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Fibrodysplasia Ossificans Progressiva: Before You Biopsy, Look at the Toes

Christin Melton, ELS, CMPP
Published Online: Tuesday, Mar 03, 2015

At first glance, a baby born with fibrodysplasia ossificans progressiva (FOP) appears no different than any other baby. Stubby, crooked big toes are initially the only clue to a progressive genetic disease that gradually transforms fascia, ligaments, muscles, tendons, and other soft tissues into bone.1 This process is called heterotopic endochondral ossification (HEO). An estimated 1 in 2 million infants are born with FOP.1 The disorder is so rare that physicians often fail to appreciate the significance of those congenitally malformed great toes until a child develops the other hallmark of FOP: painful soft-tissue swellings on the head, neck, chest, or back.

The swellings begin to appear within the first decade of life and signal the start of active ossification. Dr Frederick S. Kaplan, The Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine and chief of Molecular Orthopaedic Medicine at the University of Pennsylvania School of Medicine, has dedicated most of his career to studying FOP. He urges physicians to “take a very careful look at the toes” of any young child who suddenly develops tender, often migratory, swellings on the face, neck, or torso. “Nearly 90% of people with FOP are originally misdiagnosed with aggressive fibromatosis or cancer because doctors fail to examine the great toes or fail to recognize their critical relationship to FOP,” says Kaplan.

The lumps, which are sites of inflammation, may arise spontaneously or in response to even minimal trauma to muscle tissue.2 Viral illnesses may also precipitate a flare-up. In an overzealous inflammatory response, the body dispatches cells to destroy the damaged muscle tissue. Normally, the cells would cease their attack once they had consumed the damaged tissue, but in people with FOP, the cells switch their target to healthy muscle tissue nearby. Mesenchymal stem cells gravitate to the site of damage, where they begin creating bone—completely normal bone in a completely abnormal location.

Over time, the joints and limbs of people with FOP become locked in place. Although complete loss of mobility often takes decades, a single joint can freeze overnight. Kaplan says survival varies with FOP, but that historical studies suggest that the median lifespan of someone with classic FOP is in the mid-fifties. He notes, however, that “many people with FOP live well beyond this and lead very productive and fulfilling lives despite having substantial physical impairments.”

It takes an average of 4.1 years from initial symptoms and consultations with 6 physicians before an individual with FOP receives the correct diagnosis.2 Delays in diagnosis or misdiagnosis may have serious consequences for patients. As Kaplan explains, “Biopsies of lesions and bumps can lead to rapid and explosive worsening of FOP.” In fact, any medical procedure associated with soft-tissue trauma, including biopsies, intramuscular injections, and surgery, can provoke a flare-up. A 2005 global survey of people with FOP found almost half had undergone medical interventions that triggered bone formation and caused permanent loss of mobility.3

Although many people have never heard of FOP, the disease is not new. According to Kaplan, “The first documented patient who we are certain had FOP was reported by John Freke in the Philosophical Transactions of the Royal Society in 1740.” Freke told the case of a 14-year-old boy who had coral-like protrusions that arose from every vertebra, and whose every rib was fused together until his ribcage resembled a bone bodice encasing his torso.4 What happened to that boy has been lost to history, but what happened to another boy with FOP named Harry Eastlack is well known.5

In 1938, 5-year-old Eastlack suffered a broken leg that stubbornly refused to heal. Physicians were perplexed when extraneous bone developed at the injury site and his knee joint permanently froze. An operation to remove the excess bone from his thigh only stimulated more bone formation. By age 24, all of the vertebrae in Eastlack’s spine had fused together, and by his death at 39 years of age, all he could move were his lips. In the almost 200 years that elapsed between Freke’s patient and Eastlack, few had even tried to unravel the cause of FOP. And when Eastlack died in 1973, no one was actively researching a cure. Eastlack hoped to change that by donating his body to medicine. Today, his skeleton is on display at the Mutter Museum of the College of Physicians in Philadelphia, Pennsylvania, where it continues to yield clues to the disease that claimed him. Kaplan vividly describes the effects of Eastlack’s metamorphosis on his skeleton in “Fibrodysplasia Ossificans Progressiva: An Historical Perspective”4:

Sheets of bone cover Eastlack’s back. Ribbons, sheets, and plates of bone lock his spine to his skull and his skull to his jaw. Additional ribbons of bone join the spine to the limbs and immobilize the shoulders, elbows, hips, knees, and jaw. Thin stalagmites of bone launch themselves from his pelvis and thighs. His upper arms are welded to his breastbone by slender white bridges of bone that cross his immobilized rib cage. The extra layers of bone on the outside of his skull are a permanent signature of numerous FOP flare-ups at that site.
 
