Chapters Transcript Video Ehlers-Danlos Syndromes and Hypermobile Spectrum Disorders Clair Francomano, M.D., presents at the Johns Hopkins POTS Grand Rounds on July 15, 2021. Okay, so I'm going to give a quick overview of the Ehlers Danlos syndromes and hypermobility spectrum disorders. Um the Ehlers Danlos syndromes are a spectrum of minor genetic disorders with a very wide range of fanatic pick severity and predominantly affecting the joints, skin and the blood vessels and internal organs to varying degrees. So, um most forms of the Ehlers Danlos syndromes are caused by defects in one of the liberal college ins or of the enzymes involved in fibrillation collagen processing. Um but there are a number of other rarer types of Ehlers Danlos syndrome that have been recently found to be caused by defects in the bio synthesis of other molecules in the extra cellular matrix and molecules involved in intracellular trafficking, secretion and assembly of the extra cellular matrix molecules. So, just a brief review on the fibrillation collagen is. These are the major structural components of the extra cellular matrix and they include collagen types 12359 and 11. And the federal or collagen czar trim eric molecules that may be made up of three identical or genetically distinct chains, which we call the alpha chains. And this is a older cartoon, but it really does a good job illustrating how the three alpha chains are synthesized and they assemble into a try Merrick triple helical molecule, the amino and car boxy terminal ends are cleaved. And then the liberals line up into the mature collagen molecule, the liberals. So um In 2017 there was a new classification of. The Ehlers Danlos types And there were 13 different types that were defined at that time The classical type. The vascular type and the hyper mobile type are the most common of these 13 and the others are really quite rare with some of them. Only a handful of different uh cases have been reported. I'm gonna talk about the diagnostic criteria for the most common types the classical vascular and hyper mobile and just give a brief overview of some of the other rarer types. So the major criteria for the classical type is our includes skin hyper extensible bility and a trophic scarring and then joint hypermobility. Those two were the major criteria And the skin is considered to be hyper extensible if it can be stretched over a standard cut off in in three of the following areas. So the cut off that we use is 1.5cm For the distal part of the forearms and the door some of the hands and then three cm at the neck, elbows and knees. So um the skin hyper extensible. Itty in the classical type is really the most dramatic skin hyper extensible itty of of any that we see in the different Ehlers Danlos syndromes and this illustrates that skin hyper extensible bility. The abnormal scarring can range in severity. Many patients have extensive a trophic scarring at a number of different sites. They can sometimes be him aside erotic and a minority of the patients with the classical type of E. D. S. Have have more mild scoring. But typically when I'm wondering if a person has the classical type, I just go directly to the shins and and look at their shins because this type of scarring that you see. And um what the photograph that's labeled A here is very very typical of the classical type of E. D. S. And you start to see scarring even in youngsters. Um What happens is the skin is just extremely fragile and it can like what happens is when they're starting to walk they bump into coffee tables and the skin will split. And then you see these kind of fish fish mouth like scars that develop on the shins. And um the on the extreme right hand side of the slide here is kind of a typical a trophic scar where the edges, edges of the scar have separated out and created. Um Can a trophic looking scar? We use the biden score to define generalized joint hypermobility and I'm sure all of you are familiar with this scoring system. It's a nine point scale that looks at the elbows and knees and the ability of the person to touch their thumb to the forearm and to bend the fifth finger Back more than 90° at the Metacarpal Fallon Jill joint. And then the 9th point is if they're able to put their palms on the floor with their knees straight. So you get one point for each side for the knees being more than 10 degrees. In hyper extension, elbows being more than 10 degrees in hyperextension and the fifth finger metacarpal Fallon geo more than 90 degrees and the thumb to the forearm. So another thing that happened with the 2017 criteria is we change the cutoffs for generalized joint hypermobility depending on age. So we now consider that pre pubic, all Children and adolescents have generalized joint hypermobility. If the bite and score is more than or equal to six For men and women up to age 50, we use the cut off of five And for men and women older than 50, we use a cut