My patient with a rare condition should have formed a ‘second skeleton.’ Why didn’t he? | Medical Mystery

Outwardly, there didn’t seem to be a reason for me to see Andrew Davis. As a doctor who specializes in treating and researching fibrodysplasia ossificans progressiva (FOP), a rare and catastrophic genetic condition that causes people to grow a “second skeleton,” most of my adult patients have clearly visible disabilities: many are in wheelchairs, joints stiff or firmly locked.

But Andrew, at age 21, walked into my office 15 years ago with “some stiffness” in his neck — and that was it. So why was he here, telling me he had been diagnosed with FOP?

In 2006, my colleagues and I published our discovery that FOP is caused by the smallest imaginable mutation in a person’s ACVR1 gene, a single genetic letter changed out for another at a single location in the vast span of DNA. Since ACVR1 helps determine the fate of stem cells, making it a critical component for growing the body’s skeleton, the mutation acts as a short circuit for extra bone formation.

Characterized as growing a “second skeleton,” what actually happens in FOP is the body’s muscles, ligaments, and tendons slowly turn into unwanted plates of bone — all over the body. This can result from muscle inflammation, fatigue, or even just typical bumps that every child experiences growing up.

Symptoms can begin in children as young as 2. Almost everyone with FOP requires a wheelchair by 30. Usually in their 50s, most patients’ bone growth is so extensive that it restricts their ability to breathe normally and results in heart failure or fatal respiratory illnesses.

Such was the case for Carol Orzel, the first patient I ever saw with FOP. When I met her in 1984, she was in her mid-20s, witty, charming, and unforgettable. She stayed that way the entire time I knew her, a tireless advocate for people like her. A year after her 2018 death, Philadelphia’s Mutter Museum granted her final wish, to continue her devotion to raising awareness of FOP by displaying her skeleton permanently. It’s a testimony to the difficulties and resilience of people with FOP.

Presently, there is no cure for patients like Carol. Removal of new bone can make things worse, akin to cutting off the mythological hydra’s head, only to have two grow back. It’s estimated that one in a million people around the globe are born with FOP.

But developing an FOP cure could help untold millions, as it would be the key to the kingdom of unwanted bone growth that can occur in more common conditions—athletic injuries, hip replacements, strokes, war wounds, even calcified heart valves or hardening of the arteries.

Andrew played baseball and roller bladed as a child, with the predictable bumps and bruises along the way. But he never grew the extensive collection of unwanted bones associated with FOP.

One morning, however, after graduating high school, Andrew woke up with a stiff neck. Swelling extended from his collar bone to his ear on the right side. Initially diagnosed with fibromatosis, a benign growth, Andrew had the mass removed and recovered without any new bone formation. But Andrew’s local doctor (who eventually referred him to me) noticed that he had one of the distinctive signs of FOP: shortened curved-inward big toes. A genetic blood test later showed that Andrew had the classic FOP mutation.

So Andrew was an otherwise healthy 21-year-old whose genetics said he should have had a lot of extra bone formation. He was well when I saw him, and he remained well five, even 10 years later.

My colleagues and I started to believe that there had to be something shielding Andrew from growing a second skeleton.

And sure enough, genetic sequencing showed that Andrew had two genes affected by mutations: The one already detected in ACVR1, and a pair in the MMP-9 gene. One of the mutations in the MMP-9 gene impaired its ability to do its job: Bone formation and inflammation management.

So if the mutation to ACVR1 is the explosive packed in the FOP bomb, MMP-9 is the fuse. MMP-9‘s mutation cut the fuse: Andrew’s body never had a huge inflammation response, and the FOP bomb never exploded.

While Andrew’s genetics protect him, that is obviously not true for others with FOP. But because of the clues from Andrew unique case, we believe he showed us the way to help the others in the future, not only with FOP, but with more common forms of unwanted bone formation.

A common inexpensive antibiotic, called minocycline, inhibits MMP-9. When tested in mouse models of FOP, it stopped bone formation in its tracks. But, people are not mice. Hopefully, a clinical trial using minocycline is not far off, if funding can be secured, so that we can know for sure whether an improbable genetic clue from one patient who landed, unexpectedly, in front of us can be used to spread his good luck to others.

Frederick Kaplan is the Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine in Orthopaedic Surgery at the University of Pennsylvania Perelman School of Medicine.