Ellen Elias, MD
Professor, Pediatrics and Genetics, University of Colorado School of Medicine
Director, Special Care Clinic, Children’s Hospital Colorado

Disclosures
None

Christiaan Scott, MD
Professor, University of Ottawa
Staff Rheumatologist, Children’s Hospital Eastern Ontario
Honorary Professor, University of Cape Town
Medical Director, Tin Soldiers Global

Disclosures
Medical Director Tin Soldiers
Member of ICC on FOP (these are my opinions, not ICC)
Honoraria: Ipsen, Springer, Incyte, Abbvie, Jansen
Clinical Trials: Regeneron, Incyte, Jansen, Novartis

 

Learning Objectives

• To list early signs and symptoms of FOP

• To describe pathophysiology of FOP

FOP Transcripts

 

Ellen Elias, MD, Professor, Pediatrics and Genetics, University of Colorado School of Medicine;cDirector, Special Care Clinic, Children’s Hospital Colorado

Christiaan Scott, MD, Professor, University of Ottawa; Staff Rheumatologist, Children’s Hospital Eastern Ontario; Honorary Professor, University of Cape Town; Medical Director, Tin Soldiers Global

Introduction

Christiaan Scott, MD: Hello, my name is Christiaan Scott. I’m a pediatrician and a pediatric rheumatologist currently at the University of Ottawa. I am also formerly from the University of Cape Town and I’m the medical director of Tin Soldiers Global as well as a member of the International Clinical Council for FOP.

Ellen Elias, MD: Hello, my name is Ellen Elias. I am a clinical geneticist and pediatrician. I work at Children’s Hospital Colorado and I am the medical director of the special care clinic where we take care of more than 5,000 children with complex medical issues and underlying genetic disorders.

 

Christiaan Scott, MD: Thanks. These are my disclosures and Professor Elias has none.

So I’m going to start off with on a positive note with one of the most transformative things I’ve seen in the field of FOP for many years, and that is this law, which was promulgated in Brazil at the beginning of this year. You can see it on the 9th of January of this year, a law was passed in Brazil.

I don’t know how many of you speak Portuguese, but I’ll draw your attention to the center of the slide where you can see that the law is about fibrodysplasia ossificans progressiva (FOP). Just bear this in mind that there’s a country in the world where there’s a law on FOP, and we’ll get to what that law says a little bit later on in the proceedings.

Now, I understand that you’re all busy clinicians. We all are, and we all actually have many different interests outside of specific rare diseases. But this is a philosophy that I like to follow. It was something, a phrase coined by Thomas Huxley, who was incidentally the grandfather of Aldous Huxley, who was also the founder of Nature Journal. The Nature Journal that we all appreciate so much.

He had a philosophy, “That once you try to learn something about everything and everything about something.” So this is perhaps a situation where you as a generalist can learn something about FOP without having to know everything about it. But we hope that what you will learn will be impactful in your clinical practice.

Suspecting FOP

Christiaan Scott, MD: So I’ll start off by asking you a clinical question. Just what would you do when you are referred a child such as this, one of these two children, with lumps on their back or on the back of their heads? One might be forgiven for thinking that these painful firm lumps could represent some kind of malignancy or a dangerous abscess or something like that. One might even be forgiven for considering a referral to a surgeon or an oncologist to try and have these unusual presentations sorted out.

But in the case of this condition, Fibrodysplasia Ossificans Progressiva or FOP, that referral could potentially be disastrous and there’s a much easier way to make the diagnosis early on.

So what do you know about the toes in Fibrodysplasia Ossificans Progressiva? Ellen, I don’t know if you want to…

Ellen Elias, MD: Absolutely. So as pediatricians, we have the ability to look at the whole body of our patients and they might be coming in for a sore throat or an earache. But as a geneticist I’ve learned that it’s really important to look at the whole body and that means taking the socks off and looking at the toes. Because the abnormalities that one sees in how toes are formed in this condition is the first early clue about what might be going on. So it’s really important to always take a look at toes. If you see something that looks unusual to you, then you might want to just stop and wait and think, okay, this child has some unusual lumps that are firm and hard plus some funky-looking toes, and does this mean something?

