Brad Kinkle, who is the Division Head of Clinical Genetics at Advocate Children's Hospital in Park Ridge, Illinois. These are our disclosures. And here are the disclosures of the planning committee. And the... for ACMG. The ACMG is accredited by the ACCME to provide continuing medical education for physicians. And this activity is designated for a maximum of one Category 1 credit. For CME, you should only claim your credit commensurate with the extent of your participation in this activity. These are just some details about obtaining credits if you need it for participation. These are the overall learning objectives for the series related to genomics and genomics testing and counseling and consent for genomics testing. For today's session, it'll be a little bit different with a clinical focus related to the issues surrounding hypermobile Ehlers-Danlos syndrome. These are some of the objectives for today's session. Clinically evaluating a joint hypermobility to determine if it is a pathologic condition or a pathologic feature versus a physiologic feature, meaning whether it's indicative of an underlying genetic diagnosis or perhaps just a variable within that individual or family. Looking at... The second piece is looking at the nosology, which is comparing the Villafranch criteria for hypermobile EDS to the Brighton criteria for benign joint hypermobility syndrome, comparing those and their clinical use and addressing some of their limitations. The next objective would be recognizing clinical scenarios that suggest an alternative diagnosis because, in many cases, this can be a diagnosis of exclusion, although there are inclusion criteria, too, that I mentioned Villafranch and Brighton. And the last one is recognizing the association between joint hypermobility and multiarticular joint pain, which is often very difficult to treat. And specifically for the ACMG audience, just a few brief things about what we think a geneticist should know for patients who have management questions with these conditions. This is intended to be somewhat of an interactive session, so you can ask Dr. Tinkle or myself a question by typing it into the Q&A box in the lower left corner of your control panel. We have sort of three breaks built into the session to stop and look at those questions and hopefully answer a few of them before we move on to the next case. This session is... This is a case conference series. This session is organized into three cases meant to illustrate difficulties or areas of confusion or uncertainty surrounding a diagnosis for Case 1 a differential diagnosis for Case 2 and, in the case of Case 3, management issues. Okay, let's go ahead and look at Case 1. I think for those of you who are clinicians, this will be a relatively common scenario. This will be a relatively common scenario that you encounter, an adolescent female that comes in, and the concern of the family or the way that they respond when you ask them, why are you here today, is they want to know if the patient has, quote-unquote, EDS. This young woman has... These patients will often present to geneticists but can also present to other subspecialists. Rheumatologists are probably the other most common subspecialists who see these patients. This young woman complains of pain in many different joints and not related to any trauma or specific inciting event. She describes a sensation, especially around her hips, like they pop out of place, and when you inquire further, comments that she's always been double-jointed. She did have an injury several years back that required orthopedic surgery in her knee, just related to a twisting motion in her house while she was on the stairs. It seemed like an unusual situation to have a severe injury, not an athletic event or any trauma. They tell you that she has occasional nosebleeds that she's been looked at by ENT. There's really nothing there to cauterize, and she's been evaluated by hematology and doesn't have any sort of bleeding disorder. She also describes heavy periods. They initially thought perhaps to be related to anovulatory cycles, but they've persisted even as she's gotten older, not really following the common natural history of that type of scenario. She has a normal growth and development, and in the examination room, as she mentions her double-jointedness, she proceeds to show you a couple of tricks with her digits and moving her shoulders around, and we'll go over kind of her exam in a couple of slides. I mention here that there are no red flags and we'll also kind of go over red flags in a scenario that might make you think of an alternative diagnosis. But first, in order to kind of start working through this, we want to address some terminology and definitions around which there can be a lot of confusion and misinformation, not just in terms of what's going on, but confusion and misinformation, not just among patients and patient families, but other providers as well who don't run into this quite as often. So the initial question was, does the patient have, you know, quote, unquote, EDS? And as all of the geneticists here know, there are a number of different subtypes of EDS, and in this area, you know, as with