Laura I'd like to actually start by welcoming everybody so thank you very much for joining us I see from the chat that there are actually a number of international participants so thank you and welcome I also wanted to start by thanking Charlene Waldman Michael and Laura for really this invitation and this opportunity to tell you a little bit about FOP and what we have been doing in that area as well as what other clinicians and other groups have really have started to think about what the best strategies for diagnosis and management are for FOP so I'm going to start by sharing my screen all right so excuse me sorry my apologies okay so my apologies all right so while the slides are loading up what we're going to do today is actually discuss a little bit about FOP we're going to talk a little bit about the clinical aspects related to the presentation of FOP and then I have the pleasure of having two people from our group here at UCSF so Kelly Wentworth who is a junior faculty member and Sukie Singh who is one of our senior endocrinology fellows and they will help with some of the discussion about the cases so that we'll have so okay so hopefully okay our people a see the screen I think Michael he can just let me know if that's yes thank you all right so thank you everybody okay so just very quickly some of you may have seen the disclosures that I have I have a number of them one of the things none of these actually posed any conflicts for this presentation in addition as Laura had mentioned at the beginning this presentation is geared towards health professionals presentation does discuss the off-label use of some fda-approved medications for the treatment of FOP but because FOP is so rare please keep in mind that treatment strategies need to be discussed in with either experts if you can reach out to people with experience with FOP but certainly discussed in detail with the patients and obviously medical judgment is really important for the patients on this call welcome it's really a pleasure to have you as part of this I would really recommend that you know if you have any questions please discuss them with your physicians you can reach out to me later on if you have any questions but please do not initiate any sort of changes in your treatment plan until you've discussed it okay so I'm going to start with a very quick summary actually of the key points from FOP and the first one is that if you see great toe malformations and migratory swellings which we'll go through in more detail this should raise the possibility of FOP as a diagnosis and if FOP is suspected you must avoid trauma and biopsies and any sort of things that might cause the potential for injury until the diagnosis of FOP has been ruled out and I want to emphasize really trying to avoid biopsies I will also add that routine medical medical care with things like peripheral IVs is totally okay and that there are major medical centers that have expertise in FOP please reach out to any of us around the world and especially if intubation is needed we can provide a lot of guidance as to that we'll have one case that talks about that but the ethel key the IFO PA which is the International FOP Association or the FOP icc which is the international clinical Council on FOP have a listing of sites and different contact information okay so also just since I know this is recorded this is a list of some of the references that are probably the most useful the first one is the treatment guidelines this is a peer-reviewed consensus guidelines from 21 senators from across the world that is by far that is sort of the treatment Bible as we joke about it but it's one of the best resources for actually getting information about management of FOP of all different aspects and then these are the websites for some of the other resources okay so we're going to start with a case so let's start with a five year old girl who was product of a normal conception and birth and she started the parents started to report that she had restricted joint movement over time there were migratory and intermittent swellings that were occurring these started out at about age 2 or 3 and these were the great toe malformations were noted at Birth I don't have the picture of her toes at birth but these were pictures at age 5 and what you can see is that there's some shortening and there are sort of add room abnormalities here okay so when you start to hear about these types of situations where there is a great toe malformation and then these sort of weird migratory masses that sort of come in Oh sometimes their firm in hard this is a photograph of her back and what you can see is that there's this extra lump that is kind of present that is not present on the left-hand side that needs to start raising the possibility of FOP and one thing to note is that pain in children as with most other musculoskeletal disorders is it often extremely variable often times they present with malaise with other types of symptoms but you may not may or may not actually get pain differential diagnosis for FOP should include things like infection oncological so osteosarcoma to soft tissue sarcomas des moines humors rheumatologic causes like lymphedema or juvenile fibromatosis this is especially true if a biopsy was accidentally done often comes up with features that look like a fibroma or heterotopic ossification so not only fo ki but a related condition somewhat called voh or progressive osseous heather aplasia this is actually caused by a different type of mutation and different pathway and also presents with a diffuse heather atopic ossification phenotype and non hereditary or acquired Heather but the key thing in all of this is that the presence of toe malformation is really helpful for really ruling out above it's not completely perfect this is something that can be very helpful the gold standard is essentially genetics for the ACV r1 r2 of six-h mutation this arginine the histidine mutation is found in close to 97% of FOP patients and so this is a highly sensitive highly conserved genetic change that can be used and as mentioned earlier you need to avoid trauma things like avoiding i.m injections really until the patient is evaluated and and holding off on biopsies because that can actually so this is a relatively famous picture a series of pictures about a boy who has FOP and over time at birth