Watching 20-month-old Natalie Grace Van Wyk grab her father's cellphone and dash around in pink cowboy boots at Children's Hospital of Philadelphia, you might think the little girl was normal and healthy.
And you'd almost be right.
Natalie is a medical miracle, thanks to an innovative prenatal and postnatal care plan for generalized arterial calcification of infancy (GACI) developed by a team of doctors at Children's.
Both of her parents - Anne, 40, and Jerry, 44, of Mankato, Minn. - carry a mutation of a recessive gene called EPPN1, which can cause GACI, an extremely rare and often fatal prenatal syndrome that produces calcification of the arteries and decreased elasticity of blood-vessel walls.
Parents of three healthy children, the Van Wyks have lost two infant boys - one at 5 weeks and the other at 7 - to heart attacks from GACI.
The gene mutation leads to a deficiency in inorganic pyrophosphate, a substance that normally blocks the buildup of calcium deposits in blood vessels and arteries. Without pyrophosphate, calcification narrows vessels and arteries and restricts blood flow.
"Without pyrophosphate, you begin to calcify in places where you shouldn't and wouldn't," says Michael Levine, chief of the Division of Endocrinology and Diabetes at Children's and a member of Natalie's care team.
Because of this hardening of the arteries and vessels, babies with GACI often show clinical signs of hypertension, heart disease, and kidney disease at birth and are subject to stroke, heart failure, and kidney damage.
To stop the disease's progression, newborns with the syndrome's clinical signs are often given bisphosphonates, drugs that are normally used to treat osteoporosis.
If both parents carry the mutation, they have a 25 percent chance of having a child with GACI.
About 200 cases of GACI have been found worldwide, but many may go unreported. Many children born with the condition die in the first few weeks of life, although babies who make it through the first year often do quite well, according to Levine.
Two weeks before Christmas 2012, a pregnant Anne Van Wyk had an irregular amniocentesis. An ultrasound of the fetus showed bright spots that signified calcification, confirming a GACI diagnosis.
Given their experience, the Van Wyks knew that the calcification process progresses quickly and that they had little time to act. By January 2013, they had traveled to Children's, where they met with Juan Martinez-Poyer, an obstetrician at the hospital's Center for Fetal Diagnosis and Treatment, and David Goldberg, a pediatric cardiologist. Martinez-Poyer referred the couple to Levine, who specializes in diseases that affect bone and mineral metabolism.
Levine had treated few cases of GACI, and none in utero. Usually he saw children in the first week of life with severe GACI.
"Dr. Levine was at his desk," says Jerry. "We talked about possible prenatal treatment. He not only truly heard what we said, but he truly listened. And when we were finished, I remember he wheeled back in his chair and said, 'You know, I do like a challenge.'
"There were no guarantees, but it was a glimmer of hope to have someone agree to try."
"The parents wanted to do whatever was possible," says Levine. "After consulting with a team of doctors, we discussed with Anne and Jerry the need to do something very early and possibly using etidronate, an osteoporosis drug that mimics the missing inorganic pyrophosphate and inhibits calcium deposits in blood-vessel walls. If used in high doses for long periods, we thought that this might prevent mineralization."
There were risks.
"We had a heart-to-heart with Jerry and Anne," says Levine. "We told them it was an unknown what the drug might do to the skeleton of the baby."
The Van Wyks remained adamant: They wanted to move ahead. A plan of treatment was decided on, and in February 2013, Anne, in her third trimester, moved from Minnesota to Philadelphia to begin taking etidronate and receive weekly monitoring.
"Every Friday, we held our breath," says Anne. "Each time it was miraculous. After I started taking etidronate, there was no further calcification."
On April 8, 2013, Natalie was born and transferred to the neonatal intensive care unit. She arrived by C-section with no clinical evidence of GACI - no high blood pressure, kidney disease, heart failure, or stroke - only some remaining calcifications and narrowing of the arteries in the abdomen.
The doctors then faced their next move: to continue to treat or not?
"Doing nothing didn't seem to be a real option," says Levine. So for the second time, the team opted to try something new: the drug sodium thiosulfate, used to reverse calcification in arteries in patients with renal failure.
"Desperate times call for desperate measures," says Levine. "To treat Natalie, we pharmaceutically repurposed this drug. We looked at a drug that worked in one molecular pathway, but when we examined the genetic and molecular properties, we realized it also might be good for another use, as well."
Natalie received sodium thiosulfate intravenously three times a week for a year. Although the exact mechanism of how sodium thiosulfate works in GACI isn't fully understood, the goal for Natalie was achieved: it has stopped the calcification.
"We aren't going to have drug trials to find out how this works, because this is an orphan disease with so few cases," says Levine. But their success with Natalie has spurred research. At Johns Hopkins University and the National Institutes of Health, researchers are trying to determine the cause of calcifications, using cells drawn from patients such as Natalie. And at Jefferson medical school, mouse models are being used to test drugs to see how they compare in preventing calcification.
"The $64,000 question is understanding how the genetic defect causes clinical symptoms," says Levine.
Finished with her care, Natalie takes no further medications. She returns to Children's for quarterly scans and testing to check her heart and arteries.
"I hate to predict the future," says Goldberg, "but I am cautiously optimistic."
Since stopping sodium thiosulfate, there has been no progression of calcium deposition, which gives Goldberg hope that they may have made it through the critical period.
But there remains some narrowing of Natalie's descending aorta and the branches that come off the heart, which will have to be followed closely. She has no developmental abnormalities, but her height and teeth are delayed, Martinez-Poyer said.
While the team hesitates to generalize the findings of one person to the treatment of an entire class of patients, this case could serve as a starting point for new research and care, says Goldberg. The team plans to publish its innovative findings.
Back at the hospital, Natalie mugs for photographs and drinks from a sippy cup, every bit an active toddler.
"Our goal is that no other family needs to go through this disease," says Levine. "This case shows how a single motivated family can change treatment."