everything in genetics, continues to grow as genomics technology expands and we understand the underlying causes of lots of new molecular genetic Mendelian disorders. In fact, of these different subtypes of EDS, there are many different groups, including sort of what we think of from the past. We think of collagen, primarily structure and collagen processing abnormalities. But on the right of the slide, you can see defects and a lot of things that directly interact with collagen and even some things that don't, disorders that are autosomal dominant, disorders that are autosomal recessive. But typically, when a family comes in and makes the comment about whether or not their child has EDS, at least in my experience, 9 times out of 10, they're referring to hypermobile EDS. I do want to mention on this slide that the Villafranch criteria, the way these different subtypes were referred in Villafranch is in the left column, and the column just to the right of that is reflecting newer nomenclature. In the context of a child or adolescent who has joint hypermobility, there are a lot of different red flags that can come up that might make you think that it is not hypermobile EDS or a benign joint hypermobility syndrome situation. And I've listed some of those on this slide. It's not to say that the diagnosis of hypermobile EDS could not co-occur with one of these other morbidities, but just to say that when you see them, you should have an increased index of suspicion for diving a little bit deeper and considering what other investigations you would want to do to exclude an alternative genetic cause. A lot of these are neurologic differences, such as intellectual disability. Any neurologic sign or symptoms, such as seizures, regressive symptoms, would not be something that you would expect to see in a patient with hypermobile EDS. Again, congenital anomalies would be uncommon. If you have a short stature, you might think of a skeletal dysplasia. Conversely, if you had a very, very tall stature with sort of a dolichostenomelic appearance, you might think of a Marfan syndrome or Marfan-related disorders. The family history is an important component to the evaluation. Obviously, other heritable disorders of connective tissue are in the differential diagnosis, some of which involve vascular and cardiovascular sequelae. So other family members, especially first-degree family members who have aneurysm or dissection at a young age, should get your attention as well to consider an alternative diagnosis. Someone asked about what the BITEN score on Case 1 is, and it's going to be on an upcoming slide. So here are the current nosologic criteria for hypermobile EDS versus benign joint hypermobility syndrome. So in terms of the historical perspective, these are basically two different approaches that were developed in parallel, one by a rheumatologist and one by a geneticist, to try to give a little bit more rigor and systematize this evaluation. It is only in more recent years that it has become more generally accepted that these two conditions that were being described really represent sort of two sides of the same underlying entity. For the BRITEN criteria, which is on the top, the benign joint hypermobility syndrome, the major criteria, the BITEN score, what's considered to be an elevated BITEN score is anything greater than or equal to 4, and the major criteria also involve pain or symptoms, which the Villefranche criteria does not include in its major criteria. You can see with the minor criteria are things like arthralgia in fewer joints, joint dislocations, other different dysmorphic features that you see kind of with these types of patients. For hypermobile EDS, the major criteria, the BITEN score is different, which can be a cause of confusion, greater than or equal to 5, and then skin findings are part of the major criteria, whereas pain and dislocations are moved to the minor criteria, and then, like any good geneticist, family history was incorporated into the diagnosis because that, as we know, can often be a helpful clue. In terms of the BITEN scale, it is a 9-point clinical screening scale that can be done quickly in the clinic. A key point is it is done on a passive range of motion. Four of the points involve a bilateral test, and then the one that does not, which only counts for one point, is forward flexion of the trunk with your knees fully extended, and for this to count, you need to have your palms and hands resting flatly on the floor. It does not count to just sort of have your fingers dangling and barely touching the floor. For the fifth finger, it is helpful to have them rest their hand on a flat surface and gently bend the pinky digits backward. For the thumb, you want to have them rest their hand on a flat surface and you want to have them sort of extend their arm forward and then bring their thumb back to apposition against the ipsilateral aspect of the forearm. And for this, sort of the entire surface of the thumb should be resting against the forearm. So if you just get sort of the tip or distal interphalangeal, the distal phalanx of the thumb touching and there's sort of a lot of space that you can see there in between, that