Robert J. Pignolo, MD, Professor at Mayo Clinic, Rochester, MN, discusses fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by the organization of heterotopic hard tissues within the soft tissues, such as ligaments, tendons, and skeletal muscle.

 

 

Transcription
My name is Bob Pignolo, and I’m a professor of medicine at the Mayo Clinic in Rochester, Minnesota. I’ve been working on basic translational and clinical research on FOP, as well as patient care and management for over two decades.

FOP or fibrodysplasia ossificans progressiva is an ultra-rare genetic condition whereby heterotopic ossification, or ossification outside the normal skeleton, progressively occurs with the result of ankylosing joints and over time, making movement impossible. FOP is caused by a single base pair mutation in the ACVR1 or ALK2 gene. About 97% of patients have the so-called classic mutation, and about other 3% have variants.

The disease is very progressive. It’s precipitated by these exacerbations that we call flare-ups, and flare-ups can be precipitated by injury, by viral infection, by muscle overuse. There are certainly precipitating causes, but in about 50% of patients, their progression is spontaneous.

The Challenges of Diagnosing FOP
Patients with FOP are diagnosed at about a mean age of five years old. Often, the diagnostic journey is, unfortunately, a misdiagnosis, but the diagnosis can be made by recognizing two hallmark features. One is abnormal or shortened first toes, and the other feature is these inflammatory swellings that we call flare-ups, which ultimately resolve in extraskeletal bone formation. There are conditions that cause malformed or shortened first toes. There are some conditions which can result in lumps or bumps on the body, but that combination of the two is really unique to FOP.

The definitive diagnosis is still a clinical one, and that is the shortened and malformed first toes and these inflammatory swellings that usually occur early in life, either on the head, neck, or upper back. The changes in the first toes are the clue, and obviously, they’re present at birth prior to these inflammatory swellings that we call flare-ups. Beyond that, there may be some other clues because of some of the prenatal skeletal malformations, including fusions in the cervical spine.

Some newborns and children early in life, as they attempt to crawl, often are unable to do because one requirement for crawling is the ability to extend the neck to see where they’re going. Often, children with FOP, even before they have their first flare-up, have difficulty crawling or don’t even crawl, and they just one day stand up and begin to walk. That can be a clue.

They can have shortened thumbs, they can often have these little lumps or bumps on the scalp that appear and then suddenly disappear, and they’re dismissed. Those are the earliest signs of potential flare-up. Sometimes we can palpate clinically osteochondromas of the proximal medial tibias, and these are just these little bumps near the knee that can be palpated. They’re completely benign, but sometimes, when they’re a little bit more prominent, those can be detected on careful clinical examination. Of course, as the clinical evidence that something is not right and is beginning to suggest FOP in those countries where genetic testing is available, often we also do a confirmation of the condition by DNA sequencing.

Advice for Newly Diagnosed FOP Families
My advice for newly diagnosed families would be twofold. One is, have your primary doctors refer you to an expert in FOP, and there are centers of excellence in the United States and, frankly, around the world. My second high-level piece of advice would be to get connected to the community through the International FOP Association, through your country’s national patient organization, if not in the United States. I think that combination of initial steps will not only give families an understanding of the disease course and what to expect, but also, which I think is equally as important, get connected to the community of other patients and families for support and for resources.

Managing FOP Patients
Up until recently, the management of FOP was really either preventive or targeting symptomatic relief of these flare-ups that I described. But now there are a number of ongoing clinical trials. We have the first approved medication, at least in the United States and in Canada. We’re beginning to move in the direction of treatments beyond symptomatic treatment. Our standard of care has been and continues to be symptomatic relief using high-dose steroids, non-steroidal anti-inflammatory agents.

But now we really have the opportunity to start to use agents that hopefully will change the natural history of the disease. The first FDA-approved drug is a retinoic acid receptor agonist called paliveratine, and it targets the transition of lesion formation requiring a cartilage template before endochondral bone formation occurs. Currently, clinical trials are looking at targets that are more specific to the etiology of FOP, including small molecule kinase inhibitors that target the mutated receptor, a monoclonal antibody that targets the ligand to the mutated receptor.

I think we have hope for the future that treatment of FOP will become more target specific, and hopefully, again, as I said earlier, some of these treatments would change the natural history of the disease.

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