These observations were confirmed in numerous studies of large cohorts of PS and NSEVA patients from different ethnic populations.įigure 1 Schematic illustration of the relationship of the vestibular aqueduct with the endolymphatic sac and duct. Usami et al identified SLC26A4 mutations in sporadic and familial cases of NSEVA, showing that SLC26A4 mutations are commonly associated with NSEVA. The identification of SLC26A4 mutations associated with PS suggested a possible association of nonsyndromic hearing loss with EVA (NSEVA) with mutations of this gene. Molecular testing for SLC26A4 mutations and temporal bone imaging have established that PS is always accompanied by inner ear deformities, with enlargement of the vestibular aqueduct (EVA) as the most penetrant feature (Figure 1). The causative gene for PS was mapped to chromosome 7q in 1996 and identified as SLC26A4 in 1997. Fraser estimated this syndrome accounted for 5.6% of congenital hearing loss in his series of 2355 children. Pendred syndrome (PS) is characterized by autosomal recessive inheritance of goiter and hearing loss, first reported in two sisters by Pendred in 1896. PENDRED SYNDROME AND NONSYNDROMIC HEARING LOSS WITH ENLARGEMENT OF THE VESTIBULAR AQUEDUCT SLC26A4 mutation testing can provide prognostic information to guide clinical surveillance and management, as well as the probability of EVA affecting a sibling. Patients without any mutations are an etiologically heterogeneous group in which siblings have a lower probability of having EVA. 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. 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. 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. 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. 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. 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. However, not all EVA patients have PS or SLC26A4 mutations. 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.
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