is not a positive test. This test was really proposed initially and then retrospectively validated later, but it has subsequently been shown to predict hypermobility in other joints that aren't tested. So let's cut back to our case. Getting back to things and talking to her a little bit more, she remembers non-traumatic elbow dislocations in both elbows on different occasions. She has tried to treat her pain with several different providers unsuccessfully, and on family history, the mother mentions that she has fibromyalgia, that she's been diagnosed with fibromyalgia. On a skin exam, her skin is soft and velvety and mildly hyperextensible. Her BITEN score was a 6 out of 9 and she has flat feet with a little bit of hind foot deformity. In terms of evaluating what is hypermobile and what is not, the BITEN scale is a clinical screening tool. Obviously, it doesn't test shoulders, hips, and ankles. These are additional things that you can test on your exam if you're suspicious. And joint mobility, which has been looked at more extensively in the general population over the past decade, has been more completely understood to be a multifactorial trait with differences between girls and boys, differences between individuals depending on their physical conditioning, whether they're involved in sports that involve a lot of stretching and contortion, and it changes. And the natural history of it is understood a little bit more as change as people get older. One area of confusion that occasionally comes up with other providers is the presence of joint hypermobility does not equal hypermobile EDS. So, as we saw with the previous criteria, there are other features that you want to see in a patient and you need a more thorough evaluation to exclude other things before you would provide this diagnosis. So, in terms of our patients, what is the evidence that the joint hypermobility is pathologic? If you have a non-traumatic joint dislocation, that is some evidence. If you have multiarticular joint pain without another explanation, that is evidence that the joint mobility is pathologic. And then the fact that the BITIN scale is above the cutoff for both of these clinical criteria. So, looking at this patient, in terms of the Villafrench criteria, she would meet all major and minor criteria. In terms of the Brighton criteria, she would meet one major, which was her BITIN score, and three minor criteria, the skin, joint dislocations. The joint pain only meets the minor criteria because it only involved three joints. So, it can be somewhat strict in that sense because it's greater than three months and greater than four joints. In terms of the current nosology, this is one of the things that presents a challenge to clinicians. These nosology came out in 1998, I believe, and 2000, respectively. So, it has been well over a decade since there's been any revision. In terms of criteria for the diagnosis of hypermobile EDS, one of the major findings are skin findings, and those have subsequently been shown to be imprecise and quite subjective between different examiners. In terms of the Brighton criteria, with the BITIN scale being greater than or equal to four, many different studies looking at BITIN scores in healthy children and healthy adolescents have found a really high percentage of those individuals who would meet that mark. And so, it's a nonspecific finding, and a child who has pain could have an elevated BITIN score incidentally just because it's a fairly common finding within the general population. It is also quite confusing to have two separate nosologies for what is now generally accepted to be manifestations of the same clinical entity, and an individual could meet criteria for diagnosis with one but not the other, and it really lends itself to a need for bringing these two approaches together into a unified approach. I think this is a nice figure here that shows that joint hypermobility is multifactorial and can exist along a spectrum, and so certainly if you went out to the mall, if you went out into any public space and started BITIN-ing individuals, you would find some people who have hypermobility and are asymptomatic. There are then those who would come in and see you in a clinic, so the asymptomatic individuals might be represented by the green area. We have a selection bias in the clinic probably for those down in the red area who have a more complex systemic disorder, but then there may be many other patients who exist in the middle who are predisposed to injury, predisposed to dislocations, who might not meet checking off all of the boxes of the nosology as they currently exist. I think at this point, I would like to put up question one, if we could, and while we're doing that, I thought I would pass things over to Dr. Tinkle for a second. I think the audience would be interested to hear how you use the two different criterias in your practice and how your diagnostic evaluation has evolved over the years and where you think the nosology is headed. Well, hello, everyone. So it took several years for me to realize that the joint abnormality syndrome and the hypermobile EDS, what we called it, was probably the same disorder, not