it was noted to have great formed great toe deformities which is here but as you can see over time there is progression of the deformities and the heterotopic ossification this affects the disease affects between one point for one and one point for the two million people depending on the study that is used their recurrent flare-ups that are often associated with injury but not always associated with an identifiable injury there's ossification and muscle tendon and cartilage and there are no effective treatments except really to try to avoid injury as much as possible so there are key a few key characteristics about FOP the malformed great toe sometimes patients also have a malformed thumb so shortening of the thumb they may have complicated births such as things like a sub Gallio hematoma or head swelling these can be especially associated with situations where assisted delivery was used and then childhood they often have decreased crawling difficulty lifting the head they don't really like you know tummy time so being on their abdomens because they have difficulty actually raising their head and there are these reports of intermittent lumps and bumps and flares often start around age two or three but you know like other diseases maybe earlier or later so we keep mentioning this thing about tail malformations and so this is a x-ray of a patient with FOP and what you see is basically it's the first digital formation it's essentially loss of the joints and and this type of you know the shape is not always consistent sometimes it looks like a bunion sometimes it looks like other types of features but when you do the radiology you will almost always find that there is a the other aspects that are commonly seen in FOP patients are bridging heterotopic ossification particularly within the cervical spine there can be these elongated cervical bodies that appear to be present there's no clear functional consequence from that but oftentimes this is the initial presentation where we will hear about patients who had difficulty moving their head or neck stiffness and you see this ossification and then osteochondroma so osteochondromas can happen anywhere in a patient with FOP most commonly you know at major joints tibial osteochondromas obviously this was one in the wrist those types of okay so when we talk about patients with FOP we talk about those back swellings or on a migratory masses and it turns out that those are very variable so you saw the picture of the five year old a little bit earlier where it was a relatively flat kind of prominence and if you were in a hurry or you're doing telemedicine and there's someone who's holding up like a cellphone photograph you might not see it at first but it's useful to take a look at the spectrum of the soft tissue swelling so on the left hand side here is a nine year old boy who had a very minor injury this was just sort of like a very minor injury to the right scapula and you can see that within a couple of hours there's this huge mass which looks like a golf ball just underneath the skin it's red it's indurated it's painful it's fallen here's another child where you can see that there's this mass that's present over here but there's also a second mass up here on the left scapula and and this one is an older the one on the left is actually an older lesion that has matured and this is the active lesion if you were to feel it with the back of your hand it would probably still be sort of warm to touch as compared to other portions of the body but this doesn't have the same degree of redness that you would have have seen in some of these more active players so it's useful to keep in mind that the presentation of the FOP flares can actually be rather variable so these flares can actually occur without obvious injury so typically patients will report swelling pain and erythema sometimes warmth that is present in children that often starts in the axial regions and then in teens and result and adults really starts to shift towards the appendicular so this is a two-year-old you can see has multiple heterotopic ossification regions these are all relatively active there's not much erythema they are again probably warm to the touch and these flares can lead to bone formation the challenging thing about FOP now is that not all flares result in bone not all heterotopic ossification was preceded by a flare and the reasons for this differences are really unknown also flares can be migratory or subtle and you know as you've seen from the other photographs so it's not always easy to tell sometimes especially at the beginning when the flare is just starting up alright so over time the cumulative result is that you end up with this on the right-hand side is that this is this is Harry he is actually this skeleton is located at the University of Pennsylvania in the mother museum and what you see is that this is essentially a second skeleton there is just too much bone that is present there's the primary skeleton underneath and you can see the spine and the ribs and the skull but there's all of this other Heather topic ossification that occurs and this bone is essentially a second skeleton it has the ability to remodel Achan fracture and heal some of the bones will actually end up with bone marrow that's present so what it is is a really a second skeleton superimposed on top of the primary cells as I had mentioned before people have been very interested in FOP the mutations about 95 to 97% of the patients have this highly recurrence mutation the 617 g2a which results in arginine histidine mutation and amino acid 206 there are a number of other variants that have described but pretty much they're all in a CPR one and this is a mutation that occurs in the glycine and Syrian rich region it leads to altered activity of the AC vr1 receptor there's increased stitched of activity but also abnormal signaling and activity so the receptor itself is a severe one is in a complex with the type 1 type 2 receptors and these actually bind to bone morphogenetic proteins and they signal down through this mat and one of the features about this particular mutation is not only does it increase constitutive signaling through this man's to increase BMP activity it actually causes the receptor complex to misinterpret active in a as a BMP what's intriguing is that the AC vr1 receptor complex also signals through