SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities.

E nlargement of the vestibular aqueduct (EVA) and its contents, the endolymphatic sac and duct, is the most common radiologic malformation of the inner ear associated with sensorineural hearing loss. It may occur alone or in combination with an incomplete partition of the apical turn of the cochlea as part of a complex of malformations known as a Mondini deformity. Hearing loss in ears with EVA is typically preor perilingual in onset, sensorineural or mixed, and fluctuating or progressive. EVA may be unilateral or bilateral; asymmetry of the hearing loss and the anatomic defect is common in bilateral cases. EVA has been observed in Pendred syndrome (PS; MIM 274600), branchio-oto-renal syndrome (MIM 113650), CHARGE (MIM 214800), Waardenburg syndrome (MIM 193500, 193510, 600193, 606662), and distal renal tubular acidosis with deafness (MIM 267300). Familial non-syndromic hearing loss with EVA was described in 1996 and numerous subsequent reports (DFNB4 (MIM 600791), enlarged vestibular aqueduct syndrome (MIM 603545)). EVA is always detected when the ears of individuals with PS are evaluated by both computed tomography (CT) and magnetic resonance imaging (MRI), and it has been estimated that PS may comprise up to 10% of prelingual deafness worldwide. 12 13 PS is inherited in an autosomal recessive manner and is comprised of bilateral hearing loss, EVA, and an iodine organification defect in the thyroid gland, which may lead to goitre. PS is clinically differentiated from non-syndromic EVA by the presence of the thyroid iodine organification defect because goitre is an incompletely penetrant feature of PS. When goitre does occur in PS, it is most often euthyroidal and not evident until the second decade of life. 12 14 15 There can be intrafamilial variability of the goitre, and PS phenocopies with goitre due to other etiologies have been reported. The perchlorate discharge test can detect the thyroid iodine organification defect in PS, but has acquired a reputation as an unreliable diagnostic criterion due to its low specificity and significant variation in the criteria used for interpretation. 17 18 There has been no standardisation of iodine isotopes, doses, routes of administration, timing of perchlorate administration in relation to the iodine dose, or consensus on the definitive time point for measurement of discharge. Finally, the percent discharge criterion to differentiate normal from abnormal tests has varied widely among different studies. Host factors can also confound the interpretation of the perchlorate discharge test. Discharge may be abnormal in patients with Hashimoto’s thyroiditis, Graves’ disease, cretinism, or intrathyroidal peroxidase deficiency. Previous surgical resection or radioablation of the thyroid, or recent ingestion of thyrotropic medications, food, or liquids may also cause abnormal perchlorate discharge values, precluding a reliable test interpretation. Chronic dietary iodine intake may also theoretically affect discharge results. A complete medical history and serologic screening for Hashimoto’s thyroiditis and Graves’ disease, with thorough pre-test patient education, is required to identify these confounding factors and avoid a misleading discharge evaluation. Key points