Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene.

Pendred syndrome (PS) is the most common cause of syndromic deafness, accounting for more than 5% of all autosomal-recessive hearing loss cases. It is characterized by bilateral sensorineural hearing loss and by goiter with or without hypothyroidism. Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter. To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P. An audiological long-term follow-up of 23 yr showed that the mutation T416P is associated with a distinct type of hearing loss in each of the three sibs: moderate-to-profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing form. We show that these phenotypic differences are not caused by either different degrees of inner ear malformations or sequence variations in the GJB2/connexin 26 gene. Because the thyroid phenotype was also highly variable within the family, with thyroid sizes ranging from normal to large goiters requiring thyroidectomy, this study leads to the conclusion that other environmental and/or genetic factors have an impact on the PS phenotype.