necessarily in the spectrum, but just through evolution of the disorder. I would have plenty of parents who would fit the criteria for joint hypermobility syndrome, may be diagnosed with joint hypermobility syndrome, but their kids would be very flexible, may have joint dislocations, may have some periodic pain or even starting to have recurring pain, and they would best fit the hypermobile EDS definition. When I looked in the joint hypermobility syndrome criteria, the Brighton criteria, it did come from adult rheumatologists. It had much more of a historic perspective to it, and so it made sense that these were adults of the kids that we were typically seeing. There's been subsequent studies, some small series, some of which are unpublished and some that are published now that basically said it's really hard to distinguish between the two in multigenerational families. So we consider them essentially the same disorder, different perspectives from adult rheumatology and sort of pediatric genetics. So I make little distinction. I may apply the joint hypermobility syndrome criteria to adults given that we all step up somewhat to time. I may have given the answer to one of the questions, and so it's one of those things where they have reduced the Brighton scoring a little bit less for adults, but unfortunately we know that there's plenty of errors in the Brighton scoring based on injury and surgery, ethnic background, gender, and et cetera. The new criteria, we'll make some adjustments for that. The difficulty, like any good clinician scientist, is that we don't have enough information of where to put the actual thresholds, and so while we know it's not good and we could probably make some better guesses at where things are, we do need to fill in a lot of studies looking at males versus females, different ages, different compensations, different weighted scoring. Either other stuff we're looking for are things that we can take out. If somebody's had knee surgery, how do we adjust the scoring system for that? A lot more questions than answers, which is unfortunate. The new criteria will outlay a lot of what we just talked about, and it's coming out in American Journal of Medical Genetics in March. Scott, back to you. The question mentions joint mobility sort of in the general population, and in females in puberty, there actually can be a little peak where it increases, whereas in males it decreases. So it's not listed as C, but what would be in the C position was what I was going for. And from my experience, there's been a fair amount of hand-waving about why that might be true in females, perhaps hormonal effects. I don't know, Dr. Tinkle, if you have any comments about that. We do know hormones definitely affect collagen production and maturation through in vitro studies. Epidemiologic studies haven't done a good job of looking at either joint mobility or injury risk assumed to be joint mobility related. There's some evidence of the knee in females from jumping sports that there might be a menstrual timing for that. And anecdotally, most of us will say our patients get worse right before menstruation, which is right after a progesterone peak. So whether or not it's that responsive or not, we do feel like there's a hormonal influence, but more information is needed of which hormone and what to do about it. I have another good question here. Is there evidence that the connective tissue of people with hypermobility without pain are different from the connective tissue of people with hypermobility who do have pain? Not much that I'm aware of. When others have actually taken the connective tissue and looked at it on a more like electron microscope type, they can see disordered collagen that seems to happen a little bit more often in controls with regard to the people who have joint hypermobility, but it's nothing that we can track for the people related to one group has pain and one doesn't, and that's an interesting question itself, what makes one group have more difficulty than another. I'm going to address one more question and then move on to the next case. This is jumping around a little bit, but it's a good question. New info regarding triptase duplications and triplications, so involving copy number variance, involving this substance that's secreted by mast cells and the finding that some individuals with that have connective tissue type features, I've only sent that out clinically a few times in recent months and haven't had a lot of experience yet with it. I've only done it in patients who had those types of symptoms, flushing and the other types of things that you get with mast cell disorders, but Brad, I don't know if you want to say anything. Since about 2014, there's been a question of mast cell in this population. It does seem to be a subset, sometimes really poorly defined. It doesn't seem to affect all members and families, and like anything else, it might be something that starts out with a few, quote, chemical sensitivities, who then, as years go on, have much more full-blown type of histamine mast cell type symptoms, so it's been somewhat difficult to track. They do feel like it intersects with connective tissue