Much progress in FOP research has been made since Eastlack’s death. One person instrumental in that progress is Dr Michael Zasloff, an immunologist and geneticist. Zasloff was employed at the National Institutes of Health (NIH) in 1978 when he encountered his first FOP patient.6 Monica Anderson was 8 years old, and her mysterious condition had started 5 years earlier with a swelling on her knee. Surgical removal of the lump led to new bone growth and permanent immobility of the joint, just as in Eastwick’s case. Subsequent intramuscular injections spurred the formation of additional bone masses.

Zasloff’s mentor, geneticist Victor McKusick, reviewed the child’s medical history, examined her short, crooked great toes, and announced that she had FOP.6 Zasloff was intrigued. He sought referrals of patients with FOP, conducted tests, and amassed as much information as he could about the disease. However, the small number of patients and lack of tissue samples due to the inability to conduct invasive procedures hampered his progress.

One day, a woman with FOP named Jeannie Peeper came to see Zasloff about her condition, which set in motion a series of events that would transform FOP research. “In September 1987, I met Dr Zasloff at the NIH and was astonished to learn he knew 20 people with FOP,” Peeper explains. Zasloff provided Peeper with the other patients’ contact information, starting her quest to “learn more about FOP and each person [on the list].” She wrote to all 20 people and received 10 replies. For some, it was their first encounter with another person with FOP.

“These people inspired me to create a newsletter, the FOP Connection, to share the information about FOP that I was gathering from everyone,” says Peeper. The group continued to talk with one another about FOP and its effect on their lives. “This connection of people with FOP—sharing a common goal—sparked the need to incorporate a nonprofit organization to raise funds for FOP research,” said Peeper. The International FOP Association (IFOPA) was founded in 1988, with Peeper as its president.

That same year, Kaplan met Zasloff, who was then at the University of Pennsylvania,7 which coincidentally lies just a few miles from the museum that houses Eastlack’s skeleton. Kaplan had 2 patients with FOP, and Zasloff convinced Kaplan to help him form the FOP Collaborative Research Project at the university. Although Zasloff later moved on to other areas of medicine, Kaplan remained resolutely focused on FOP. In 1992, Kaplan and Dr Eileen Shore established the FOP Research Laboratory at the University of Pennsylvania.8 Today, they direct the university’s Center for Research in FOP and Related Disorders and are considered the world’s foremost experts on FOP.

It was inevitable that Kaplan and IFOPA would connect. In 1991, when IFOPA held its first official FOP family meeting with 8 families, Kaplan was invited. The meeting provided him with an opportunity to learn more about the natural history of FOP. Since then, IFOPA has held several more FOP family meetings and connected hundreds of people with FOP across the globe. “The combination of our IFOPA families’ countless fundraising and awareness efforts has transformed our 11-member pen-pal group into the leading international FOP association, with 12 sister FOP organizations in 18 countries,” Peeper says. The families that IFOPA brings together do much more than fundraising and advocacy—they contribute prediagnosis biopsy specimens, medical records, and DNA to the cause of finding a cure.

Securing grants to research a rare disease that few know much about is challenging, and IFOPA does whatever it can to support Kaplan, Shore, and other researchers dedicated to finding a cure or treatment for FOP. “Our IFOPA mission to fund FOP research while supporting individuals and families through education, public awareness, and advocacy has helped advance the knowledge and understanding of FOP,” says Peeper.

In pursuit of this mission, IFOPA was an early sponsor of the research behind a seminal discovery in 2006 that identified a single mutation in the activin A receptor type 1 (ACVR1/ALK2) gene as the culprit in FOP.9 “It took our team of researchers and collaborators more than 15 years of diligent effort to unravel the genetic cause of FOP, which had been shrouded in mystery for so long,” says Kaplan.

The heterozygous mutation they uncovered in the ACVR1 gene causes approximately 97% of cases. The remaining 3% of cases, which represent an atypical form of FOP, arise from an atypical mutation in the same gene. Kaplan says the ACVR1 mutation occurs spontaneously in 95% of people and is inherited in 5%; individuals with an inherited mutation have a 50-50 chance of passing FOP on to their children.

Further research has validated the group’s initial hypothesis that the ACVR1 mutation promotes increased activity along the bone morphogenesis pathway (BMP), which previous studies have implicated in the pathogenesis of FOP.10 Kaplan says, “The emerging insights into the mechanisms of action reveal at least 4 approaches to treatment or prevention of FOP:
  1. Blocking activity of the mutant receptor and its downstream pathway that causes increased BMP signaling
  2. Inhibiting triggers of FOP flare-ups
  3. Directing FOP stem cells to an alternative tissue fate other than cartilage or bone; or
  4. Blocking the body’s response to microenvironmental signals that promote the formation and expansion of FOP lesions.”
Kaplan lauds his team’s discovery of the genetic key to FOP as “a critical milestone around which much of the subsequent worldwide interest and activity in FOP has crystallized.” Whereas only a handful of groups were tackling FOP before 2006, today Kaplan is aware of  “at least 30 distinct venues, including university laboratories, pharmaceutical and biotechnology companies, and international government agencies…that are researching various aspects of FOP and are engaged in a worldwide effort to create meaningful treatments and a cure.”