So it’s actually critically important to make a correct diagnosis of FOP early on. Not only can you treat the child correctly if that happens, you can have an explanation for what might be a painful process and treat the patient appropriately for pain. You can also reduce unnecessary worry and doctor’s appointments. For example, patients might be petrified that they might have some kind of a tumor if they have a lump, but it’s not a tumor at all.

One of the very, very important things that we would like to convey in this talk is the necessity of not performing any kind of surgical procedures on a child with FOP because that can lead to significant progression of the FOP disease. Making a diagnosis can just lead to proper management and therapy that is now available for this very rare disease.

So I wanted to just let Dr. Scott explain this very interesting slide and then tell you a story about what I mean about preventing harm in medicine and what we do. Dr. Scott.

 

Christiaan Scott, MD: Thanks Dr. Elias. Indeed. I think what you’ve mentioned about the diagnosis is so critical, and as a geneticist who sees many different kinds of rare diseases, I’m sure you’ll agree that the difficulty for family in not knowing the diagnosis is one of the really troubling components of FOP. So in this desperation to find a diagnosis, people might resort to all kinds of avenues.

In the case of FOP, if someone ends up with a physician who wants to do a biopsy, for instance, to diagnose FOP, one could take a child who was previously running around playing until their third or fourth birthday as a happy child and send them to a wheelchair or a life of severe disability very early on.

One could also, if one inadvertently performed dental procedures that might involve the masseter muscle, one could sentence a child who was previously eating happily and healthily as you can see there a nice big hamburger, one can sentence that child to a life where they’re no longer able to open their mouth at all ever again. Which is really one of the most horrific things that can happen to a child. I wonder, Dr. Elias, if you can speak to us about some of the examples you’ve seen.

Ellen Elias, MD: Absolutely. So I wanted to have a very compelling story about one of my patients with FOP, which really drives home the importance of making a diagnosis as early as one can. So I have been following a young woman who’s now in her mid-20s, but when she was a young girl of around 10, she had had some small lumps here and there, but she developed a very firm lump in the middle of her right upper arm, right in the middle of her humerus. Her pediatrician was very concerned about that lump and was worried that it could be an osteosarcoma and for that reason referred her to see an orthopedic surgeon to do a biopsy to rule out cancer.

So this child underwent that biopsy, turned out it was not cancer. And as a consequence of that surgical procedure, she developed severe heterotopic ossification. So she developed bone where there should not be bone, which progressed incredibly rapidly. What happened to this child from a small biopsy in the middle of her right upper arm, she developed a bony bridge that connected her right arm to her anterior chest so that she was no longer able to move that arm at all.

Her scapula in the back on the right became attached by a bony bridge to her posterior rib cage, but that wasn’t all. She also developed abnormal bone that went all the way down the right side of her thorax involving her right hip and into her right thigh and she lost her ability to ambulate and is now confined to a wheelchair.

So this healthy and active child just from one small bone biopsy became completely encapsulated in bone on her right side. And that was a problem that could have been averted had someone actually looked at her toes first.

Christiaan Scott, MD: Thanks for that example. And I think that mirrors exactly what I experienced with the first patient of FOP that I encountered a very similar story. That’s actually what motivated me and I’m sure motivates you to do this awareness raising about these toes. The toes of FOP are very specific. I wonder if you want to talk us through the features of these abnormal toes that we can see.

Ellen Elias, MD: So it’s the big toe predominantly that’s impacted in this condition. And there are several things that one can see and it can go from being quite obvious to being a little bit more subtle. But first of all, the toe appears shorter than the other toes and instead of the big toe being usually as long as the second toe, it appears much shorter and it’s originating a little bit more proximally in the foot. The toe also tends to be deviated laterally. We call that hallux valgus.

