Rare mutation find may offer clues to treating osteoporosis

By DAVID WILLIAMSON
UNC-CH News Services

CHAPEL HILL-- Unsightly, defective teeth -- but extraordinarily strong bones -- result from an unusual genetic mutation identified, located and cloned for the first time by researchers at the University of North Carolina at Chapel Hill School of Dentistry and Wake Forest University.

"Tricho-dento-osseous syndrome is so rare that it probably only affects a few thousand people around the world, and we are confident that the few extended families we found it in are related even if they don't know it," said Dr. J. Timothy Wright, professor of pediatric dentistry at UNC-CH. "Still, our work on TDO syndrome is potentially extremely important because it could give us clues about how to treat osteoporosis more successfully."

Osteoporosis -- the thinning of hip and other bones -- eventually affects everyone who lives into later life, Wright said. For many of the oldest, the condition becomes a life-threatening medical emergency, and it promises to become a greater problem nationally as baby boomers age.

"Bones of people with TDO, however, are so dense they fracture only rarely," he said. "Affected people are born with kinky, curly hair, and their chief health problem is that they develop little or no enamel on their teeth, which can become painful and very unsightly."

"If we can understand how the mutation stimulates bone density, we might be able to take advantage of it to help older patients."

A report the findings appears in the March issue of Human Molecular Genetics. Besides Wright, authors are Drs. Thomas C. Hart and Donald W. Bowden, associate professor of pediatrics and professor of biochemistry, respectively, and graduate student Jennifer Price, all at Wake Forest.

Researchers extensively studied six large families, including 46 people affected by TDO and 24 not affected. They found all affected people to have an identical genetic defect: four pairs of nucleotides -- building blocks of proteins -- were missing from chromosome 17. Those without the kinky hair and with good teeth showed no missing nucleotides.

Hart, a dentist and medical geneticist, called the discovery "quite exciting scientifically," partly because it is the first mutation of its kind ever found in humans. A Scottish sailor who came to the Colonies before the Revolution appears to have been the source of the first TDO mutation in the Americas.

Patricia Salevan, 41, a Cary, N.C., office manager, was born with TDO syndrome in 1956. Two of her three children now have it, as did her mother, her grandfather and his mother. She wears crowns on all her teeth to prevent them from wearing away. Cavities were not a major problem for her growing up because of fluoride-treated water and because large gaps between her teeth did not trap food particles.

"I started going to the dental school in Chapel Hill when I was about 6 years old," she said. "Because they took such good care of me, I take my children down there now as well."

Her biggest concern is what to do about her son's teeth.

"He's in the sixth grade, and that's a time when other children can be cruel -- calling names and such," she said. "We are struggling to decide what the best options for him are physically, psychologically and cosmetically."

The National Institute of Dental Research supports the UNC-CH and Wake Forest research, which involves other genetic abnormalities and may evolve into a center for genetic and clinical craniofacial research.

"With these families, we have heard all kinds of interesting patient histories such as kids getting hit in the head with baseball bats and were not hurt even though the bats broke, " Wright said. "Even in car and motorcycle wrecks, they rarely broke any bones."

Note: Wright can be reached at (919) 966-8822, Hart at (910) 716-6735 and Patricia Salevan at (919) 380-0447 (h) or 772-8548 (w).

Contacts: UNC-CH School of Dentistry, Alice Lockhart, (919) 966-4563; News Services, David Williamson, (919) 962-8596.

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