off of four for the classical type of Ehlers Danlos syndrome. We can make a clinical diagnosis if they have the major criterion one which is the skin hyper extensible itty and a trophic scarring. And then in addition um either the major criteria to of joint hypermobility, generalized joint hypermobility based on the biden or three of the eight minor criteria which are listed here, including easy bruising, soft, doughy skin, skin fragility or traumatic splitting molests. Coed pseudo tumors. These are the the lesions that you saw in the knees of that gentleman in the earlier slide where molests coed pseudo tumors on his knees. Subcutaneous for your roids are kind of under the skin. They feel almost feel like a little piece of gravel underneath the skin hernia or a history of hernia, epic until folds, uh complications of joint hypermobility or a family history of a first degree relative who meets the clinical criteria. So um four classical E. Ds confirmatory analysis is recommended for any patient meeting the clinical criteria. And we look at the genes col five A. One and col five A. Two. Um and molecular analysis of those two genes should find a causal mutation and more than 90% of patients with classical e. ds. And we use that as the standard confirmatory test. And this was the reference from dr Andy PAPP slab That showed that 90% of patients with those redefined criteria should have variants in Type five college and now the vascular type of E. D. S. Um The major criteria include a family history of vascular E. Ds. With documented variant in cul three A one arterial rupture at a young age and typically these are the medium sized arteries in the abdomen, like the splenic artery, paddock artery, gastric artery, those those sized arteries, um spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology, um uterine rupture rupture during the third trimester in the absence of a previous C. Section with or without severe peri partum perineum tears and then finally a carotid cavernous sinus Fishel of formation in the absence of trauma. The minor criteria include bruising, thin translucent skin with increased venous visibility. There's a characteristic facial appearance and I'll show you a picture of a woman with that characteristic facial appearance in a minute um spontaneous pneumothorax. Ah an older looking appearance especially of the hands. Um club foot congenital hip dislocation, hypermobility of the small joints in the hands. And often people with the vascular type of Ehlers Danlos syndrome will not have generalized joint hypermobility but we'll only have obvious hypermobility in these small joints in the hands and sometimes the feet tendon and muscle rupture, karate, Conus, ginger, ville recession and ginger ville fragility and the early onset of varicose veins. These are all the minor criteria for the vascular type of U. D. S. And this is the kind of typical what we consider to be the typical facial appearance with a sort of a triangular face, very prominent eyes, um diminished subcutaneous fat and a thin thin nose. Uh and thin lips. When you see this facial appearance, it's very suggestive of the vascular type of VDs. But not every person with the vascular type of E. D. S. Will have this facial appearance. So it's not and it's not seen in every case. And you can see the older looking hands in this uh this woman who's just in her 30's And um the biochemical analysis that shows the diminished presence of the amount of collagen type three. So the committee that defined the new criteria for vascular E. D. S. Really they decided against making um uh I mean hard and fast diagnostic criteria and instead offered us minimal criteria suggestive for vascular EDS. And um so they basically they said if you see any of these things you should really be thinking about the vascular type of E. D. S. And if you're thinking about the vascular type of E. D. S. You should be ordering testing to rule it in or out. So um those minimal criteria are the family history of the disorder Arterial rupture or dissection and a person less than 40 years of age, an unexplained sigmoid colon rupture, spontaneous pneumothorax and in the presence of other features consistent with vascular E. Ds. Any of these criteria should lead to diagnostic studies to determine if the person has vascular E. Ds. Or not. Um And testing for vascular E. Ds should be considered in the presence of a combination of the other minor clinical features listed here. So the diagnosis of vascular E. Ds rests on the identification of the causative variant in one alil for col three A one which is a gene encoding type three collagen. The sequence analysis were called three A 1 will identify a pathogenic variant in 95% of cases And deletion duplication analysis will give us another 2% or so. Um There has been really good work from dr peter buyers laboratory demonstrating that there's a very um interesting phenotype genotype correlation um where