So the toe is short, starts too early in the foot and turns out to the side. I think you can see different levels of severity of that in these pictures from these different children.

So often the toe if you do x-rays is missing the middle phalanx, and that’s part of the reason why the toe appears much shorter. You can sometimes see more subtle abnormalities in the hands and thumbs as well, but it’s really the toes that is the big, big clue about what is going on. So if you ever, ever see a child with unusual lumps that are hard, they’re hard because it’s abnormal bone there, you must take off the socks and look at toes. And if you see toes that look like this, then your suspicion should be raised significantly that you’re dealing with a patient with FOP.

Christiaan Scott, MD: Thank you. So I mean I completely agree and you’ve described the toes beautifully. The message that I want to reiterate is that if you see that combination of the malformed toes and the tumor-like swellings, usually it’s the tumor-like swellings that present to the pediatrician. Although in many cases malformed toes are noted at the, early in life, they’re often disregarded and overlooked. I’ve even seen some patients who’ve had their toes straightened surgically at a very young age before presenting later on with the tumor-like swellings that were the harbinger of FOP. So the differential diagnosis for things that give you abnormal toes and swollen lumps is very, very small.

I want to show you an interesting example on the right of how the diagnosis can be made in this case. Several centuries earlier, this man presented and was described in a book that I inherited from my grandfather called the Anomalies and Curiosities of Medicine. I’m sure Dr. Elias will be very interested in paging through that book. But there are many examples of things that we know nowadays that were rare diseases.

One of the things I came across in this book, which was published in the 1800s, recounted this story of a man who was known as the ossified man. You can see there that he was described as having ankylosis of the articulations. It was very obvious when one just zoomed in on the slide from the ossified man that one could identify his abnormal toes in valgus and shortened as was just beautifully described. So that leaves us in no doubt that this man suffered from FOP.

So the first step in diagnosing FOP and the reason we’re passionate about this message is that one should not do a harmful procedure that is our first oath and one that is easy to inadvertently incur harm for a patient, if one doesn’t know about FOP. If one knows about the toes of FOP, it’s very much easier to avoid this harm. So the reason we say that is when you do a biopsy, if someone does a biopsy on FOP muscle, the end result is ossification, increased ossification in the area that was damaged and that muscle that instead of being replaced with muscle again, will be replaced by cartilage and then bone, as you’ll see when we talk about the pathophysiology. So it’s for this reason that if any trauma to any muscle in the body can result in ossification of that skeletal muscle.

Interestingly, ocular muscles are not involved, the diaphragm and the heart are not involved, intestinal muscles are not involved, but every other muscle in the body can become ossified and develop heterotopic ossification leading to the destruction of the function of that muscle. So for instance, a mandibular block can lead to ossification of the masseter muscle and locking the jaw as we described with the hamburger and as Dr. Elias has described with the removal of that tumor and the humerus, that set of a cascade of severe heterotopic ossification which led to immobilization in her patient’s case of many joints.

Here you can see an example of a child who was immunized intramuscularly and this led to ossification of the right hip. You can see how that hip is locked in and tethered by a bony bridge analogous to the humerus that was earlier described. This is locked onto the pelvis and that child will never ever move that hip again, not an inch.

Ellen Elias, MD: One of the other stories I wanted to discuss for a minute. As Dr. Scott mentioned, the muscles anywhere can be impacted and can present with this painful process where you develop ossification. We call that a flare. So it commonly can be on the torso, can be on the long bones, but there are also muscles internally that can be impacted as well.

One of my patients developed a flare, a painful lesion of the iliopsoas muscle in the right side of the pelvis. And the presentation of this pain really mimicked acute appendicitis. The surgeons were wanting to do surgery because they thought this child had a ruptured appendix. And I said, “Wait, stop. No.” This child has these abnormal toes, had a molecularly proven variant in the gene causing FOP, which we’ll discuss in just a moment.

