Imprisoned in bone

Disorder calcifies muscle, connective tissue

Ashley Kurpiel uses a golf cart to stay mobile

In this story: An irreversible choice Genetic clues Unnatural bone growth Changes as quick as overnight RELATED SITES

By Michele Dula Baum
CNN.com Health Writer

(CNN) -- At birth, short, malformed big toes are the only indication of the genetic disaster that is fibrodysplasia ossificans progressiva, or FOP.

Perhaps fewer than 2,500 people worldwide share the mystery of this disorder that slowly -- but sometimes as quickly as overnight -- immobilizes those who have it in a cage of bone.

"These people are literally imprisoned in a second skeleton," says Dr. Fred Kaplan, a University of Pennsylvania specialist in molecular orthopedics who has dedicated much of the past 10 years to finding the key to FOP. "It transforms muscles, tendons, ligaments -- connective tissues become sheathed in bone. It spans joints, locking them into place and rendering movement completely impossible."

In many ways, Ashley Kurpiel of Peachtree City, Georgia, is a typical 18-year-old. She shows off snapshots from a family vacation and proudly points out her boyfriend of 14 months, Shawn.

She is enthusiastic about starting college studies on the Internet next month, and plans to focus on a career in the computer industry. At one time, she had dreams of working with children, but the realities of her condition have made that increasingly unlikely.

"It gets to me that I can't dress myself or do my hair, but I remember that I could always be worse," she says.

Though she can still walk (the hips and knees of many FOP patients become locked by the time they are teen-agers), Kurpiel's most severe handicap was caused by a childhood misdiagnosis of infantile fibromatosis, a nonmalignant yet extremely aggressive tumor, in her right shoulder.

Doctors told her parents the tumor had spread too far to save the arm, and it was amputated, along with the shoulder joint and a portion of back and chest muscle. Ashley was not quite 3 years old at the time.

In actuality, the tumor was another early sign of FOP.

"Right after the amputation, my left arm started freezing up," says Kurpiel, who can no longer lift her arm above her head, but can still write longhand and manage a keyboard.

One of the heartbreaks of the disease is that any bump or trauma -- even something as seemingly insignificant as a vaccination shot -- can trigger a flare-up. Beginning as an inflamed, red and tender swelling, flare-ups are often the first real sign of the disease.

Eventually, the swellings subside, to be replaced by new bony growth. Such ribbons and sheaths of bone form bridges across the skeletal framework, building a new frame that often contorts posture as well as immobilizing those with FOP. Some are left in a perpetual standing position, while others may freeze hunched into a forward sitting pose.

"This is catastrophic beyond belief," says Kaplan.

Jack Wilson in his kitchen

Kaplan and other researchers continue to make discoveries about the nature of the disorder, which seems to be linked to a particular chromosome. So far, only one family -- a father and three children -- has been identified with multiple members affected. Others are randomly scattered throughout the world. Doctors peg the odds of a child being born with FOP at one in 2 million.

The mapping of the human genome is a great stride for scientists who are researching all kinds of diseases, and FOP also is yielding clues.

"What happens in FOP is children continue to make new pieces of the skeleton after birth," explains Kaplan. "The signal is not just 'make more bone.' "

Extra bone forms in a known pattern that echoes skeletal formation during fetal development. It starts at the head and neck and progresses down the trunk to the extremities, ranging from back to front.

To be able to identify a gene for FOP would truly be "the skeleton key," says the orthopedist.

Several proteins have been identified as vital for bone growth, including one called BMP4. "We know BMP4 is one of the terrorist agents that triggers new bone formation," says Kaplan. "We're working on therapies to limit the production of BMP4 in people who have FOP."

Promising research is being done in Philadelphia and elsewhere on a compound called noggin, which blocks BMP4, and an agent called squalamine, which comes from shark cartilage.

Squalamine inhibits the formation of blood vessels, a vital link to bone tissue growth. Similar research is ongoing with such substances, known as anti-angiogenics, as cancer therapy, since tumors also need blood vessels in order to grow.

Locating the precise gene for FOP can have far-reaching consequences, and not only for FOP, he continued, saying, "If you can figure out how to turn it off, you can turn it on."

Normally, the body breaks down and grows new bone all the time, focusing and speeding the process only to repair a break before settling into the routine of maintaining a skeletal system already complete.

In FOP, this system goes on overdrive. They need an "off" switch. But an "on" switch would be just as useful to grow new bone to replace that lost by accidents, tumor removal, congenital malformation or other trauma.

The skeleton of a man who suffered from FOP

"Even if the answer to FOP is only for FOP, it wouldn't in any way dissuade me from working on it," says Kaplan. "I would hope we can make a difference for these kids (and find) medications, treatment or therapy that would enable them to prevent a joint from turning into bone or restore movement to some joint already frozen."

For now, there is little medicine can offer other than education -- especially for other physicians.

"You can't keep a child in a glass box," says Kaplan, explaining that parents often say they are as fearful of the disorder stealing their children's childhood as they are of the progressive disability.

But prudence to avoid trauma makes sense. If you know that a routine inoculation can cause inflammation and bone formation, you can decline the shot.

Physicians who suspect FOP should not biopsy swellings, for instance, Kaplan says. "That can send the condition into a wild state of flare-up."

An injection for dental work "can cause the jaw to lock up within hours," he adds.

One woman with FOP remembers going to sleep still able to use her left wrist, and waking up to find it frozen with the hand cocked upward.

Jaws frequently lock early in life, reducing those with FOP to eating only pureed food.

Jack Wilson of Chattanooga, Tennessee, hasn't swallowed a thing since 1987. Now 45, his neck muscles are locked tightly in bone. He has a tracheotomy, and can move only a few shuffling steps with help.

But he is determined to make a difference with his life for as long as he can.

Before his elbows locked up, he played piano. When they began to stiffen, he taught himself guitar, and then taught others how to play.

These days, he regularly visits a psychologist at a Chattanooga rehabilitation hospital for guidance in staying focused on the world outside the four walls of his basement apartment.

He can still move his hands, and is an active computer correspondent, as is Kurpiel.

"The FOP association helps me be able to be in touch with other people, too," he says through perpetually clenched teeth. "And I'm thinking about getting a power wheelchair."

Life expectancy for people with FOP is "tremendously variable," says Kaplan. "The average life span is mid-40s, but it ranges from the teens to the 80s."

Those who die at midlife or younger generally succumb to respiratory complications such as severe bronchitis or pneumonia. Because of restrictive bone formation in the chest wall, lungs often cannot expand properly, making it that much harder to overcome infection.

"Generally, though, these people are quite healthy," Kaplan notes. "Perhaps there is an auto-inflammatory component because they tend to be tremendously resistant to infections. But if they happen to get a cold or respiratory infection, it's more likely to become a complicated issue."

International Fibrodysplasia Ossificans Progressiva Association
University of Pennsylvania Orthopedic Journal article on FOP
Dr. Frederick Kaplan faculty page
National Organization for Rare Diseases

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