Rare Disease Turning Little Girl to Bone

F O R T   L E E, N.J., Dec. 10, 2000 -- 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.

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 withfibrodysplasia ossificans progressiva, or FOP.

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

Like detectives in a medical thriller, he and other scientistsare racing to identify the strange force in Sophia’s limbs. Andthey’re finding clues in the unlikeliest places—a shark, a fruitfly, a tadpole.

Daily Courage

Oblivious to the genetic time bomb ticking in her, the littlegirl skips through the kitchen hugging her stuffed rabbit. Sheloses her balance and falls backwards, landing in her sister’sarms. The impish grin disappears. Fear shines in her eyes. Sherights herself, puts on a smile—and runs off.

“It takes a lot of courage to live like this,” says ConstanceGreen, 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, pushingher arm to its limit. Her hand gets stuck in a coat sleeve, but shewiggles out, exclaiming, “Hey, I found my fingers!”

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

FOP Riddle

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

A spontaneously mutant gene enters the fetus, carried either bysperm or egg. Sometime during childhood, this unknown gene triggerspainful swellings in muscles and tissue that then turn intorenegade 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 errantcode that spurs the wild bone growths? How can this master switchbe turned off?

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

Examination

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

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

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

“I need a hug!” he tells Sophia. With peals of laughter, shegrabs his hands, glee bursting from every part of her that is stillagile. 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 helast saw her several months earlier?

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

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

What she really needs is a miracle.

Human Genome Run Amok

So do the children whose photographs line the white corridor atPenn’s Division of Metabolic Bone Diseases and MolecularOrthopedics, which has been waging the FOP battle for eight yearsunder Kaplan’s leadership.

His typical 14-hour-plus workday starts at 9 a.m. Today, he’swearing his special tie, decorated with playful skeletons doingvarious sports. The New Jersey native trained as an orthopedicsurgeon, but he decided to make FOP his quest after seeing a babywith a bumpy, swollen body.

What he witnessed was the human genome run amok. A bone-buildinggene that normally shuts off when the child is born was startingall over again, strafing the body with bone in the same sequence ababy’s skeleton is first formed, from the head, shoulders and armsdown to the legs.

Most FOP patients live into adulthood, having been diagnosed aschildren or teen-agers; Sophia was one year old when diagnosed.

Captives

“The adults captured my headlight—but the children capturedmy heartlight,” says Kaplan, whom the kids call Uncle Fred.

His office is ringed with images of patients who visit, writeand send their drawings. And he gets daily phone calls reportingpainful flareups, which signal that muscles, ligaments and jointsare solidifying. The jaw muscles can lock, making speech difficultand with time, bone squeezing the throat or chest may causestarvation or suffocation. Two adults died recently because theycouldn’t breathe. Last fall, the tissue in Sophia’s neck beganswelling, threatening to strangle her.

Kaplan’s FOP patients remind him of Michelangelo’s unfinishedsculpture “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.

Which Gene Is It?

Only the answer to one question, Kaplan believes, can stop thedevastation: “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 one mile left,” says Kaplan. “But that’s not good enough. We now have to go door to door, house tohouse. And then we have to find the right room.”

A solution to FOP, says Kaplan, holds clues to otherbone-related conditions like arthritis, osteoporosis and ossifiedheart valves.

What will fix the faulty gene?

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

Labyrinths of bone locked his arms by his side, froze his neckand immobilized his hips.

Symposium

Since few people with FOP bear children, the researchers mustrely on data obtained from patients scattered around the globe. InNovember, about 90 people with the disease, plus their families andhundreds of scientists, attended a four-day symposium inPhiladelphia.

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

Some families faced this in a haze of grief.

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

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

Life Goes On

Though FOP remains uncured today, life must go on.

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

A one-time travel agent, she now lives with her parents inWinter Springs. In 1988, tapping her Social Security income, Peeperstarted the International FOP Association, a support network thatnow connects hundreds of her fellow FOPers in 26 countries.

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

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

And children.

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

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

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

Modern Crusade

The modern crusade against FOP began in 1979 when an 8-year-oldgirl was examined by Dr. Michael Zasloff, a Harvard-trainedpediatrician 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 waspopulated by fragments of bone just scattered all over.”

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

In 1994, in a Penn hospital archive, pathologist Frank Gannondiscovered what Kaplan calls the Rosetta Stone of the FOP puzzle -snapshot biopsies from a 30-year-old man done over several weekswhen he was only five years old.

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

Fruit Fly Gene Offers Clue

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

Geneticist John Wozney identified the gene of a protein thatstimulates normal bone growth in an embryo—bone morphogeneticprotein, or BMP. He ran it through a computer database to hunt forany similar DNA sequence that makes this kind of protein. Theclosest match was a gene from—of all things—a fruit fly.

“This was astonishing, since flies don’t have bones and peopledon’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 afruit fly with a defective BMP gene was missing parts of its wingsand legs—just as children with FOP are born with a joint of thebig toe missing, while the rest of the skeleton overdevelops.

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

Hope For Treatment

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

The next afternoon, a bus drops off “Fifi”—as her mothercalls 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 ifshe were a porcelain doll.

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

While a cure for FOP may not be imminent, there is hope oftreatments that could slow the spreading bone.

That effort led one scientist to the dogfish shark. Zasloff, thepioneering FOP researcher, discovered that the ground-up liver ofthis fish with soft cartilage may slow bone growth by restrictingthe blood vessels that spawn the growth. Squalamine, theshark-liver derivative now produced synthetically, is already beingtested as a cancer treatment and awaits government approval for useon FOP patients within several months.

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

Kaplan says noggin, still in laboratory research stages, mayhelp patients regain some mobility if bone can be surgically freedwhile the protein neutralizes growth. But it could take years forthis protein derivative to be tested on humans.

For now, the thousands of people with FOP must simply face dailylife -and an uncertain future. That knowledge makes even smallthings sacred.

When Sophia gives a hug, “she kind of extends an arm as much asshe can,” says her father, David Forshtay, a psychiatric nurse wholives nearby. “There’s no squeeze, no clasping. But when she does that, it’s such an all-enveloping feeling. There’s an aura, andhers 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 smallyellow flower. She strains to pluck it. Then she holds up the wildblossom, her face glowing. And she asks, “Can you hear this?”