phenotype. The question is whether it defines a subset or is it just something that makes people present a little bit more. The concern is that this represents much more of a, just like the pain question, much more multifactorial, and so when you have intersection of other disorders that could be fairly benign, all of a sudden you have people seeking help for it. We're all experienced of knowing people, personally and professionally, who flush with stress or anxiety or scratch themselves, and you see it with patients all the time outside of connective tissue where they get nervous, they kind of scratch their neck because they're feeling the histamine release and they need all these red scratches. That's the same type of histamine response that we can see in patients with connective tissue phenotype, but we're also seeing the same thing in Marthian and Loewy-Steeds, so it's unclear what role, but it's an interesting thing, and hopefully that also leads us to better management of some of their symptoms. And another challenge is, as with all these things, basal serum atryptase is elevated in a certain small percentage of the general population. Right. Okay, I'm going to move on to Case 2. So Case 1 was regarding a diagnosis. Case 2 with attention on a differential diagnosis, this is a female who had some delayed onset of gross motor skills, such as walking, who wore AFOs when she was younger. I did not see her until she was much older, and then she began to have pain around age 8, which would not be uncommon for a hypermobile EDS situation, maybe a little bit younger than most, but not out of the realm of possibility, and her pain was in her knees, her ankles, and her feet, and she especially commented on it on school days when she had a gym class. Her mother made the comment that she had become more pigeon-toed over the past year and that she had some difficulty opening jars and using buttons and zippers. Another red flag was the comment that she needed some help to hold the railing when she went up and down stairs. Due to her foot pain, she saw a podiatrist who started them on a track for EDS, and then I saw orthopedics who also mentioned EDS. On her physical examination, there was a valgus positioning of the knees. Her gait was clearly not normal, and I'll show you a video in just a second after I get through this slide. It was somewhat unsteady. She could not hop on a one foot. Some neurologists who were also involved commented on a few subtle, perhaps sensory changes. I thought her pedal arches were high, but they did flatten some with standing, and as part of the session, obviously when we bidened her out, she was a six, and so it was elevated. She as part of her evaluation was seen by a neurologist a couple times. She had MRIs of both her brain and lumbar spine that were negative. A SNP array was done mostly...she was cognitively normal and at an appropriate grade for school and grade level work, and was done really to look for a PMP22 duplication or a CMT1A, which she did not have. She subsequently went on to have EMG and nerve conduction studies that were negative, and due to somewhat concern for a progressive course and an abnormal neurologic exam centered back to the neurologist, but they centered back to us, still with a concern that this might be a hypermobile EDS. And then I... So this video is about 40 seconds, and hopefully everyone can see it. Can you turn around and come back? And are you able to...are you able to walk up on your toes? Why don't you turn around and walk up on your toes for me? Okay, turn and walk back toward me on your toes, up on your toes like that. Is that hard? Very much so. I feel very balanced. Now can you sit down on the floor for me? And just go ahead and get back up, but don't push against the wall. You can see that when she went up on her toes, she had a lot more difficulty standing. She had the in-toeing gait with femoral anteversion, and that was new. That was not something that she had done before, and this was concerning to us. And as part of her evaluation, we sent a Type 6-related collagenopathy panel, which showed a frameshift mutation in COL12A1. Unfortunately, we weren't able to determine if it was a de novo because the father was not available. And, you know, this is sort of perhaps in a Bessel myopathy group of disorders. Some authors sort of refer to it as a myopathic EDS form, but I think the take-home message is that there were some red flags noted listed there in red. And, you know, the take-home message from the standpoint of joint hypermobility would be that just because she did have joint hypermobility and she did have pain, but, again, that does not necessarily represent hypermobility, but, again, that does not necessarily represent hypermobile EDS. And in the presence of other red flags, continued investigation is warranted. I did include it on this slide. There are obviously many more different subtypes of EDS. I just sort of tried to hit highlights of ones that would cover the different mechanisms. And so this is in the green row here. You see that this is known to have an overlap with EDS related to defects in the structure and function of the myomatrix. So, again, red flags