survival is affected by the mutation type and the molecular mechanism in vascular E. Ds. So variants that cause loss of a millennial will have a more mild phenotype than um variants that are missed sense variants in and cause changes in the sequence of the particularly for substitution in the um uh huh triple helical region of the collagen. Okay, moving on to the hyper mobile type of Ehlers Danlos syndrome. The criteria that were offered in 2017 were designed to emphasize the syndrome IQ. Nature of the condition to reduce clinical heterogeneity and to facilitate research into the underlying causes of hyper mobile E. Ds. Because hyper mobile E. Ds is the most common of the types of Ehlers Danlos syndrome and the only one for which we do not have a molecular explanation. And we certainly expect that further clinical experience and research will lead to revision of these criteria with time. So just to go back to the 1997 criteria for what we were calling the hypermobility type of E. D. S. at that time. Um this was a publication. Peter Biden was the first author in 1998. And um the major criteria then we're skin involvement with hyper extensible bility and or smooth velvety skin and generalized joint hypermobility. And the minor criteria were recurring joint dislocations, chronic joint and limb pain and a positive family history. And the only guidance that that 1998 publication gave us in terms of establishing a diagnosis was that the presence of one or both of the major criteria was necessary for a clinical diagnosis. So this was not a very uh specific set of uh diagnostic criteria. Person with generalized joint hypermobility alone could be diagnosed with the hypermobility type of E. D. S. Under these criteria. And actually a person just with smooth velvety skin could be diagnosed with the with the hypermobility type so it was too wide a net. And So the the effort in 2017 was too narrow that the diagnostic criteria and generate a more homogeneous group of people in that bucket of people. And it was renamed hypermobility Ds. And now requires three different criteria for establishing the diagnosis. So those three criteria are, well the first criteria is generalized joint hypermobility again with the bite and score same cutoffs we discussed for the classical type of ebs The committee also said there there's a questionnaire called the five point questionnaire which was designed by rheumatologists uh to establish whether or not a person has generalized joint hypermobility. And so if uh if a person is one point below the cut off for the bite and score and they have two positive items on this five point questionnaire we can kind of push them over the over the finish line and say okay we'll call this generalized joint hypermobility in this person. And this is the five point questionnaire. It's can you now or could you ever place your hands flat on the floor without bending your knees? Can you now or could you ever bend your thumb to touch your forearm as a child? Did you amuse your friends by contorting your body into strange shapes? Or could you do the splits um as a child or teenager, did your shoulder or kneecap dislocated on more than one occasion? And finally just simply do you consider yourself to be double jointed? So some of these questions are redundant to the biden. And um I think this is one area where uh as the criteria are considered the inclusion of this five point questionnaire. I I think it may eventually be excluded from from the consideration but that's still to be seen. No. So um criterion two has three features in it. And we need two of the three features to say that criteria two is met. So the three features are systemic manifestations of a more generalized connective tissue disorder, a positive family history and muscular skeletal complications of the condition. The systemic features. We need at least five of a list of 12. Those things include unusually softer velvety skin, mild skin, hyper extensible itty not as extensive as what we see in the classical type, unexplained stretch marks without a history of significant significant weight change, bilateral pai pai estrogenic popsicles on the heels. These are little bumps that appear on the heels when you put all your weight on your heels. Um Recurrent or multiple abdominal hernias. A trophic scarring in at least two sites um pelvic floor, reptile and or uterine prolapse without a history of morbid obesity or other known predisposing conditions. Dental crowding and a higher narrow palette. Um Arachnid actually defined by the positive wrist and thumb signs. Those are. We put the thumb across the ponds and close our fingers over it. If the thumb sticks out the full distal phalanx, that's a positive thumb sign and the wrist sign is positive if the little finger and the thumb overlapped by the full distance of the nail on the little finger. Um An armed stand to height ratio more than one point oh five michael valve