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Mutation of Key Protein Causes Rare Form of Hearing Loss That’s Easily Confused with Otosclerosis

August 1, 2002

A still and lifeless stirrup-shaped bone in the middle ear may, at first pass, seem like a clear-cut case of the progressive hearing disorder otosclerosis to most ear, nose, and throat specialists, but it could also indicate a rare genetic syndrome, says a new study to appear in the September 2002 issue of the American Journal of Human Genetics. Research supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) demonstrates that the mutation of a gene responsible for normal bone and joint development in humans and mice is the cause of a form of congenital hearing loss called autosomal dominant stapes ankylosis, which is sometimes mistaken for otosclerosis. The study was published in advance in the journal's June 27, 2002, online version.

Otosclerosis is an abnormal growth of bone in the middle ear that frequently immobilizes the stapes, the smallest and final bone in a three-bone chain in the middle ear. Under normal conditions, the stapes helps transmit sound vibrations from the eardrum to the inner ear. When the stapes is unable to vibrate, it can no longer transfer sound energy, resulting in a conductive hearing loss. (A conductive hearing loss occurs when the outer or middle ear does not transmit sound to the inner ear, whereas a sensorineural hearing loss occurs when the inner ear or auditory nerve fails to work properly.) Otosclerosis progresses as a person ages and may be hereditary.

Like otosclerosis, autosomal dominant stapes ankylosis is characterized by an immobilized, or "fixed," stapes. However, in the latter disorder, the conductive hearing loss is present at birth and does not progress over time. In addition, autosomal dominant stapes ankylosis is part of a syndrome and associated with other inherited characteristics. A person with the syndrome may have thumbs and big toes that are unusually broad, farsightedness, a sloping forehead, a cleft chin, and other minor skeletal abnormalities. The term "autosomal dominant" means the gene that causes it--named NOG because it codes for the protein noggin--is located on a chromosome other than a sex chromosome and will be expressed when one parent passes on an altered or mutated copy. Noggin plays a crucial role in the development of the mammalian skeleton and has been linked to other syndromes affecting the mobility of joints and bones in the body.

Researchers at the University of Michigan Medical School, working with colleagues at the Boston University School of Medicine, compared DNA from 11 members of a family. Eight family members who were previously diagnosed as having or suspected to have otosclerosis exhibited physical characteristics of the genetic syndrome. The researchers also studied DNA from three members of a second family who exhibited similar physical traits. The researchers discovered that the eight members of the first family with like characteristics all had the same mutation on the NOG gene. Members of the second family carried a mutation of the same gene, though the mutation was different. Samples from one family member who did not have the syndrome, two spouses of family members, and 100 controls did not contain the mutation.

While otosclerosis can be effectively treated with a stapedectomy, a type of surgery in which a prosthetic device is inserted to replace the malfunctioning stapes and transmit sound waves to the inner ear, a similar surgery for people with the genetic syndrome produces mixed results, according to David J. Brown, M.D., first author of the paper. For this reason, doctors should be aware of a patient's skeletal abnormalities and family history for hearing loss and farsightedness before recommending surgery, he cautions. "Hearing aids may be a better option for people with this syndrome," he said.

In addition to the NIDCD, other organizations that supported this study are the Research Fund of the American Otological Society, Margaret G. Bertsch Endowment Fund, and University of Michigan General Clinical Research Center. As the nation's focal point for research in human communication, the NIDCD supports and conducts research and research training on normal mechanisms as well as diseases and disorders of hearing, balance, smell, taste, voice, speech, and language that affect millions of Americans.

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