Mutations in the Pendred Syndrome (PDS/SLC26A) gene: an increasingly complex phenotypic spectrum from goiter to thyroid hypoplasia.

Pendred syndrome is an autosomal recessive disorder traditionally defined by sensorineural deafness, goiter, and a partial defect in the organification of iodide (OMIM 274600; http://www.ncbi.nlm.nih.gov/omim) (1). The syndromic association of goiter and deafness was first described by the British practitioner Vaughan Pendred in 1896 (2), and the partial iodide organification defect was recognized by Morgans and Trotter (3) in 1958 by submitting affected individuals to a perchlorate discharge test. The molecular causeunderlying thisdisorder,whichaccounts for about 10% of hereditary hearing loss and is one of most common forms of syndromic deafness, was identified in 1997 through the demonstration of biallelic mutations in the SLC26A4 (solute carrier 26A4) gene (4), which encodes the multifunctional anion exchanger pendrin. Pendrin functions as a coupled electroneutral iodide/chloride, iodide/bicarbonate, and chloride/bicarbonate exchanger with a 1:1 stoichiometry (5). In the thyroid, pendrin is expressed at the apical membrane of follicular cells and is thought to mediate iodide efflux into the follicular lumen, although this step likely involves an additional, unidentified anion transporter or exchanger (6, 7). Clinically, the hallmark of Pendred syndrome is sensorineural hearing impairment. Most patients present with severe prelingual deafness, and others develop progressive hearing impairment later in life. Radiological studies of the innerearrevealanenlargementof theendolymphaticsystem, which is most readily detected by documenting an enlarged vestibular aqueduct (EVA) (8). The thyroid enlargement is variable among affected family members, and functionally some individuals are euthyroid, whereas others have (congenital) hypothyroidism. It is thought that the variability of the thyroid phenotype is, at least in part, influenced by the nutritional iodine intake (1). In countries with a high iodine intake, goiter development and thyroid dysfunction are usually not seen in patients with biallelic mutations in the SLC26A4 gene. Without performing molecular analyses and/or a perchlorate discharge test, which is unfortunately poorly standardized and subject to other factors such as iodide intake, it is not possible to clinically distinguish Pendred syndrome from nonsyndromic familial EVA (8). The patients withfamilialEVAhaveanidenticalphenotypeatthelevelofthe innerearbutabsent thyroidabnormalities,andtheyhaveeither no mutations or monoallelic mutations in the SLC26A gene, indicating that Pendred syndrome and nonsyndromic EVA are distinct clinical and genetic entities (8). Now, thephenotypic spectrumassociatedwithmutations in the SLC26A4 gene is unfolding with further complexity. In this issue of the JCEM, Kuhnen et al (9) report on two patients from distinct families with thyroid hypoplasia and biallelic mutations in the SLC26A4 gene. A heterogeneous groupofdevelopmental abnormalities, referred toas thyroid dysgenesis, is found in approximately 85% of all patients with sporadic congenital hypothyroidism. Thyroid dysgenesis includes a spectrum of anomalies: (hemi)agenesis, ectopy, and hypoplasia. In an effort to identify novel genetic defects underlying thyroid dysgenesis, these investigators performed whole exome sequencing of the DNA obtained from a patient with thyroid hypoplasia from a consanguineousfamily.Theinvestigatorsdetected760biallelicsequence variants with the potential to alter the encoded proteins, but only 17 were predicted to have damaging consequences based on prediction programs assessing the functional consequences of these alterations. Surprisingly, this led to the