Lyrical Child Sings Fear Away, Copes With Disease

Sophia Forshtay wakes up on a Sunday morning, a 4-year-old singing happily to herself in bed. Her tiny melody floats through the house, mixing with the aroma of breakfast coffee.

But there’s a sad note: Lying on her back, she can’t turn her head. She can’t lift her arms.

Sophia’s body is slowly, inexorably turning to bone.

She is one of about 2,500 people around the world with fibrodysplasia ossificans progressiva, or FOP.

“It’s like a terrorist setting off a bomb inside these children, a supreme sabotage. But we can’t predict where and when it’ll strike,” says Dr. Fred Kaplan, an orthopedist who has devoted his life to solving the mysterious genetic disorder.

Like detectives in a medical thriller, he and other scientists are racing to identify the strange force in Sophia’s limbs. And they’re finding clues in the unlikeliest places--a shark, a fruit fly, a tadpole.

Oblivious to the genetic time bomb ticking in her, the little girl skips through the kitchen hugging her stuffed rabbit. She loses her balance and falls backward, landing in her sister’s arms. The impish grin disappears. Fear shines in her eyes. But she rights herself, puts on a smile--and runs off.

“It takes a lot of courage to live like this,” says Constance Green, Sophia’s mother. “It’s got to be terrifying not to be able to stop yourself when you’re about to fall.”

In vain, Sophia struggles to put a peanut in her mouth, pushing her arm to its limit. Her hand gets stuck in a coat sleeve, but she wiggles out, exclaiming, “Hey, I found my fingers!”

And she reassures a concerned friend holding on to her as she mounts the stairs, “Don’t be scared! I’m here.”

In a Philadelphia laboratory, Kaplan and molecular biologist Eileen Shore, the lab’s director, are working with a dozen researchers to solve the riddle that began at conception for Sophia and the other “FOPers,” as they’ve dubbed themselves.

A spontaneously mutant gene enters the fetus, carried either by sperm or egg. Sometime during childhood, this unknown gene triggers painful swellings in muscles and tissue that then turn into renegade bone cells. Eventually the body is imprisoned in a “second skeleton”--quite literally, a life sentence. A joint can lock overnight, never to move again.

Exactly where in the vast library of human genes is the errant code that spurs the wild bone growths? How can this master switch be turned off?

“I wanted to tackle something big. I wanted a mountain to climb,” says Kaplan, who is leading the work at the University of Pennsylvania Medical Center.

One recent afternoon, Kaplan examines Sophia, gently touching a reddish bump that signals newly forming bone.

“Don’t hurt me! Stop that!” she pleads.

Minutes later, the doctor is sitting cross-legged on the floor of the hospital waiting room, a slight 47-year-old man bouncing on the carpet, giggling and chatting.

“I need a hug!” he tells Sophia. With peals of laughter, she grabs his hands, glee bursting from every part of her that is still agile. He pretends to be asleep, and she nudges him: “Get up!”

This isn’t just play. It’s how the doctor examines the girl, watching her every motion. What inroads has the bone made since he last saw her several months earlier?

As he examines fresh lumps on her back and spine, his brow creases with his own pain. But he keeps laughing--for her.

Then the doctor takes Sophia into the examining room, where she sticks her bunny into the rib cage of a plastic skeleton. “I need red sparkles,” she announces.

What she really needs is a miracle.

So do the children whose photographs line the white corridor at Penn’s Division of Metabolic Bone Diseases and Molecular Orthopedics, which has been waging the FOP battle for eight years under Kaplan’s leadership.

His typical 14-hour-plus workday starts at 9 a.m. Today he’s wearing his special tie, decorated with playful skeletons doing various sports. The New Jersey native trained as an orthopedic surgeon, but he decided to make FOP his quest after seeing a baby with a bumpy, swollen body.

What he witnessed was the human genome run amok. A bone-building gene that normally shuts off when the child is born was starting all over again, strafing the body with bone in the same sequence as a baby’s skeleton is first formed, from the head, shoulders and arms down to the legs.

Most FOP patients live into adulthood, having been diagnosed as children or teenagers; Sophia was 1 when diagnosed.

“The adults captured my headlight--but the children captured my heart light,” says Kaplan, whom the kids call Uncle Fred.

His office is ringed with images of patients who visit, write and send their drawings. And he gets daily phone calls reporting painful flare-ups, which signal that muscles, ligaments and joints are solidifying. The jaw muscles can lock, making speech difficult. With time, bone squeezing the throat or chest may cause starvation or suffocation. Two adults died recently because they couldn’t breathe. Last fall, the tissue in Sophia’s neck began swelling, threatening to strangle her.

Kaplan’s FOP patients remind him of Michelangelo’s unfinished sculpture, “Captives”--figures who, he says, “struggle to extricate themselves, to escape from their marble prison.”

Any attempt to surgically remove the extra skeleton sets off anexplosion of new bone.

Only the answer to one question, Kaplan believes, can stop the devastation: “Which gene is it?”

Among tens of thousands of genes in a human being, the researchers have eliminated most as possible FOP triggers. “We’ve traveled 99 miles, and there’s 1 mile left,” says Kaplan. “But that’s not good enough. We now have to go door to door, house to house. And then we have to find the right room.”

A solution to FOP, says Kaplan, holds clues to other bone-related conditions like arthritis, osteoporosis and ossified heart valves.

But what will fix the faulty gene?

Kaplan, Shore and their colleagues draw inspiration from Harry Eastlack, who died just before his 40th birthday in 1973 and willed his body to medicine. A preserved skeleton of an FOP victim, he stands at the Mutter Museum of Philadelphia’s College of Physicians. They call him “Harry.”