But on a CT scan, we were able to appreciate heterotopic abnormal ossification of this iliopsoas muscle and we’re able to treat that child with pain medication and steroids that treated the symptoms of right lower quadrant pain. Save that child a surgical procedure that could have been absolutely devastating and lead to the horrible ossification of all the surrounding tissue and joints that might’ve occurred had a surgical procedure been done.

So making this diagnosis early and correctly is so important to avoid all kinds of trauma that might induce heterotopic ossification.

Pathophysiology

Christiaan Scott, MD: Indeed. And by now you must be asking yourself, how does this all work? How does it happen that the body suddenly takes healthy muscle and makes bone from it or replaces it with bone? And you’ll have noticed as well that all the young people that were presented with lumps on the back of their heads and on the upper backs. So what this reflects is the fact that the new bone that is being formed is being laid down in the same way as the original embryonal skeleton was laid down and this is because of the influence of the bone morphogenic proteins. In the case of FOP, there’s a receptor called ACVR1 or ALK2, and it’s a mutation in the gene coding for this protein, this receptor, that has undergone a mutation and as a result of this mutation, the receptor doesn’t function properly and tends to be hyper responsive and to send more BMP signaling. So signals for a skeleton to be formed when there is no need to be building a skeleton.

So that’s really at the heart of the FOP pathophysiology. This slide tries to demonstrate that. There is normally in panel A, there’s a normal ACVR1 receptor. If the BMP ligand binds to that, there’s intracellular processes that result in the nucleus in expression of endochondral ossification genes as you would need to be able to build a new skeleton.

In the normal, in panel B, Activin A normally binds to the receptor. In the case of Activin A binding the receptor, it regulates inflammation genes. So it’s got all kinds of roles in controlling inflammation. But when the ACVR1 gene receptor is mutated or it was incorrectly formed as a result of a mutation, that you can see in panel C, then the BMPs and the activins can bind to this and both cause endochondral ossification of genes. And so you get this excessive stimulation of genes, of bone expression and skeleton building which results in the clinical picture of FOP.

I don’t know if you want to add anything there, Dr. Elias.

Ellen Elias, MD: I was just going to just add, you explained it quite nicely, that the whole production of bone is a very, very complicated multi-step pathway, which starts with a receptor being activated in the cell membrane, leads to an activation of a gene cascade, which then stimulates the nucleus to produce these genes that lead to bony formation. So it’s this abnormal ACVR1 receptor. There’s one specific mutation called the common mutation, the R206H variant, which is seen in the vast majority of patients that leads to a patient having FOP.

There are some other very, very rare variants that can cause a slightly different presentation that’s more severe. But this is the common variant that can be seen with a simple blood DNA test, once you suspect the diagnosis. Having identified this pathway and where the problem is once you know that you have the ability to develop drug strategies, that you can prevent this whole cascade from being set off in an abnormal way. That is one of the most exciting things about this disease which has come down the pike for patients.

So I just wanted to mention a word about the genetics of FOP and how does a person end up having a variant in this ACVR1 gene? Well, there is this common variant, the R206H variant, that almost all of the patients have. So many patients with this end up having this change because of a new out-of-the-blue variant that has happened just for the child. In genetics we call that a de novo variant.

But once a person has this variant, it is possible that it could be passed on to future generations. There’s a genetic mechanism called autosomal dominant inheritance where if a parent carries a gene change, there’s a 50/50 chance of passing it on to a child. You cannot always predict how severe the problem might be from having that gene change. Only that there is a 50/50 chance of passing it on once a parent might have this change. That has been seen in families with FOP.

