Published online May 28, 2013. doi: 10.5319/wjo.v3.i2.26
Revised: April 25, 2013
Accepted: May 8, 2013
Published online: May 28, 2013
Pendred syndrome (PS) is characterized by autosomal recessive inheritance of goiter associated with a defect of iodide organification, hearing loss, enlargement of the vestibular aqueduct (EVA), and mutations of the SLC26A4 gene. However, not all EVA patients have PS or SLC26A4 mutations. Two mutant alleles of SLC26A4 are detected in 1/4 of North American or European EVA populations, one mutant allele is detected in another 1/4 of patient populations, and no mutations are detected in the other 1/2. The presence of two mutant alleles of SLC26A4 is associated with abnormal iodide organification, increased thyroid gland volume, increased severity of hearing loss, and bilateral EVA. The presence of a single mutant allele of SLC26A4 is associated with normal iodide organification, normal thyroid gland volume, less severe hearing loss and either bilateral or unilateral EVA. When other underlying correlations are accounted for, the presence of a cochlear malformation or the size of EVA does not have an effect on hearing thresholds. This is consistent with observations of an Slc26a4 mutant mouse model of EVA in which hearing loss is independent of endolymphatic hydrops or inner ear malformations. Segregation analyses of EVA in families suggest that the patients carrying one mutant allele of SLC26A4 have a second, undetected mutant allele of SLC26A4, and the probability of a sibling having EVA is consistent with its segregation as an autosomal recessive trait. Patients without any mutations are an etiologically heterogeneous group in which siblings have a lower probability of having EVA. SLC26A4 mutation testing can provide prognostic information to guide clinical surveillance and management, as well as the probability of EVA affecting a sibling.
Core tip: Enlargement of the vestibular aqueduct (EVA) is a common inner ear anomaly. We review the correlation of phenotype with genotype of SLC26A4. SLC26A4 mutations are the most prevalent known cause of hearing loss associated with EVA. The number of mutated alleles is correlated with the presence or absence of a thyroid iodination defect, thyroid gland volume, severity of hearing loss, laterality (bilateral vs unilateral) of the inner ear anomaly, and probability of recurrence of EVA in a sibling. We discuss the risks and benefits of genetic testing and counseling for affected patients. These concepts may be of broad interest to otolaryngologists, audiologists and other clinicians.