other pathways including p38 and also the NF kappa-b pathways and these become important because these pathways are probably important for monocytes and macrophages activity and so we have additional resulting phenotypes that are probably result of non smads signaling as compared to some of the other pathways there's more classical pathway there's been a lot of research from a lot of different labs and I'm not going to be able to go through all of that but one of the things that we have been thinking about as to what the pathology or the pathophysiology of FOP is is that you have this activating mutation that's present in the patient and that there's some sort of primed innate immune system that has increased pro-inflammatory cytokines sort of increased myeloid activity and trauma infection some sort of event which you may or may not be able to identify actually results in an activation of this process and you end up with a clinical flare that's highly inflammatory as you've seen you get these lesions it may be responsive to steroids which is the the standard of care therapies at the moment and again we'll talk about that in a little bit but ultimately what ends up happening is that you end up with increased fibrosis basically an inflammatory infiltrate at the site of the injury that eventually and causes hether topic classification and we think that a lot of this is because of activated pro-inflammatory or cytokines and chemokines activation of the immune system by various different factors causes inflammatory cell recruitment and ultimately activation of some sort of tissue specific progenitor so the fibro atom aside for genders or fats are probably the cells that are most likely to be involved but there's a lot of other information that suggests that multiple cell types are actually affected by this mutation and contribute to the heterotopic ossification all right I should also note that in other studies what's been interesting is that cell fate instability seems to be a feature of the are two of six-h mutation and this was actually shown in a series of studies using human induced pluripotent stem cells where the ability to create the human iPS cells from fibroblasts of fop patients was easier and that's a rare finding it's most of the time we find mutations that make it harder to make IPS cells but in the case of FOP the mutation does seem to make it easier to transition between states and since then multiple tissue specific cell types appear to be able to also lose their ability to lock in their cell fate and it turns out can actually serve as the potential stem cells for okay so what I thought I would do is just go through a couple of quick diagnostic pearls again toe malformations and unexplained swellings you need to really think of FOP and so it's proven otherwise if FOP is suspected you have to avoid invasive procedures no biopsies or surgeries the the situations that we hear about sometimes which are extremely challenging are that you know a child aged 2 or 3 is playing in the playground has fallen and gets a bump on their head they're not entirely sure what this is goes to see the doctor and then the biopsy is done and then that trauma from the biopsy or the surgery Ashley there's more Bo information those are the types of situations that we would really like to try to avoid x-ray imaging can be extremely helpful stopping immunizations during this period of time while you're trying to sort out the diagnosis and is important and simple vey venipuncture blood draws these are okay as long as it's done by an experienced provider I don't want somebody trying to hunt down the vein trying to you know poke through and certainly there's something about crossing the tissue fascial plains that seems to trigger worsened hether top classification so really making sure that you have an experienced team available heterotopic ossification and the skeletal malformations are the most obvious symptoms and things like osteochondroma so tibial are usually the easiest to palpate that they're usually present at other sites the malformed cervical vertebrae that we saw fusions of the spine this can sometimes resemble ankylosing spondylitis and so we've had referrals come through I'm saying it's like well this looks like a s but it might not be a s so we would like some thoughts and then sort of the malformed first digits in the hands and feet and you should consider genetic testing for a severe one since that is by far the most useful so treatments so there are a couple of treatment pearls the guidelines are the most up to date for the recommendations and steroids can be used for severe flares in kids and also in adults so the typical dosing is two milligrams per kilo per day of prednisone or equivalent we usually do this for four days to try to calm things down and then possibly consider a taper so as with any steroids and and other even non fop patients coming off of the series can be challenging it's important to start as soon as possible after trauma or a flare start because it does seem to be that if you delay longer that the ability to block hether type of classification or manage to flare does seem to go down avoiding trauma as much as possible is important so things like non elective surgeries like rupture dependence those appendix those should go ahead but other situations where you know you can avoid things are great so things like Corrections of the malformed toes you know those types of surgeries we really try to avoid if surgery is needed there are protocols for giving steroids in the setting of surgery intubation can be extremely difficult and risky needs to be done by an experienced team fiber optic guidance is key immunizations couldn't be given using a modified routes so in most cases converting the intramuscular immunizations to subcutaneous will work not in the case of tetanus and certainly not in the setting of a recent flare because it seems like the immunizations can actually also contribute and there's emergency contact information for on the IFO PA website for clinicians you know if there's any questions that come up please don't hesitate to reach out alright so as we think about therapies one of the exciting aspects about FOP that there are a lot of investigational therapies that are out there and I am NOT going to go through the mechanisms in a lot of detail but this is all currently