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Abram P. Vore; Eugene H. Chang, MD; Jane E. Hoppe, RN, MSN; Merlin G. Butler, MD, PhD; Shawnia Forrester, MS, CGC; Michael C. Schneider, MD; Luke L. H. Smith; Daniel W. Burke; Colleen A. Campbell, BS, CGC; Richard J. H. Smith, MD

Arch Otolaryngol Head Neck Surg. 2005;131:1057-1063.

Objective  To analyze the physical manifestations and genetic features of 2 families segregating X-linked deafness, which is most commonly reported to be caused by mutations of the POU domain gene POU3F4 at the DFN3 locus.

Design  Computed tomographic study of the temporal bone in probands from each family, followed by mutation screening and deletion mapping of POU3F4 in family members.

Setting  Two midwestern genetics clinics.

Participants  Two families with X-linked deafness.

Main Outcome Measures  Anomalies of the inner ear in the probands; results of gene mapping and severity and effects of hearing loss in the family members.

Results  In the first family, a large deletion was identified that includes POU3F4 and extends upstream approximately 530 kilobases; in the second family, a novel serine-to-leucine (S228L) amino acid mutation was identified in the POU-specific domain of POU3F4. Both the deletion and the missense mutation segregate with the clinical phenotype and are causally related to the deafness in these families.

Conclusions  Deafness related to the POU3F4 gene is associated with dilation of the internal auditory canal and a spectrum of other temporal bone anomalies that range in severity from mild to severe dysplasia of the cochlea and semicircular canals. The consequence of these anomalies is a congenital mixed hearing loss, the sensorineural component of which progresses over time. Affected males can also present with vestibular dysfunction that is associated with delayed developmental motor milestones. Intrafamilial variability occurs.

Author Affiliations: Molecular Otolaryngology Research Laboratories, Department of Otolaryngology–Head and Neck Surgery (Messrs Vore, Smith, and Burke; Drs Chang and Smith; and Ms Campbell), and Interdisciplinary Program in Genetics (Dr Smith), The University of Iowa, Iowa City; Department of Genetics, Children’s Mercy Hospitals and Clinics, Kansas City, Mo (Ms Hoppe and Dr Butler); and Department of Pediatrics, Southern Illinois University School of Medicine, Springfield (Ms Forrester and Dr Schneider).

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