where you would not want to necessarily settle on the diagnosis of hypermobile EDS. And this case is meant to sort of illustrate neurologic features. You know, pictured here is a nice atrophic scar that you might see in a classical EDS and someone with a blue sclera who could have more of an osteogenesis imperfecta variant. I think that we've all seen patients who were diagnosed or labeled as having hypermobile EDS who turned out to have a separate distinct identifiable cause for their joint hypermobility. Dr. Tinkle, are there conditions that, in your opinion, are common culprits at mimicking hypermobile EDS? The most common is you have to remember in the general population 15-ish percent will meet criteria on BITIN, so technically have generalized joint hypermobility. Many of those, most of those, are going to be benign. They're not necessarily benign joint hypermobility syndrome, they're just benign. They don't have an issue with it. We definitely rule out rheumatologic conditions, you know, asking simple questions about joint pain, warmth, swelling, those kinds of things. Your hypermobile EDS may have some minimal swelling, but they're not going to have that warmth. They're not going to have that recurrent swelling, et cetera. You know, other connective tissue disorders, that's probably the most common mimicker. People with vascular EDS or other types of low EDS, et cetera, a lot of times can get labeled hypermobile and then we do the testing, et cetera. Somewhat the good news is a recent study in England at their EDS center where they had the money to actually do the testing for most of the stuff. There was only one hypermobile form that came in labeled as such that turned out to be something different and there were some additional red flags with that case. Most of the others were sort of mislabeled based on other things that the clinician was picking up on and just misattributing to one diagnostic label or another and was able to sort of sort that out through testing. So for most of the EDS forms, we do recommend that the criteria be used to actually test and confirm. Classic EDS, you could probably make a clinical diagnosis. Hypermobile, until we know more, is still going to be the diagnosis of exclusion. So anytime I have a red flag, I'm sending to the appropriate people to help with the information. And a person like you just saw in the video, that's where I'm going to work with my physical therapist. I'm going to get some idea that this is not a typical gait pattern. It does seem to be progressive. And I'm going to use my physical therapist to take a look at this and really sort of tell me about the weakness or whatever. And if that's atypical, then we're going to be asking neurology or somebody else to be involved. I'm sorry, I forgot. Can we get question 2 put up for the break? There was a question about TNX-B, how it fits in. Okay. Is TNX-B related EDS a subtype of hypermobility type EDS? So the TNX literature suggests either homozygous or compound being more classic-like, having more skin hypersensibility but without the atrophic scarring. Maybe a condition we would have called mild classic EDS in a couple of criteria ago. When they looked at heterozygotes, they saw phenotypic expression more in females than they did males. And so it was of interest to sort of say that kind of parallels what we see in hypermobility EDS. They also looked at those that have congenital adrenal hyperplasia. They're in the same locus. They looked at the pseudogenes of TNX and the gene for congenital adrenal hyperplasia and found a higher incidence among those. So we know that TNX works in a cellular matrix. It can be something that is connecting some of these macromolecules. The numbers to suggest that this would be responsible for a significant portion of what we call hypermobile doesn't really exist. It would suggest as high as maybe 7% or lower would be TNX. One of the difficulties is because of the pseudogenes, sometimes it's hard to get reliable sequencing information out from those individuals to make sure that you're looking at real mutations and not there are a few strategies that help but that they're somewhat difficult. The TNX protein assay, which is long-run research but is used to characterize this group in England and elsewhere, is probably the most helpful but I personally have not found it professionally. I would probably use it more often if it were available. In terms of the survey question, which was an individual who pushed his thumb and sort of put his elbow over a rail to kind of get a higher BIDEN score, nearly everyone got the point, which is that he's not attesting passive range of motion. And I think, at least in my experience of patients that are referred to me, that's one of the most common things that I see other specialists where they get kind of a falsely elevated BIDEN. Brad, would you agree with that? Yes, and the newer guidelines coming out in March is going to unify the BIDEN score. We're going to tell you very specifically how we want it done. And it's mostly because of things like that. People view them very differently, sitting, standing, different arm positions. So we just want to start saying, this