Christiaan Scott, MD: Thank you indeed. I just wanted to focus on one other aspect which also informs the therapeutic pathways as we’ll see a little bit later. And that is that people with FOP have been shown to have a primed innate immune system. They have at baseline more pro-inflammatory monocytes and higher levels of pro-inflammatory and myeloid cytokines. So when one induces trauma or infection and that triggers the immune system in a person with FOP that could result in a clinical flare-up as was described where there’s a lesion, clinical lesion of pain and swelling that will eventually potentially result in the formation of bone. That system of damage-associated molecular patterns and pathogen-associated molecular patterns being recognized by the immune system, which is already primed to be more responsive than in people without FOP. That leads to recruitment of these inflammatory cells to the area and that they all participate in the milieu that causes the activation of the tissue-specific osteoprogenesis that lead to heterotopic ossification.

As was pointed out, there are many places along this pathway, this complex pathway of bone formation where we are able to consider intervening in specific ways. So I’m just going to zoom in on that slide. On the first step, as you can see there, the inflammatory component lends itself to being managed or abrogated by glucocorticoids and non-steroidal anti-inflammatory drugs. We know by the way that using these don’t stop bone formation in the end, but they might reduce the duration and intensity and painfulness of a flare.

Marcell inhibitors have been used in the past as well. Again, not totally effective in controlling heterotopic ossification, but at least providing some relief for that initial phase.

There are then other modalities that are being investigated. We mentioned Activin A and Garetosmab for instance, is an Activin A antibody that works against that. There are ALK2 or ACVR1 receptors such as blockers, receptor blockers such as Saracatinib that are being investigated and intervening in different places in this pathway. You also see a role for rapamycin there.

Further down the pathway, once there’s been angiogenesis and a fibroproliferative lesion that has formed, there’s the opportunity to intervene in the formation of the chondrogenic lesion or the transition from a chondrogenic lesion to a bone lesion by using a retinoic acid receptor antagonist such as Palovarotene, there are many opportunities to intervene in this very complex bone formation pathway.

Dr. Elias, if you want to just talk slightly more about the course of FOP and the clinical scenarios as it progresses through the patient’s life.

Ellen Elias, MD: Of course. I just wanted to say one word about the Palovarotene that you mentioned in the previous slide. Palovarotene was approved by the FDA for use in children. So it’s the only medication, after recent studies were done, showing that it seemed to be effective in reducing heterotopic ossification. The FDA approved for its use in patients. It’s a medication that’s a retinoid, and so it has side effects similar to other retinoids, so you have to be careful in using it. I think we’re going to talk about that a little bit more later.

But in terms of how FOP presents in children and then across childhood, this is a condition that you can tell right from birth that there’s something a little bit unusual with how the toes are formed. Sometimes you can see nodules of the posterior scalp, but these are less common in my personal experience with FOP. What I have seen instead have been these unusual lumps that are forming mostly on the torso and the long bones.

These start sometimes during the first 10 years of life, the first decade that children will have what we call their first flare. Then these can be precipitated by an intercurrent illness. The child will get a viral infection or a strep throat or they might have an injury, they might be active in sports activities and injure their soft tissue. Sometimes it can be as innocent as getting an intramuscular vaccine.

So as a pediatrician, I’m a strong proponent for vaccinating children and preventing horrible, terrible illness. Now that we’re seeing in this country an epidemic of measles in unvaccinated children, the importance of vaccinating children comes up. But sometimes even something as benign as giving a child an intramuscular vaccine can precipitate a flare. So we’ve developed ways in some vaccines that have been proven efficacious to give as subcutaneous shots rather than intramuscular shots. We can safely vaccinate young children that way and prevent them from developing flares from their routine childhood vaccines.

Then as patients get older and they get into their second decade of life, and in my experience, puberty plays somewhat of a role in this because what I have seen is that the frequency of flares and the intensity of flares really seems to go along with timing of growth spurts that children are having as they’re going through a normal pubertal process. So that they can develop progressive deformities in joints that have become involved with heterotopic ossification, which can limit ability to ambulate.