prolapse or an aortic root dilatation with a Z. Score of plus two. I have a feeling also just watch this space. I'm not sure exactly how it's gonna pan out. But I think the echocardiogram traffic criteria probably going to come out of these criteria eventually. Um Also especially because if we see aortic root dilatation we really should be going down a different diagnostic pathway. Um We do see mild aortic root dilatation and some patients with the hyper mobile Alessandro syndrome but it is usually uh not progressive almost always not progressive. In fact if it is progressive it makes me think it's got to be some other hereditary disorder of connective tissue and specifically not the hyper mobile type of E. D. S. So we call a positive family history If one or more first degree relatives independently meet the diagnostic criteria for hyper mobile E. Ds And the muscular skeletal complications. We fulfill feature see if at least one of the following are present musculoskeletal pain in two or more limbs daily for at least three months, chronic widespread pain for more than or equal to three months. And recurrent joint dislocations or frank joint instability in the absence of trauma. So one of those being present fulfills features. See. And then criterion three basically says that we have done our due diligence and we have excluded um all other different items in our differential diagnosis. We really thought carefully. We've asked about other heritable and acquired connective tissue disorders and the exclusion of alternative diagnoses that may also include joint hypermobility because they cause either hipaa Tonia or connective tissue laxity. Now, some of our patients with hyper mobile Ehlers Danlos syndrome may have autoimmune rheumatoid logic conditions. They may have lupus, they may have rheumatoid arthritis. Um The criteria suggests that if that is the case that we not use the presence of pain as one of the features in um criterion to but if they have either a first degree relative, so they have A. And B. Or if they have instability, you can still um get them across the finish line and say that they meet criteria. Now when we think about syndromes, the mannequin at all um defined it as a pattern of anomalies at least one of which is morphological better thought to be causally related and um when the committee that was looking at the hyper mobile type of E. D. S. Back in 2000 and 16 and 2017 thought about this, they recognize that the presence of joint hypermobility in combination with secondary muscular skeletal anomalies that does not suffice for delineation of a genetic syndrome and that the joint hypermobility may occur independently or in the context of multiple genetic disorders. So in terms of thinking about classifying patients with joint hypermobility, they came up with this idea that really hypermobility there's a spectrum of hypermobility which includes people who have asymptomatic joint hypermobility and that asymptomatic joint hypermobility may be localized in only one or a couple of joints. It may be generalized meeting the criteria for the bite and scale or it may be peripheral as we see in the vascular type of Ehlers Danlos syndrome where um it's just the small joints of the hands and feet that are hyper mobile. So we may have people with asymptomatic joint hypermobility. We may have people who have a well defined syndrome that includes joint hypermobility and then we may have some people with symptomatic joint hypermobility but who do not meet the diagnostic criteria for a syndrome. And those people we consider to have the hypermobility spectrum disorders. So the spectrum of joint hypermobility then includes asymptomatic hypermobility which may be generalized peripheral or localized generalized hypermobility spectrum disorder, peripheral hypermobility spectrum disorder, localized hypermobility spectrum disorder or historical hypermobility spectrum disorder which includes the presence of the historical presence of joint hypermobility but which we do not now see an exam. And then at the extreme end of this spectrum of joint hypermobility, we have the hyper mobile type of Ehlers Danlos syndrome, in which the biden score is positive and muscular skeletal involvement is possible and usual, I would say. Alright, now I'm gonna move on to talk about a few of the rarer types of Ehlers Danlos syndromes. Um Tenacity X deficiency is an artisanal recessive form of VDs characterized by Mark's skin hyper extensible itty, easy bruising joint laxity without a trophic scarring or poor wound healing. And people with this to Nasonex deficiency also may have severe diverticular intestinal disease. They may have mitral valve prolapse that's severe enough to require valve replacement. And they also may have obstructive airway disease. You also have very typical kind of wrinkling of the palms of the hands and also on the feet. There is an autism almost dominant form of to Nasonex