off-label use or investigational therapies so there are strategies for actually targeting things like the inflammatory steps mTOR signaling the Heflin pathway so things like rapamycin imatinib anti active and a antibody il-1 inhibition there are efforts to try to target progenitor cell activation and sort of the bone formation process so there are BMP inhibitors like the LDN i'm using small interfering RNAs and Sark at the hitter and also efforts to try to target things like Condor Genesis or the later stages so these are like the RA are again and then though the long-term goal is really to do some mutation specific inhibition if you can do something that is extremely specific for the a severe one activating mutations that would be ideal and sort of the personalized therapy and so a number of those therapies are actually okay so there are a couple of other important patient issues to sort of keep in mind quality of life is a major issue for our FOP patients as you can imagine many of them start out very functional they're able to do all sorts of different types of activities and they have this progressive on really unrelenting loss of mobility cognitively they're pretty much completely intact there's there's really no compromise of that and so as patients get older mental health is really a major concern you know as they realize that they are school and work accommodations and adaptive devices are really important I will point out that if you have a patient with AI with FOP my FOP a is an excellent patient organization and really engaged to help with you know help getting these types of things together and they are very well connected with the local FOP patient groups in different countries dentistry this is a challenging problem partly because if any of you go to the dentist you probably remember that you have to open your mouth for long periods of time usually and what that does is that actually put strain on the master muscles and the strain can actually lead to a flare and locking of the jaw routine cleanings are generally fine it's usually once you end up in the situation where a procedure needs to be done and so making sure that there you have a pediatric dentistry person involved early on is extremely important that can be extremely beneficial for you know continuity of care and one of the things that we identified is that if you have patients who are adults even referring them back to pediatrics because they have smaller tools they can sort of squeeze in and and and clean things that can be extremely helpful but making sure that a good dentistry team is all this great and I will add that the IFO PA website actually has a list of dentists with expertise in physical therapy and occupational therapy we try to limit the use of this and it's active motion only because of the risk of injury we'll talk about this a little bit more in one of the cases but really the goal here is not anatomic correction it's really for comfort of the patient and trying to prevent flares and and then the last one I'll just touch upon really briefly is pain management pain is highly variable extremely difficult to manage especially during flares we're not entirely sure why that is the case it's there's some thought that this is actually related to the FOP mutation itself but trying to make sure that the patient is comfortable can require the services of an integrated pain management team to really help out okay current research opportunities for anybody who's interested many of the FOP patients and their families are actually really engaged in this arena so there are clinical trials there multiple companies which I won't mention here extra skeletal manifestations are an aspect that we're trying to understand more so these include like the GI and your logic phenotypes their number of investigator-initiated studies there are multiple sites across the United States in the world we're interested and love support and we just to let you know we have a couple of studies at UCSF including bio banking for different types of tissues share those tissues for research purposes we have interest in inflammation the GI and neuropathic pain manifestations as well as human disease in their studies and I also again point out that the IFO PA the patient registry and biobank are really really a centerpiece of a lot of the research that can go on the patient registry is worldwide and has collected a large number of FOP patients and includes patient reported data and soon will include physician or the data as well as the IFO PA biobank which also we participate in and allows the use of biological samples from patients okay so quick summary great toe malformations and migratory swellings sorry if I sound like a broken record but that's the main thing that is really important to keep in mind that needs to raise the possibility of FOP if it's as if FOP you suspected avoid trauma and please contact a major FOP Center for any sort of guidance and there are different guides that are available through the eye FOP and again the key resources that we had at the beginning so I will stop here I will just acknowledge a lot of people these are collaborators that had we had the pleasure of working with as well as my lab both the wet lab as what was the clinical research side that has contributed to some of the knowledge that's out there and this is our contact information here at UCSF if any questions come up we're happy to serve as sort of a starting point and refer you to closer centers that may be able to also help out with things like FOP or FOP related diagnoses and one thing just really quickly before I and I do want to have a shout out to Amanda Callie and the radiant Hope Foundation and just for disclosure purposes they have supported my research there is a really nice documentary called tin soldiers and this was an outreach project for trying to identify patients with FOP particularly in third-world countries but if anybody has a chance to look at it there's a short I think a 12-minute video summary which is really touching and really I think brings home some of the the channel just about diagnosis and there is a longer version that amanda has been helping with the screening so I'd strongly encourage people who are interested so with that I will stop and I think I'm happy to take some questions before we launch into the cases creak [Music]