If the ossification is involving the chest wall, it can have significant impact on pulmonary function. So children can have significant issues if they get an intercurrent pneumonia or upper respiratory tract infection can have significant issues with their ability to clear those infections. And those infections themselves, the inflammation from that, can precipitate further pulmonary function decline.

So by the time you get into your third decade of life, your skeletal abnormalities can be really quite pronounced and extreme and land you in a wheelchair.

Christiaan Scott MD: Indeed, that progression that’s been shown is quite linear in terms of there’s a score known as the CAJIS score, C-A-J-I-S, cumulative analog joint involvement score. That just measures how many joints are involved over time and it’s a fairly linear process of deterioration of limitation that happens over the life course until they’re in the third decade, people are really severely disabled.

Just to give some faces to the clinical picture, this is a young girl that I looked after in South Africa, or at least I wasn’t her primary caregiver. I knew her from South Africa and she had severe chest restriction and actually at a very young age died of asphyxiation probably related to the use of burning fossil fuels in the home. But it shows the vulnerability of the respiratory system in these children, especially when the thoracic cage is severely limiting lung expansion.

This young man demonstrates the fact that children with FOP are at high risk for falls. That’s why he is wearing this helmet, which our occupational therapists provided for him. He’s a very busy child as you can see from his background, dinosaur and railway tracks and everything, but he was unable to lift up his arm. So in children with FOP fall, they have no way of reaching up to protect their head or their face and they fall straight down and could develop potentially severe head or neck injuries. And indeed, that unfortunately is not an uncommon situation that involves.

I’ve seen a number of people with FOP who have had cervical fractures broken their necks essentially, and who’ve also had skull fractures or orbital fractures from falling straight down and being unable to protect themselves.

This slide shows just the spectrum of the disease. This is a young 5 or 6-year-old girl sitting on the lap of someone in her mid-20s and you can see the limitation progressing. The young girl is still ambulant able to run around. Her arms are limited, but she functions by running around. The lady in her 20s is in a wheelchair, not all the time she can still move one of her knees and one of her hips and is able to move around, but you can see that her arm is also locked in position. But the man next to them is in his early 60s at that point and he’s completely immobilized, unable to walk at all, even with support. He’s unable to move essentially any part of his body except very minimal movements in his wrist, which he uses to control his motorized wheelchair.

Now this is your specialty, Doctor Elias.

Ellen Elias, MD: Right. So I wanted to spend a couple of minutes just describing the medical complexity that one might see in a patient with FOP. Again, as younger children, they can still be quite active. It’s important to protect them. I talk about no trampolines, really being protective so that kids… you can try to limit injuries as much as is reasonably possible, but this is a disease that progresses as kids get older and even no matter how careful you try to be, they’re still going to be progression of the disease.

What that looks like in the age that that looks like can be variable and is quite unique patient to patients. So it’s really important to have a kid who loves sports and wants to participate in them. But if they really start to become more and more involved, more and more painful flares, sometimes you have to intervene and try to help the child be more comfortable and not have as many recurrent flares as they’re starting to show.

So feeding problems we’ve already mentioned a couple of times, and these can be multifactorial. So there can be progression of jaw function where you’re just not able to open up your mouth very well. There can also be physical limitations in a child’s ability to feed themselves if they’ve lost the capacity to raise their arms or get the food to their mouths. Some of my older patients actually get to the point that they need to be fed by a parent or a caregiver.

The respiratory problems are something that really is important to think about trying to prevent respiratory infections that we can prevent. So it’s important to give these patients flu shots, but we have a protocol for giving flu vaccines subcutaneously rather than intramuscularly to prevent flu infection. If anybody is around as a contact who gets another viral infection, they need to stay away from your FOP patients and protect them as best as you can from exposure.

There was a lot of controversy and conversation about giving COVID vaccines and COVID is a terrible illness that can cause severe respiratory disease. So the FOP Society discussed giving COVID vaccines in a place where a person already has ankylosis. So you’re not going to make that so much worse.

