Skeleton Crew

Children with disabling bone and mineral
diseases get needed support and specialized care through this research-oriented collaboration.

BY GILA Z. RECKESS

Brooke and Cierra Bowen

“Our common commitment to state-of-the-art care and research is what has made the bond between the two institutions so tight for nearly 80 years.”

CAROLYN GOLDEN,
SHRINERS HOSPITALS–
ST. LOUIS

THERE WAS NO REASON FOR CONCERN when Michelle Hall arrived at the first neonatal checkup for her seemingly healthy newborn daughter, Brooke Bowen. But the pediatrician was puzzled: Despite Brooke’s healthy appetite, she was inexplicably losing weight. The infant was rushed from the family’s hometown of Dry Ridge KY to Children’s Hospital in Cincinnati OH. After a week of tests and diagnostic research, the Ohio doctors reached an alarming conclusion: Brooke had a rare—and so far, untreatable—metabolic bone disease called hypophosphatasia.

Much is now known about hypophosphatasia, a disorder that affects bone development and mineralization. The Cincinnati doctors decided to contact researcher Michael P. Whyte, MD—a leader in the field of bone and mineral disease—whose name appeared on the publications they referenced spanning the past 25 years. Whyte, professor of medicine, pediatrics and genetics at the School of Medicine, is affiliated with Shriners Hospitals for Children-St. Louis, an institution dedicated to caring for the special needs of children with skeletal disease. Soon, Whyte was consulting regularly with Brooke’s doctors about her condition.

Whyte is the medical-scientific director of the Center for Metabolic Bone Disease and Molecular Research at Shriners. He is one of more than 60 School of Medicine physicians and surgeons who provide clinical care at Shriners. The Washington University staff’s surgical and medical expertise, coupled with the Shriner organization’s commitment to providing free care to children with orthopaedic deformities and diseases, has built the reputation of Shriners Hospitals for Children-St. Louis as one of the leading facilities of its kind—particularly for unusual, difficult cases like Brooke’s.

Michael P. Whyte, MD, examines patient Bryan Stearns.

Advancing care for kids

Shriners Hospitals for Children is the official philanthropy of the Shrine of North America, an international fraternity of approximately 500,000 members. The 22 Shriners Hospitals for Children located throughout North America, funded entirely by the Shriners and heavily reliant on volunteer efforts of individual Shrine members, are dedicated to the care of children with bone diseases, burn traumas and spinal cord injuries. Shriners Hospitals for Children-St. Louis, once located on what is now part of the School of Medicine campus, specializes in orthopaedic surgery, serving Missouri and eight surrounding states.

“Shriners Hospital and Washington University share a similar mission—to provide the highest quality care in a compassionate way,” says Carolyn Golden, administrator for Shriners Hospitals for Children-St. Louis. “Our common commitment to state-of-the-art care and research is what has made the bond between the two institutions so tight for nearly 80 years.”

Washington University physicians have been the primary source of medical care at Shriners Hospitals for Children-St. Louis since its inception in 1924 and have been formally in charge of staffing the facility since 1976.

“St. Louis’ Shriners Hospital is a major provider of pediatric orthopaedic care in the central Midwest and, without a doubt, is a leader in the advancement of care for kids with a variety of conditions,” says Perry L. Schoenecker, MD, Shriners’ chief of staff and School of Medicine professor of orthopaedic surgery. According to Schoenecker, who also is acting head of pediatric orthopaedics at St. Louis Children’s Hospital, Shriners is an acknowledged pioneer in pediatric orthopaedic care.

Shriners also has long recognized the importance of research. Because its staff treats unusual and often difficult skeletal disorders, it serves as a unique resource for Washington University physicians and surgeons to investigate innovative solutions to childhood bone disorders.

In 1981, the late Louis V. Avioli, MD, former director of the division of bone and mineral diseases and founder of the American Society for Bone and Mineral Research, convinced the Shrine’s board of directors to dedicate an entire hospital wing to the pursuit of researching rare, heritable bone metabolism disorders.

Whyte then designed the Center for Metabolic Bone Disease and Molecular Research, which has developed an international reputation, attracting patients from 43 states and from countries as far away as Kuwait, Albania and Australia. The center is the only inpatient facility in the United States exclusively dedicated to diagnosing, treating and researching pediatric metabolic bone diseases and skeletal dysplasias.

That means that children like Brooke Bowen with any of more than 100 rare metabolic bone disorders can participate in and benefit from research done at the center. Brooke and others under Shriners’ care periodically visit St. Louis for as long as a week so that researchers can monitor their progress and collect data in a precisely controlled environment.

“The dedication of Drs. Whyte and Avioli to the science of bone biology and to bench-to-bedside research engenders the community support and national recognition that permit the development of this truly unique research, training and clinical resource in St. Louis,” says Dwight A. Towler, MD, PhD, director of the division of bone and mineral diseases and associate professor of medicine and of molecular biology and pharmacology. “Ongoing support provided by Shriners Hospital, the Barnes-Jewish Hospital Foundation, the Department of Medicine and the National Institutes of Health ensures that our division can remain true to this mission of improving skeletal health.”

Steven Mumm, PhD, in the laboratory with Ladue High School senior Stefanie Wiegand, left, and research technician Sara Obrecht.

Looking for root causes

While Whyte currently monitors Brooke, now 9, treating any complications and gathering data on her disease, researchers at the Center for Metabolic Bone Disease and Molecular Research have identified the underlying cause of this rare disorder. Since 1985, in collaboration with molecular biologists, the precise genetic cause of hypophosphatasia has become understood.

Hypophosphatasia is characterized by abnormally low levels of alkaline phosphatase in blood and bone cells. A deficiency of alkaline phosphatase causes poorly mineralized bones and skeletal deformities. It also can lead to the accumulation of phosphates, calcium and other chemicals in the bloodstream and kidneys, sometimes resulting in renal failure.
The most severe form of hypophosphatasia affects about one in every 100,000 newborns, half of whom die from the condition within six months. The disease’s milder forms, such as Brooke has, are more common. Different mutations in the gene that encodes alkaline phosphatase explain some of the disorder’s variability.

Separately, in the mid-1980s, Whyte and colleagues including those at Shriners discovered that patients with hypophosphatasia have abnormally high levels of vitamin B6.

“We took advantage of that discovery to gain a better understanding of how alkaline phosphatase works,” explains Whyte. “Now we can translate that knowledge to devising medical treatment.”
His Shriners team now is testing a way of elevating alkaline phosphatase levels in Brooke and other patients with hypophosphatasia by adjusting their dietary phosphate levels.

Because hypophosphatasia and most other diseases under investigation at the center are hereditary, other exciting information comes from genetic research.

Thanks to the Human Genome Project (accomplished in part at the School of Medicine) and the efforts of the center’s molecular biologist, Steven Mumm, PhD, research assistant professor of medicine, Whyte’s team already has identified genetic mutations responsible for a number of bone metabolism diseases.

Studying Brooke’s genes could prove particularly interesting in light of the most perplexing thing about her condition: Her 6-year-old sister, Cierra, has the exact same molecular defect and the same levels of blood alkaline phosphatase as Brooke. But, while Brooke has a wobbly, stiff-legged walk and skeletal deformities in her skull, Cierra barely shows any symptoms.

The difference between sisters suggests that something more than the already identified molecular and metabolic defects accounts for the variable severity of hypophosphatasia. Mumm, Whyte and Towler plan to scrutinize other aspects of the girls’ DNA to determine just what this might be.

Their dedication is what mom Michelle Hall appreciates the most: “It’s wonderful to know the doctors are looking for treatments and may one day find a cure for children like Brooke.”