Mutations in SLC26A4 cause Pendred syndrome (PS) and a non syndromic deafness associated with the enlargement of the vestibular aqueduct (LVAS). In many patients with a PS/LVAS phenotype, mutation screening of SLC26A4 fails to identify two disease-causing allele variants, suggesting that other genetic factors could be involved. Indeed, mutations in the SLC26A4 promoter (FBS1), in FOXI1, a transcriptional activator of SLC26A4, and in a K+ channel gene (KCNJ10) have been very recently found in few patients with a PS/LVAS phenotype, some of whom carriers of a single SLC26A4 mutation. In the present study, 12 patients (6F and 6M, age range 6 months55 years) with PS or LVAS have been submitted to the genetic analysis of SLC26A4, FBS1, FOXI1, and KCNJ10. All patients had a severe to profound sensorineural hearing loss (SNHL) associated with inner ear malformations. In three patients, a multinodular goiter with subclinical hypothyroidism were documented, whereas the remaining patients were euthyroid with normal thyroid volume. All patients were connexins 26 and 30 negative. In three patients, homozygous or double heterozygous SLC26A4 mutations, one of which novel and lying in exon 2, were found. In one patient a single SLC26A4 mutation was documented, while in another case a novel FOXI1 mutation was identified. Finally, a variant in the KCNJ10 gene has been found in 3 patients. As far as genotypephenotype correlation concerns, it is interesting to note that the only 3 patients with two SLC26A4 mutations had a classic PS with SNHL and goiter, whereas in all the other cases no thyroid alterations were observed.
In conclusion, SLC26A4 is the gene more frequently mutated in patients with PS/LVAS, and seems to be specifically linked with the typical Pendreds phenotype. Nevertheless, mutations in FOXI1 and KCNJ10 have been also found, further suggesting that PS/LVAS is a multigenic complex disease.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology