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CME / ABIM MOC

A Pediatric Conundrum: Can you Diagnose This Rare Bone Disorder?

  • Authors: Marelise Eekhoff, MD, PhD; Arend Bökenkamp MD, PhD
  • CME / ABIM MOC Released: 5/10/2022
  • Valid for credit through: 5/10/2023
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for pediatricians, orthopedists & orthopedic surgeons, hem/onc specialists, medical geneticists, and endocrinologists.

The goals of this activity are for learners to be better able to make an early diagnosis of fibrodysplasia ossificans progressiva (FOP) and to make appropriate care recommendations to patients.

Upon completion of this activity, participants will:

  • Greater competence related to
    • Diagnosing FOP
    • Recommending management approaches for patients newly diagnosed with FOP


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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated according to Medscape policies. Others involved in the planning of this activity have no relevant financial relationships.


Moderator

  • Marelise Eekhoff, MD, PhD

    Internist endocrinologist
    Amsterdam UMC
    Internal Medicine Section Endocrinology
    Amsterdam Rare Bone Diseases
    Amsterdam Bone Center
    Amsterdam, The Netherlands

    Disclosures

    Disclosure: Marelise Eekhoff, MD, PhD, has no relevant financial relationships.

Faculty

  • Arend Bökenkamp MD, PhD

    Pediatrician
    Amsterdam UMC
    Amsterdam, The Netherlands

    Disclosures

    Disclosure: Arend Bökenkamp, MD, PhD, has the following relevant financial relationships:
    Speaker or member of speakers bureau for: Kyowa Kirin

Editor

  • Walid Amara, MD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Disclosure: Walid Amara, MD, has no relevant financial relationships.

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Disclosure: Susan L. Smith, MN, PhD, has no relevant financial relationships.


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    For Physicians

  • Medscape, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 0.25 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

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CME / ABIM MOC

A Pediatric Conundrum: Can you Diagnose This Rare Bone Disorder?

Authors: Marelise Eekhoff, MD, PhD; Arend Bökenkamp MD, PhDFaculty and Disclosures

CME / ABIM MOC Released: 5/10/2022

Valid for credit through: 5/10/2023

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Activity Transcript

Dr Marelise Eekhoff, MD, PhD: Hello, I am Marelise Eekhoff, internist endocrinologist from the Amsterdam University Medical Center in the Netherlands. I will present this webinar together with my colleague Arend Bökenkamp, who is a pediatrician linked to our Amsterdam rare bone disease team. The title of the webinar is a pediatric conundrum. Can you diagnose this rare disorder?

Patients are often referred to our center late at an older age, even often misdiagnosed. But sometimes, things can go very differently. Just a few years ago, we had a very young patient who was referred to our multidisciplinary rare bone disease center. Arend, what did you find striking about this young referred baby?

Dr Arend Bokenkamp, MD, PhD: Yeah, this was a very special case, which I can't forget. It was a young girl who was referred to us at the age of about six months because of abnormal feet. The GP had noticed that she had bilateral hallux valgus, as you can see in the slide and on physical examination that was the only abnormality which there was. For the rest, it was a perfectly happy, healthy baby. The baby had been referred to a peripheral pediatrician and the pediatrician had made a photo of the feet and she had noticed that there was an abnormality with the first metatarsal, which led to hallux valgus and bilateral hallux valgus. In children, in babies that doesn't exist. It is very uncommon because hallux valgus, that's an age of elderly people who are wearing fitting shoes and in babies, I had never seen that before. So that was the reason of the pediatrician to do further diagnostics and then, refer the baby to our center.

Dr Eekhoff: Well, we have a question for you. What disease are you thinking of in this case, especially if no other features are present, than only hallux valgus? Well, in this case, you need to think about Fibrodysplasia Ossificans Progressiva or FOP where muscles, tendons, and ligaments are turned into bone. What are the criteria needed if you can detect this disease at this very young age?

Well, first of all, the malformation of the big toe, that is really classic in FOP and the classic FOP encompasses greater than 97% of the FOP patients, but only together with confirmation by molecular testing, the ACVR1 gene, as previously has been explained in other webinars. Mutation in FOP concerns the BMP, the bone major protein type 1 receptor, ACVR1 or ALK2. In elderly, the diagnosis can also be made on basis of the hallux valgus or a mis-formed big toe together with science of progressive heterotopic ossification. But genetic confirmation is also then recommended, if possible. In this young child, the disease progressive heterotopic ossification, usually starts at somewhat later age. Mostly between five and seven years. And here, it wasn't present yet. Arend, I will go over to you. How did the girl's story go?

Dr Bokenkamp: Yes. It was very striking. The pediatrician had found FOP as a differential diagnosis on internet and had sent in more molecular diagnostics. And in fact, the baby had ACVR1 mutation, common mutation in the Arginine 206 Histidine mutation. So, the diagnosis of FOP was made before the child had any complaints, apart from the hallux valgus. So to us, it was very important to explain the disease to the family and also give them information on how to handle it, in case the child would get into trouble. Because of course, we know normally children get all the vaccinations at this early age, and it has been shown that the vaccination in itself can produce a flare. So, we made clear arrangement with the other caregivers, with the GP, with the peripheral pediatric pediatrician about which vaccinations may be given. The subcutaneous may be given, but not the intramuscular vaccinations.