I talk a lot about never smoking near a child who has FOP and if the parent is a smoker or grandma’s a smoker, they need to never do that near a child with FOP. Then there are ways to treat the painful flares that I think we’ll talk about in just a moment.

I wanted to spend a second talking about school issues and related services that we can do for our families because if you have a child with medical complexity, they might be missing a lot of school. It’s going to be difficult for them to get around a junior high school or a high school, especially if they’re in a wheelchair. We have to limit physical education, gym classes, especially for the younger kids. Contact sports where they might get injured. So we write a lot of special letters for that.

We have medical plans in place for our patients. Many of the patients who aren’t too significantly impacted yet the younger kids have 504 plans that allow them to just have extra time to get from class to class so that they’re not in the hallway when the hordes of elephants are potentially going to injure them as they get from class to class.

We can do a lot of work online. They can have friends who take notes for them. They can dictate the answers to their responses instead of having to write things down. There are lots and lots of common sense school accommodations that can help children have a better quality of life and a better educational experience.

In terms of therapies, sometimes I use physical therapists to help and occupational therapists to help figure out how accommodations can be made for the child to have them be more successful with their activities. So if a child has this diagnosis, you can plan and help prevent illness, treat illness, give them appropriate nutrition and deal with the issues that arise in school.

Christiaan Scott, MD: And as you said at the bottom of your slide, that can only happen if you have the right correct diagnosis from the start. So I think you’ve covered most of the complications that are in this slide. Scoliosis, restrictive lung disease, pneumonia, respiratory complications, jaw ankylosis and dental problems. I can just mention we have specialist dentists in the FOP world who specifically look after dental problems. As you can imagine, people have great trouble brushing their teeth or even opening their mouths to allow someone else to brush their teeth. So this is a real problem and especially early on in order to prevent masseter muscle dysfunction or ossification. Pristine dental health is of primary importance. We talked about falls and fractures as well.

Most people, the mortality from FOP is mostly related to the cardiorespiratory problems that develop, that we’ve spoken about. The restriction of the chest wall leading to pulmonary insufficiency and pulmonary hypertension. But falls and a range of other complications are obviously also important. One of the things that must be mentioned is the complications of general anesthesia.

The people with FOP have extremely limited mouth openings, A, as we’ve stressed several times, but they’re also unable usually to extend their necks. So anesthetic airway is a particularly dangerous situation for these people with FOP. Anesthetic is not to be undertaken without the advice of specialist anesthetists who can do fiber optic awake intubations, for instance.

I’ll also let you know that through the International FOP Association you can get in touch with anesthetists who have a special interest and who specialize in the anesthetic administration of people living with FOP. It’s an absolutely critical and dangerous undertaking for children or adults to be anesthetized when they have FOP.

Just touching again or just pulling together all the opportunities for looking after people with FOP, it’s critical to connect people to patient support organizations such as the International FOP Association. Associations like this can have banks and toolkits of physical aids that can help people with FOP do the basic tasks such as self-care and eating and combing their hair and going to the toilet, et cetera. Those things are all available on the website. There are talks on immunizations as Dr. Elias had spoken about. There’s a specific talk on managing vaccinations in children with FOP critical not to avoid harm. So no biopsies, no intramuscular injections, and no non-essential surgeries. So that story of the child, who would’ve potentially had a not indicated appendectomy is one that should stick in the forefront of your mind.

There are situations where people with FOP need essential surgery, but it needs to be an absolute last resort to go to surgery for this and then only with appropriate anesthetic support and one can also avoid harm by improving mobility support, wheelchairs, walking aids, et cetera, to prevent falls.

There are some new medical therapies that are on the horizon and one that has been approved, as was mentioned, Palovarotene is approved in Canada, the USA and Australia for the treatment of FOP. That’s a whole talk on its own. But there certainly are opportunities to help people with FOP today that they weren’t a couple of years ago.

