Noggin Mutation Causes Rare Congenital Hearing Loss

Otosclerosis is a form of progressive conductive hearing loss, which usually begins in young adulthood. It occurs when a bone in the middle ear called the stapes becomes immobilized or fixed, which prevents it from transmitting sound vibrations from the outside world to the inner ear and brain.

"About 1 percent of Americans have been diagnosed with otosclerosis, but it may affect up to 10 percent of the total population," says Marci Lesperance, M.D., an assistant professor of otolaryngology-head and neck surgery in the U-M Medical School.

In recent research, Lesperance and her colleagues discovered the gene underlying a rare hearing loss syndrome, called autosomal dominant stapes ankylosis, which is easily confused with otosclerosis. People with this condition have the same fixed stapes bones as those with otosclerosis, but their hearing loss is present at birth and doesn't get worse as they grow up. People with the syndrome are often farsighted and have unusually broad thumbs and great toes, as well as other skeletal abnormalities.

Lesperance says the syndrome is caused by a genetic mutation occurring early in embryonic development. Since the mutated gene is dominant over the normal version, a child has a 50:50 chance of being born with the syndrome, if one parent carries the mutation.

Comparing DNA from seven members of one family and three members of another family with closely related symptoms, U-M researchers found similar mutations in a gene called NOG. NOG holds genetic instructions for the production of noggin – an essential protein for normal bone and joint development in humans and all mammals. One family member in the study who did not have the syndrome, spouses of family members, and 100 DNA control samples all had the normal version of the noggin gene.

"Seven members of this family were diagnosed with garden-variety otosclerosis by different physicians," Lesperance said. "The skeletal anomalies associated with the syndrome can be subtle, and the typical ENT physician doesn't ask patients to take off their socks, so she can examine their toes."

A surgical procedure called a stapedectomy is up to 90 to 95 percent successful in curing otosclerosis, according to David J. Brown, M.D., a U-M resident who worked closely with the family described in the study and is first author of the paper. In this procedure, the fixed stapes bone is removed and a prosthesis is inserted in its place to restore normal vibration.

"But the surgery is more difficult and seems to work only for a limited time in people with the genetic syndrome," Brown says. "So it's important for clinicians to look for skeletal abnormalities and ask about a family history of hearing loss and farsightedness before considering surgery. Hearing aids may be a better option for people with this syndrome."

"The only reason this family contacted us was that 7 of 8 family members were affected," Lesperance says. "There are probably many more families where only one or two have the syndrome. If two people in the family have hearing loss and similar physical characteristics, an evaluation by a geneticist would be appropriate."

###Results from the U-M study will appear in the September 2002 issue of the American Journal of Human Genetics. The paper was selected for advanced publication and published electronically on June 27, 2002 on the American Society of Human Genetics web site at: www.ajhg.org/journal/rapid.html.

In addition to Brown and Lesperance, collaborators on the study from the U-M Medical School include: Elizabeth M. Petty, M.D., associate professor of internal medicine and human genetics; Catherine A. Downs, M.S., genetic counselor; Peter J. Strouse, M.D., associate professor of radiology; Sayoko E. Moroi, M.D., Ph.D., assistant professor of ophthalmology and visual sciences; Donna M. Martin, Ph.D., research investigator; Theresa B. Kim, research intern; and Jeff M. Milunsky, M.D., from the Boston University School of Medicine.

The study was funded by the Research Fund of the American Otological Society, the National Institute on Deafness and Other Communication Disorders, the Margaret G. Bertsch Endowment Fund and the U-M General Clinical Research Center.

For more information on inherited hearing loss, please see the following web sites:

http://www.med.umich.edu/childhearinginfo

http://otosclerosis.khri.med.umich.edu

http://www.khri.med.umich.edu/research/lesperance_lab/index.htm