Also, we discussed with the parents what to do in case of a flare. Cooling medication. And the most important thing was, that they got our telephone numbers, so they know how to find us. In case there is any doubt on disease activity, they can contact us 24x7. So, this was very important for the family, to avoid manifestations of the disease where possible, to avoid unnecessary surgery and give good advice to the family and the treating physicians.

But, there was also a downside to this. And that was that, especially the mother became very concerned about the future of her child, which we really of course understand. Because, it's a very severe disease. She found it very difficult to let the child develop normally, have all the normal activities a little girl should have. I've been following her now for four years and she's growing up perfectly fine and hasn't had any trouble until now. Yes. So, this is my part of the story.

Dr Eekhoff: Thank you. The patients ask us about the flare-ups because she hasn't had one yet until already a few years. But the flares we explained are characterized by local swelling, redness, and pain. And that question was, are all flare-ups becoming bone. Well, that isn't. In 20% of the cases, the flare-ups doesn't turn muscles, tendons and ligaments into bone and that is difficult.

The next question of the parents was, whether you can predict which flare up in the future will become bone. Well, there's no marker known in the blood yet. But in early stage, at least within three weeks after flare-up, we found out that you can show the active bone formation already on an 18F sodium fluoride PET/CT, while you can't see any malformation on the CT yet, the PET can show it. Because fluorine can incorporate into the bone matrix only while the bone is active and you can even measure it. So, there is a possibility to show early during the flare-up, whether it's become ossified.

Arend, at which age can you perform an 18F PET/CT?

Dr Bokenkamp: Well, of course, this depends on the individual child, because it's important that the child doesn't get afraid when it's in the machine and also has to lie very still. And of course, you need someone who really knows how to bring in an IV line to give the tracer. So in general, I would think about five, six years of age. That's realistic. You're in our hospital. We even have some kind of a dummy pet CT where children can try, or the family can try, if the child can undergo the test easily, without blocking the machine. So this is ideal in our hospital.

Dr Eekhoff: Yes. At the next slide, we showed pictures of patients who had already for three weeks, an enormous, impressive flare-up of her whole thigh. But, on the PET, you see that only a small part of her upper leg was active and becoming bone. While you see on the right side, on the CT, no bone was visible yet. And we published a very nice paper where you can see how seven months later, the flare-up wasn't active anymore. After many, many treatments with prednisone and eventually the flare-up faded away, but only where the PET was positive bone had formed. So, there is a method to early show, the fate of a flare-up. And you can show whether it becomes bone, if necessary. We also found that nearly every patient, once the disease has become active, has some kind of effective bone formation. Heterotropic bone formation. Patients are not aware of that, but you can show this with a 18F PET/CT.

You can show the fate of a flare up if no, and you can show whether and where the activity of chronic bone formation in the body is. At present, there are no active medicines yet. For flare-ups, we advise immuno-suppressive drugs starting with NSADs. Second, if necessary high dose prednisone are given for flare-ups that are close to important joints. For this, we refer to the guidelines. You can see it on the slides, and it's important that you always contact a center of expertise to discuss the starting of the prednisone.

Happily, fortunately new developments are going on. A lot of efforts are being made to find effective medication. And as you can see in the next slide, there have been 2 studies already, which are still in the investigation to assess the efficacy. This one is palovarotene, retinoic acid receptor gamma agonist and garetosmab, which is an antibody against activin A, which worked well. But, there is further investigation for safety.

In addition, the known mTOR inhibitors like rapamycin are also an investigation. However, this takes place in Japan. We know it's going on. Also, we didn't hear much for many years now. Studies that are open and investigating new possibilities, medications and enrolling patients at the STOPFOP trial with a kinase inhibitor saracatinib, that has been explored in many studies before. And, other new kinase inhibitors have been developed and are now in study. The Falcon study and insights will start soon. So, there are many opportunities developing. However, the disease is very complex. So, more medication will likely be needed. Arend what has been the benefits of the early diagnosis in this patient? Can you comment on that?

Dr Bokenkamp: Well, the big benefit for this child is that the signs, which in general, people do not understand that's the soft tissue swelling with redness, which might initiate people to do diagnostic testing, to do biopsies and all kinds of unnecessary and even harmful things which will just activate the disease more and more. This can be avoided in this family. The parent knows that if it's redness and if it's swelling, if it's not an infection, of course, then it will be a flare-up of FOP. And then, they will discuss with us the methods to predict if that it will become an ossification. And very important, they can start giving NSAID, which is always useful and if necessary in a dangerous position of the soft tissues surrounding, also give steroids. But always in cooperation, in discussion with the FOP team. The other big advantage is that, there is a large team around this girl. Fortunately, she hasn't needed this yet. But, if in the future things go bad, we have the dentist, we have the anesthesiologist, we have all kinds of specialists in our team, who can help the child.

Dr Eekhoff: Yes. I can add that it is important. We always do the consulting together. She already had quite a seen quite a lot, also the dermatologist and the lung specialists. At least 15 different disciplines are needed to perform very good care for these patients.

In conclusion of this webinar, the take home messages of my colleague, and Bokenkamp, and myself are look for the malformed big toe, because this is a clue. Always think about FOP when you see this and perform further investigations. Once FOP has been diagnosed, try to prevent traumas. Whenever you have a question, look at the guidelines, but also discuss it with the expert centers. The very good message, as well, is new medication are in development.

Thank you to Bokenkamp. Thank the audience for participation. Please follow the evaluation questionnaire here after. Thank you very much.

This is a verbatim transcript and has not been copyedited.

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