There are also a number of clinical trials enrolling newer agents or different agents in the pathway of FOP. If you make the diagnosis and make the referral, your patient could have the opportunity to participate in a clinical trial depending on where they are.

Then we’ve spoken about dentistry, anesthesiology, and we haven’t mentioned audiology, but people with FOP are prone to deafness. We recently held an FOP meeting in South Africa where we invited around 30 patients from all over Africa to come. We did hearing screening for all of those 30 patients and every single one of them had a hearing deficit and could benefit from hearing aids.

So here’s a question for you. Do you think… This is a bit crazy, I was talking about a rare disease for so long and trying to get general pediatricians, orthopedic surgeons and the like to recognize and understand FOP. Well, I think we can make a difference.

I should have mentioned at the beginning, I’m the medical director of an organization called Tin Soldiers, but in actively looking for people with FOP and through doing talks such as the one we are giving at the moment, and by raising awareness around FOP in specific groups of people who are likely to see children with FOP, Tin Soldiers has managed to diagnose 77 patients in just two years, just by educating people and by doing it in multiple languages in Russia and Africa, in Asia, in South America, in Australia. These are 77 people who have been diagnosed who had, almost without exception, been looking for a diagnosis for a number of months or years. So it can be done.

It’s an important note to finish on. Just before I finish, it’s important to recognize that if you need any additional support, you can go to the International FOP Association website, which is listed there, and you can empower yourself to be able to help anyone that comes into your office who might have FOP and eventually perhaps someone who does have FOP.

So on a positive note, the law that I showed you, right at the beginning, the Brazilian law, which was given in Portuguese, is a law around FOP as I pointed out. But what it does is it makes it mandatory for every pediatrician or every doctor in Brazil who examines a newborn baby should examine the toes of a child with FOP. And it creates not only that imperative, but creates a payment mechanism for people to be recompensated for doing their basic screening or including it in their screening. And also for the costs of any referrals that come out of that screening to be covered by the national health system.

So that’s an important law which was passed by my colleague and friend. Which was introduced into the Brazilian government by my colleague and friend, Dr. Patricia Dulli, who’s a dermatologist in Brazil, who managed to raise awareness to the extent which she could get this law passed in Brazil, which is truly astonishing. But it shows you that very basic neonatal screening is probably one route to identify everybody living with FOP.

On a personal note, this is my son, when 2010 and now, or last year in 2024, time goes so quickly, it’s urgent that we identify people with FOP as young as possible. As Dr. Elias has pointed out, there’s so many things one can do to assist people not only in living a better life, but actually nowadays to manage and treat the condition.

It all starts by just a simple investigation of looking at the toes, a dream for any clinician, a test that doesn’t actually require anything except the knowledge that the test should exist. Dr. Elias, I don’t know if you want to say some parting words.

Ellen Elias, MD:

Thank you. So I think that as pediatricians seeing children from early infancy and onwards, we can have an enormous impact for the health and wellness of our patients. Even just making one diagnosis like this, you might just see one patient like this in your whole career, can make such a huge difference for that child and their families to prevent harm and to have correct information given to the family. It can just be the most important diagnosis you ever make.

So there are centers around the country that treat children like this so you don’t have to be doing this in isolation and ways to contact people who are experts and have experience in this all over the US.

As Dr. Scott mentioned, there are clinical trials looking at newer drugs that hopefully will be effective and not have as many side effects. So I’m just hopeful for the very first time over the past couple of years for my FOP patients that the future will lead to great advances in their care.

Christiaan Scott, MD: Thank you. I think we can leave it there. That was beautifully said.

Consider Rare: Suspecting and Diagnosing Fibrodysplasia Ossificans Progressiva (FOP)

Patrick McKiernan, MD and Nadio Ovchinsky, MD

*Consider-Rare-FOP-Slides

IFOPA Resources

FOP Symptoms

Preventing Misdiagnosis

FOP FAQs

Additional Resources