is how we want it done uniformly across so that we are comparing apples to apples. We're getting a little tight on time. The last, so we've looked at, I see there are a few more questions. We've done diagnosis and differential diagnosis. And I think the last case is related to management where you have a patient come in who really hurts everywhere, has been diagnosed somewhere else, appropriately using appropriate criteria, and has really affected school, really affected her interests, is on sort of a laundry list of both things that medical practitioners have prescribed, including some things that she's sort of tried herself and has been pretty dissatisfied with all of the doctors that she's previously seen. And I think that, you know, in terms of management, I think there is some limitation in terms of evidence bases for effective things. And then in different areas of the country, different healthcare systems, the involvement of the geneticist can be quite different. But in terms of some of the basic things that I think that, you know, geneticists are obviously more, you know, our bailiwick is a diagnosis, differential diagnosis, testing, and certainly you'll be going over that with this patient that you would see. But you want to at least have some basic ideas of sort of the important crux of management. And so for this patient, obviously, you know, functionality is a big issue. You want to get someone to a better place than where they are, but they need to be counseled and their expectations need to be managed. It's obviously a really vicious cycle when you have someone who hurts too much to move and really what they need to do is sort of get moving again and how do you rehabilitate them. In terms of interventions for pain, you know, the highest level evidence studies out there really point toward psychological interventions, which is not to say that this is all in their head or that they're making it up. It's just in terms of what we have available to us, suggesting what works. That's one of the areas where there's the highest level of evidence. We also try to supplement that with physical therapy and with some pharmacologic interventions, but it is not something where you can just prescribe a medication and it won't always help for everyone. In fact, in a lot of cases, the patients really tell you that it's not helpful. One of the big problems a lot of these patients have is sort of a disjointed medical team and that they have trouble finding a provider who will sort of put everything together for them and be their medical home. They won't have that consistency of care, and this is an important issue for these patients. It doesn't necessarily need to be a genetics doctor. It can be a rheumatologist, and it's challenging in pediatrics. A lot of places may not have a pain management specialist, a tertiary care center available for them, and then as far as pain management in an adult, they may not be familiar with EDS or the EDS issues. I think I just want to... I'll just really briefly say common concerns that get brought to me include cardiovascular issues due to autonomic dysfunction. A lot of patients report tachycardia, atypical chest pain. Usually when people come in, they've sort of found things on the Internet about aortic complications, and so you can reassure them that in the case where your diagnosis is correct, the risk to that seems to be very, very, very low. You may do an echo and see some aortic root dilation, but it's thought to be nonprogressive and not really necessarily indicate any underlying vessel wall sickness. As far as dysautonomia, POTS, Neurally Mediated Hypotension, are common features and can be confirmed by a tilt table test, but that may not be needed. You may be able to just manage that symptomatically, and the autonomic dysfunction may affect other organ systems such as the GI, neurologic, et cetera. Then I just wanted to... A lot of other providers sort of want clearance for surgical interventions, concerned about increased postoperative complications. There's not a lot of good large studies on that. They're mostly retrospective survey studies, and, you know, there could be some suggestion that there's sort of a higher-than-general population risk for some complications, but it doesn't seem like the absolute risk is actually that high, and so if surgery is indicated, generally they should get surgery regardless of this underlying diagnosis. Can we go ahead and get question three up, please? Okay. Let me see where we are here. So while you're working on that question... Dr. Tinkle, what are your thoughts about sort of the role of the geneticist in terms of our ongoing understanding of these disorders and the management of these disorders? The ongoing part is I think geneticists tend to be more... and a lot more scientific-minded as far as this. We're looking for a gene. We're looking for uniformity and stuff. Not to say that we can't be clinicians. So one of the difficulties is try to describe this population very similar to Marfan in a more rigid way so that we can do gene hunting and whatever else so we can find are there subtypes of hypermobile. Maybe it's a mast cell subtype. Maybe it's a