deficiency. There's a paper from 2000 and three in which as weirs and colleagues looked at 20 obligate hetero zygotes with the Nasonex mutations And um they saw a generalized joint hypermobility. In 45% of these obligate hetero zygotes. All of these were women. None of them had skin hyper extensible itty or easy bruising. And then in another study in 80 patients with hyper Mobile Ehlers Danlos Syndrome. Six had low levels of the Nasonex in the serum and two of those had hetero scientists to Nasonex variants. So I think this is an area to Nasonex is is a very difficult gene to analyze in the laboratory because there are pseudo genes uh For 10 Nasonex and it's in a region that's hard to sequence. So um we may yet find that there are more patients with hetero zegas to Nasonex variants in that hyper mobile E. D. S. Population. Um The typhus Coley attic type of Ehlers Danlos syndrome is um presents with neonatal Caiaphas scoliosis, generalized joint laxity which can be really quite extreme skin fragility, severe muscle hipAA Tonia at birth and biochemical analysis identifies the deficiency of Lysol hydroxy ellis. And the variants are in plod won, the gene that encodes the enzyme um which which hydroxy L. It's slicing on the on the on the collagen molecules and this causes the pascal idiotic form of A. D. S. The arthur Local asia type of E. D. S. Presents with bilateral hip dislocations and really doughy kind of redundant skin. Some of the patients have contractors of the fingers and toes. Umbilical hernia infosys of historical lumbar spine and muscle hipAA Tonia and um this type of E. D. S. Is caused by variants in either the alpha one or the alpha two chain of type one collagen. And these variants are in a very specific location that interferes with the cleavage of the end pro peptide. So this is an artist's omo dominant condition. The arthur local asIA type. It can be caused by either col one a one or call 182 variants. The derma dose paralysis type has epic until folds down sloping, palpable fisher's bleus clarey um michael abernathy, a very prominent lips um and facial scarring, easy bruising. And this is an interesting kind of counterpoint to uh the previous one because these this is these are it's an autism, a recessive condition but the molecular consequence of this is the same as um if you have a col one a one or call one a two variant that prevents the cleavage. In this case it's the enzyme that's deficient and in the um arthur collision type it's the substrate. So in this case the mutations are in adam T. S. To you and that's the enzyme I mean the gene that encodes the pro collagen and protein enzyme which cleaves that and pro peptide of types one and two. So this is an artist so more recessive condition. The muscular o contractual type um is manifest by mailer hyperplasia and down sloping palpable fisher's blue scary micro cornea along filter um thin upper lip macron Athi a so prominent chin which is often pointed in appearance. And this condition is caused by mutations in ch. C. H. S. T. 14 which encodes an enzyme called derma toe for sulfur transfer race which is key in the synthesis of Dermot newton sulfate and um so if if you're not sulfate ng your this, if you're not creating Dermot in sulfate, it disrupts the ratio of Dermot in sulfate to con droid and sulfate, which is an important regulator for multiple glycoprotein components of the connective tissue. The cardiac valvular type is characterized by cardiac valvular insufficiency. The mitral and aortic valves can be affected and require surgical correction, patients have joint hypermobility and hyper extensible skin and this condition is caused by a lack of alpha two. Type one chains in type one collagen. Um So type one collagen is ahead of a trimmer with two alpha one chains and one alpha two chain. But if you don't have call one A two you get a home a trimmer Of Alpha one chains. Um and that results in this cardio cardiac valvular type of Ehlers Danlos Syndrome. Now, just for a few minutes, I'd like to talk about the fact that Ehlers Danlos syndromes in general are complex and multidisciplinary disorders and we know for most of most of the patients we see are hyper mobile Ehlers Danlos syndrome. Many of the patients who were diagnosed with hyper mobile hypermobility spectrum disorders also present with complex multidisciplinary issues. Um So Heidi Collins coined this phrase if you can't connect the issues, think connective tissues. We see uh musculoskeletal involvement with joint laxity and stability. Subluxation is dislocations, a tendency for tendon ruptures and tears, chronic musculoskeletal pain and frequent sprains, cardiovascular manifestations. Uh This is this audience needs no introduction to the Ortho static intolerance, but we also see mitral valve prolapse in the aorta group. Dilatation I mentioned earlier, neurologic involvement can include headaches, the cervical medullary syndrome and I'll say a little