Inspired by the growing interest in FOP research, IFOPA hosted its first FOP Drug Development Forum in November 2014. The forum “brought together academic researchers, biopharmaceutical companies, and patients from around the globe to collaborate on developing treatments for FOP,” says Peeper.

IFOPA and others in the FOP community are closely following the development of palovarotene, a drug being evaluated for FOP. Palovarotene is a retinoic acid receptor gamma (RARγ) agonist originally developed to treat emphysema. In preclinical studies, treatment with palovarotene after injury prevented heterotopic bone formation in a mouse model of FOP.11 Because the safety of palovarotene in humans had already been established in clinical trials of patients with emphysema, and because no treatments are available for FOP, the US Food and Drug Administration (FDA) allowed Clementia Pharmaceuticals to proceed straight to phase 2 clinical trials in patients with FOP. Trial sites include the University of Pennsylvania, University of California-San Francisco, and Necker-Enfants Malades Hospital in Paris, France, which are actively recruiting participants.12

Kaplan, a lead investigator for the trial, notes that “this is first double-blind, randomized, placebo-controlled trial in the long history of FOP.” The 2-part proof-of-concept study will use an adaptive trial strategy to determine the optimal regimen and dosage. Once the trial has concluded, investigators will review the data and decide whether to move forward with a phase 3 study. Asked whether he is hopeful that palovarotene will improve outcomes for people with FOP, Kaplan says, “There is hope in all therapeutic efforts based on sound scientific principles. We all have hope; now, we need data.”

Important Links

International Fibrodysplasia Ossificans Progressiva Association
http://www.ifopa.org
 
Emergency Medical Information and Treatment Guidelines
http://www.ifopa.org/living-with-fop-menu/treatment-guidelines.html
 
Palovarotene Clinical Trial
https://clinicaltrials.gov/ct2/show/NCT02190747

References

  1. International Fibrodysplasia Ossificans Progressiva Association. FOP fact sheet. http://www.ifopa.org/what-is-fop/overview.html Accessed January 30, 2015.
  2. Kaplan FS, Chakkalakal SA, Shore EM. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech. 2012;5:756-762.
  3. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005;116:e654-e661.
  4. Kaplan FS. Fibrodysplasia ossificans progressiva: an historical perspective. Clin Rev Bone Miner Metab. 2005;3:179-181.
  5. Angier N. “Bone, a Masterpiece of Elastic Strength.” The New York Times. http://www.nytimes.com/2009/04/28/science/28angi.html?_r=0. Published April 27, 2009. Accessed February 27, 2015.
  6. Zasloff M. The roots of the IFOPA and Monica Anderson. FOP Connection. 2006;19:1,9-10.
  7. Zimmer C. The girl who turned to bone. The Atlantic. http://www.theatlantic.com/magazine/archive/2013/06/the-mystery-of-the-second-skeleton/309305/. Published May 22, 2013. Accessed February 27, 2015.
  8. IFOPA. FOP research laboratory. http://www.ifopa.org/fop-laboratory.html. Accessed February 27, 2015.
  9. Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38:525-527.
  10. Shen Q, Little SC, Xu M, et al. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009;119:3462-3472.
  11. Clementia Pharmaceuticals opens clinical trial site in Europe for phase 2 study of palovarotene in patients with fibrodysplasia ossificans progressiva (FOP) [press release]. http://clementiapharma.com/wp-content/uploads/news/Clementia_20150112_English.pdf Published January 12, 2015. Accessed February 27, 2015.
  12. ClinicalTrials.gov. An efficacy and safety study of palovarotene to treat preosseous flare-ups in FOP subjects. https://clinicaltrials.gov/ct2/show/NCT02190747. Updated February 9, 2015. Accessed February 27, 2015.

Images

Classic abnormality of the great toes in a child with FOP. (Image courtesy of IFOPA)
Skeletal image of fibrodysplasia ossificans progressiva by Joh-co (talk · contribs) - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Fibrodysplasia_ossificans_progressiva.jpg#mediaviewer/File:Fibrodysplasia_ossificans_progressiva.jpg
Jeannie Peeper, IFOPA President and Founder (Image courtesy Daniel Burke Photography)
Eileen M. Shore, PhD, and Frederick S. Kaplan, MD (Image courtesy Daniel Burke Photography)


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