tenacin X subtype or whatever else. Find out what the differences are and hopefully then study them going forward, looking at natural history and intervention trials and stuff. The geneticist role kind of depends. I'm kind of stuck in this because I was raised essentially through residency by somebody else who attracted EDS patients, and so they've accumulated around me. I provide that clinical service. Just like in other places, you may not have the facility, the support behind it. I've built more of an EDS-type clinic with physical therapy, wholly integrated. So that makes me a lot more comfortable when I assess these patients, not only for the initial diagnostic assessment but for the therapeutic interventions as well. It is best to try to do this as a team approach. Whether the geneticist is that central hub or somebody else, I think it depends on the players and it depends on other people. Many are best for their primary care provider, but a lot of times we do have to help educate the primary care provider with that information. So it can be a very complex disorder involving multiple specialties, very similar to any other chronic medical condition, and it takes a unique physician sometimes to be that central hub, but truly these patients need a medical home. We're running out of time. I'm going to try to get in. Unless somebody tells me otherwise, I'm going to try to get in. Two quick questions. One is, what is the youngest age at which a clinical diagnosis of hypermobile EDS may be affirmed with reasonable confidence? So I typically don't like to evaluate to about four or six, and that's because the BIDEN scoring is difficult to differentiate amongst age peers about that age. I'll feel better if I have a known family history and this is the youngest sibling coming up through the ranks kind of thing because then that tells me I have an a priori risk and I'm going to feel better. Anything below that I think is hugely dangerous. This trend by some individuals of diagnosing hypermobile EDS in infants that have multiple fractures is dangerous for the child and in my opinion should not be done. Do you recommend an echo for each hypermobile EDS patient? It's a question I get asked a lot, and what I recommend and what I do is a little bit different. I feel more comfortable evaluating different forms of connective tissue disorder and knowing when things are sort of yellow flagged and I need to look for a few other things here. If you're not as comfortable differentiating among the connective tissue disorder, obviously you can go to a panel genetic testing and try to determine it that way, or you can do an echo and kind of reassure the family. Right now I don't see anything that's consistent with Marvian or Loewy's Dietz or whatever else, but obviously if you're talking about VASCR or Loewy's Dietz Syndrome, it may not be the thoracic aorta that you're worried about, it's other things. So I think it can lead you to a false sense of security, but when you have families who come in and they've heard about the aorta and et cetera, sometimes that's a way to sort of do this. It's a little bit of anxiety lowering. There are other places. Australia puts an algorithm up that they want everybody screened by echoes first. So it's not necessarily a bad idea. I don't think you should be chastised for doing it. I feel comfortable not doing it. In terms of the last question, this is another patient who had been previously diagnosed with hypermobile EDS but had some other red flag features, short stature, renal cysts, dysmorphic facies, speech articulation disorder, and the real clue was that the child had MODY and then when they had a specific gene testing done, the full gene was deleted, which hinted at that actually it was a larger deletion encompassing not just that gene but additional genes around it and so to get a microarray. So, again, there's a wide spectrum of things that I think that can be in the differential diagnosis for this condition under different circumstances. So just to recap, these were the objectives for the session around diagnosis, so distinguishing joint hypermobility, pathologic from physiologic, looking at the two nosologies for criteria and sort of where we are today and where we're going, talking a little bit about the differential diagnosis and red flags, and then a few basics about the management and how to help these patients and families get on the right track. Here are some references for the session, and I think that's all the time for questions that we have today, but I thank you for joining. A recording of this seminar will be available in the ACMG Genetics Academy, and you see the link there, and the next session will be on February 15th, hosted by the Greenwood Genetics Center. Thank you for joining us. If we're still live, anybody that has a question, is welcome to email me with a question, and I'm happy to answer that for you. Thank you.

ACMG Genomics Case Conference

genome-scale testing

Ehlers-Danlos Syndrome hypermobile type

differential diagnosis

recommendations for management

QIAGEN Bioinformatics

The Ohio State University College of Medicine

Advocate Children's Hospital

geneticists

case studies