Labyrinths of bone locked his arms by his sides, froze his neck and immobilized his hips.

Since few people with FOP bear children, the researchers must rely on data obtained from patients scattered around the globe. In November, about 90 people with the disease, plus their families and hundreds of scientists, attended a four-day symposium in Philadelphia.

There, Green saw what could be her daughter’s future--a group of adults, a few frozen into standing positions, others sitting, many in wheelchairs.

Some families faced this in a haze of grief.

But in the next few days, amid tears and laughter, scientists and patients alike embraced what one mother called “a new normal.” A ballroom party capped the conference, with wheelchairs gliding across the dance floor to raucous music.

Those at the symposium were living examples of the genetic error first recorded in 1736, by British physician John Freke.

Though FOP remains uncured today, life must go on.

In Florida, Jeannie Peeper, who at 42 has only one movable joint, her right wrist, pushes on: “I go to the beach, I go shopping, I have a boyfriend.”

A onetime travel agent, she lives with her parents in Winter Springs. In 1988, tapping her Social Security income, Peeper started the International FOP Assn., a support network that now connects hundreds of her fellow FOPers in 26 countries.

“My feeling is that God has given me a mission in life,” she says. “Mine is to help others with FOP.”

Many still hold business positions. Several are teachers. Another is a photographer. There’s a museum director, several artists, a few computer experts.

And children.

“I bought a special switch that allows Sophia to turn on her own light,” Green says. “Then I worked on a way she can get herself out of bed.”

And one day, Green wrote a seven-word poem expressing how she draws the endless energy to meet Sophia’s daily needs, plus those of two other daughters, Olivia, 10, and Julia, 15, and of her job as a singer.

“Fierce is a mother’s love. Cold fire,” she wrote.

*

The modern crusade against FOP began in 1979 when an 8-year-old girl was examined by Dr. Michael Zasloff, a Harvard-trained pediatrician now at Penn’s biophysics department.

“I’d never seen anything like this,” Zasloff says. “When we looked at her X-rays, what we saw was a girl whose body was populated by fragments of bone just scattered all over.”

Financial backing to probe the rare ailment was scarce, and Zasloff almost surrendered after a decade. But during a chance meeting with Kaplan in Philadelphia, he found a partner who was ready to declare full-scale war on FOP.

In 1994, in a Penn hospital archive, pathologist Frank Gannon discovered what Kaplan calls the Rosetta Stone of the FOP puzzle--snapshot biopsies from a 30-year-old man done over several weeks when he was only 5.

Kaplan and Zasloff suddenly understood how muscle turns to bone: Disease-fighting blood cells were somehow decimating healthy muscle and kick-starting bone formation. When an FOP child falls or gets a bump, the blood that rushes in fuels bone growth, even after an injury as minor as dental work or a vaccine shot.

A Boston scientist found the next piece of the FOP puzzle.

Geneticist John Wozney identified the gene of a protein that stimulates normal bone growth in an embryo--bone morphogenetic protein, or BMP. He ran it through a computer database to hunt for any similar DNA sequence that makes this kind of protein. The closest match was a gene from--of all things--a fruit fly.

“This was astonishing, since flies don’t have bones and people don’t have wings,” Kaplan says. “What could possibly be the association between a very powerful gene in man that makes bones, and a gene in the fly?”

Enter Harvard biologist William Gelbart, who observed that a fruit fly with a defective BMP gene was missing parts of its wings and legs--just as children with FOP are born with a joint of the big toe missing, while the rest of the skeleton overdevelops.

Translating these clues into a cure could take years, an eternity for an FOP child whose only remedy is anti-inflammation medicine.

“Mommy, I’m afraid, I’m afraid!” Sophia says one night at bedtime, after a day of flare-ups.

The next afternoon, a bus drops off “Fifi”--as her mother calls her--from a preschool where she plays with healthy children. Eugenia Anderson, a strong, gentle woman who helps care for Sophia, climbs the bus steps and takes her in her arms, as carefully as if she were a porcelain doll.

“I fell today in school,” Sophia tells her. A huge new lump appears on her back.

Although a cure for FOP may not be imminent, there is hope of treatments that could slow the spreading bone.

That effort led one scientist to the dogfish shark. Zasloff, the pioneering FOP researcher, discovered that the ground-up liver of this fish with soft cartilage may slow bone growth by restricting the blood vessels that spawn the growth. Squalamine, the shark-liver derivative now produced synthetically, is already being tested as a cancer treatment and awaits government approval for use on FOP patients within several months.

Another drug that appears to limit skeleton production was found in the embryo of the African clawed frog by Richard Harland, a molecular biologist at UC Berkeley. This protein, called noggin, latches onto the bone-producing protein BMP and curbs skeleton production in a human fetus.

Kaplan says noggin, still in laboratory research stages, may help patients regain some mobility if bone can be surgically freed while the protein neutralizes growth. But it could take years for this protein derivative to be tested on humans.

For now, the thousands of people with FOP must simply face daily life--and an uncertain future. That knowledge makes even small things sacred.

When Sophia gives a hug, “she kind of extends an arm as much as she can,” says her father, David Forshtay, a psychiatric nurse who lives nearby. “There’s no squeeze, no clasping. But when she does that, it’s such an all-enveloping feeling. There’s an aura, and hers is like golden light.”

She’s not just Sophia. “I am Sopheeea!”

And her world sings to her.

In her backyard, she walks across the grass and spots a small yellow flower. She strains to pluck it. Then she holds up the wild blossom, her face glowing. And she asks, “Can you hear this?”

*

AP video documentary on FOP:

https://www.wire.ap.org

International FOP Assn.:

https://www.ifopa.org