bit more about that in a minute neuropathic pain. Occult tethered cord, cerebral venus, insufficiency, degenerate this disease, final instability and small fiber neuropathy. The cervical medullary syndrome was defined by a consensus statement of the chiari answering go Malia Foundation, Multidisciplinary colloquium in 2013 to include headache and sub occipital or neck pain and bold bar symptoms of um altered vision, double vision, Stagg mus, diminished hearing, dizziness and balance, vertigo, choking, difficulty swallowing or speaking disorder. No mia disordered sleep architecture and sleep apnea and symptoms of myeloma apathy. So when we see a constellation of symptoms uh such as this, it suggests the cervical medullary syndrome, which can be due to either chiari malformation or instability at the cranial cervical junction or at C. 12 G. I manifestations are very common in this population. And again, I'm talking about both the hyper mobile type of Ehlers Danlos syndrome. Hypermobility spectrum disorders and also in uh we see these complications in the classical type of Ehlers Danlos syndrome as well with irritable bowel syndrome, bloating abdominal pain and suffering, field reflux, food intolerance, diarrhea constipation fecal, incontinence hernias and sphincter of od dysfunction recognizing that there's a significant overlap with autonomic dysfunction with the G. I. Manifestations and also with potentially with mast cell activation um urologic features. And again patients may be diagnosed with interstitial cystitis um and that can be secondary to mast cells. So important to think about that mast cell involvement with multiple different organ system involvement but urinary urgency, frequency burning on urination, difficulty initiating the urinary stream or emptying the bladder completely and urinary incontinence and frequent urinary tract infections. So some of these can be due to occult tethered cord and some can be due to mass cell and some can be due to an atomic variants in the urinary tract itself and hematology allergy department. We think about the history of hives, rashes, flushing, itching, frequent infections, severe allergies, autoimmune disorders and the history of blood clots. And certainly these first four items would make us wonder about the presence of naso activation. Some things I think about in terms of treatment strategies for the muscular skeletal issues um to stabilize unstable joints on an as needed basis. People sometimes worry that braces will cause weakness but if patients continue to use their muscles. I don't they they should be protected against that. Um Physical therapy is a whole really a mainstay for treatment. Um It should include manual therapy to get the muscles to relax before patients do the toning and strengthening necessary to stabilize their joints and that would include dp ultrasound massage use of electrical stimulation for infrared laser therapy, among other things and dry Needling can be very helpful If the 10s machine is helpful in the PT Office. We consider using one at home. They're now very affordable and easily obtained for home use. Epsom, salt baths or foot baths can help with muscle relaxation and then Petey for toning and strengthening the muscles, particularly considering aquatic petey is really really helpful to many of these patients. I prescribe a compounded analgesic cream that has a combination of diclofenac, cyclamen, supreme baclofen, gabapentin, lidocaine and magnesium. Some of my patients called the zebra sauce. Um and they really like it. But the problem is that it's it can be very difficult to get insurance to cover a compounded product. There's another product that's marketed through amazon manufactured by a company called Golden Sunshine. It's called pain terminator which is a combination of different chinese herbs and that one um is more affordable and can be very helpful to. We use muscle relaxants and if necessary. And I always say beware Botox, especially in the muscles in the neck because of the muscles of the neck are paralyzed and a person can lose their ability to hold their head up for three or 4 months which is not a desired outcome. So coping strategies include cognitive behavioral therapy, mindfulness based stress reduction biofeedback and neural feedback patient support groups and exercise can be extremely helpful. Um The international classification is available at the Ehlers Danlos Society website and all of these diagnostic criteria are available there. The there was a special issue of the American Journal of Medical Genetics that was published in March of 2017. And all of the papers from that issue are available freely at the Ehlers Danlos Society website. So that is the end and thank you very much for your attention and thanks so much to the society and my patients and their families for letting me be part of their journey. Created by
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