New insights into rare-among-rare genetic bone disorder

I have been writing about conditions that cause out-of-place bone formation for over 10 years – since the discovery of the gene in 2006 for the rare bone disorder, FOP (fibrodysplasia ossificans progressive). But it was while interviewing geneticist Eileen Shore, PhD last spring about another bone disorder, progressive osseous heteroplasia, or POH, that it really hit me how much more rare POH is compared to FOP. About 850 people worldwide have been diagnosed with FOP in the last five decades. Contrast that to the fewer than 100 individuals with POH who have been identified around the world since Fred Kaplan, MD, a professor of Orthopaedic Molecular Medicine and renowned expert on these conditions, first described it in the early 1990s.

"That makes FOP an ultra-rare genetic disease and POH ultra-ultra rare," Kaplan said.

In disorders that cause out-of-place bone growth, the progression and stages of bone formation at a cellular level appear normal, but normal bone forms in the wrong place at the wrong time. POH is usually first noticed in babies with the appearance of small "rice-grain" particles of bone under the skin, a condition called osteoma cutis. In POH, the bone continues to grow deeper in the first layer of fat next to skin cells and progresses deeper into connective tissue such as skeletal muscle and joints. This can cause stiffness and stop growth in the affected bones, and for some patients, eventually rob them of their ability to walk, among other symptoms.

Cases of POH were initially recognized following FOP misdiagnoses – the condition actually differs from FOP in several ways. "In the early 1990s, after I had seen about 40 FOP patients, I coincidentally saw six patients who clearly did not have FOP symptoms," Kaplan said. "We knew this because their big toes were not malformed as it is in FOP patients, and in X-rays of POH patients, we saw that the extra bone growth looked lacy, while FOP scans showed more robust ribbons and sheets attached to existing normal bone, among other differences."

At the time, Kaplan and colleagues were hard-pressed to understand those salient differences. Curiously enough, when Kaplan was visiting his parents in Florida, he recalls having a "Eureka" moment while perusing the meat counter for a steak to grill for dinner. "The fat marbling in the Porterhouse steak looked very similar to the lace-like patterns of bone formation in my patients' fat tissue. I had seen biopsies from my POH patients showing bone arising from fat tissue under the skin and in the muscle, but the revelation occurred at the meat counter in the supermarket. That's when the anatomy, pathology, and radiology of POH came together for me." From there, it was back to Shore's expertise to figure out this genetic, molecular and cellular puzzle.

Kaplan and colleagues eventually named the condition POH. Although medical science finally had a term for this "new" condition, patients still had to find Kaplan – a connection that often came only serendipitously.

Christine Fennell's daughter was diagnosed with the disease at age 8, and is now a teenager. New Jersey-based Fennell is president of the Progressive Osseous Heteroplasia Association, and her husband Brian is a board member. "When she was a toddler, she had some bumps on her ankle and a large nodule on the outside of her right foot. These two signs caught my attention, but it took four more years to find out that she had POH," Fennell recounts. "We had gone down several different paths with different doctors, but finally we saw a young resident who had recently sat in on a seminar given by Dr. Kaplan. It was our saving grace."

Meanwhile, Back in the Lab…

Shore and colleagues investigate the genetic causes of POH and FOP and the cellular cues that cause normal and misplaced bone formation. "Our ultimate goal is to be able to develop treatments for these and other bone disorders," said Shore, a professor of Orthopaedic Molecular Medicine.

"With the identification of the mutated genes in POH and FOP in the last several years, we have been able to pinpoint the functions of these genes and what happens when they are mutated," she said. These basic studies are part of an overall translational strategy to develop drugs for POH.

In 2000, the Penn team discovered that POH is caused by a mutation that inactivates a gene for a key player in a molecular pathway that passes on chemical signals. When the gene's protein is produced at its normal level, fat stem cells in the skin eventually become mature fat cells. But, when the gene is mutated, smaller amounts of the protein are produced, which in turn cause the stem cells in the skin to receive the wrong signal and become bone cells. Shore investigates the source and identity of the cells that mistakenly turn into bone to identify the exact moment and cause in the stem cells' wrong-way development.

"POH research can also teach us about more common cases of out-of-place bone growth," Shore said. "Many of these cases are like FOP, with bone formation starting as cartilage cells, but many patients – such as those who've experienced trauma and burn injuries – can have bone that forms in the skin. We think this is because mistakes in common pathways that influence extra bone growth are similar in POH and other disorders."

For example, Shore says a protein called "hedgehog" is active in many of these pathways, and inhibitors of hedgehog activity are used to tamp down rampant cell replication in cancer. POH researchers are now collaborating with biotech firms to design clinical trials to test use of these hedgehog inhibiters to stop POH-related bone growth.

In the midst of the incremental steps of preclinical research towards a treatment for POH, I am reminded there are families behind all of the pathways and stem cells. Fennell says her daughter has been "pretty lucky" considering she is not unduly limited by the condition, but POH has affected her ability to play certain sports. However, there are many other children who have worse symptoms, with some needing a wheelchair in time.

"Finding a cure for POH is very important to my whole family," Fennell said. "My daughter has a 50 percent chance of passing on POH to her children. We're all working in our own individual ways to push research forward for every POH patient."

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