Clinical and molecular analysis of three Mexican families with Pendred's syndrome

Background: The autosomal recessive Pendred's syndrome is defined by congen ital sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the Pendred's syndrome (PDS) gene that encodes p endrin, a chloride/iodide transporter expressed in the thyroid, the inner e ar, and the kidney. Objective: To perform a detailed clinical and molecular analysis of patient s with Pendred's syndrome from four patients from three unrelated Mexican f amilies. Methods: Thyroid function tests, perchlorate test, thyroid scintigraphy, au diometry, computer tomography and magnetic resonance imaging were performed in all affected individuals. Haplotype analyses were performed using micro satellite markers flanking the PDS locus, and the PDS gene was submitted to direct sequence analysis. Results: All patients presented with sensorineural deafness, Mondini malfor mations of the cochlea. an enlarged vestibular aqueduct, goiter, and a posi tive perchlorate test. Two patients were hypothyroid, two individuals were euthyroid. Sequence analysis revealed a complex homozygous deletion/inserti on mutation at the end of exon 4 in the index patient of family 1 resulting in a premature stop codon at position 138. In family 2, the affected indiv iduals were compound heterozygous for a splice acceptor mutation (IVS2 -1G > A) and a 1231G > C transversion substituting alanine 411 by proline (A411 P). In family 3, the index patient was found to be homozygous for a transve rsion 412G > T in exon 4 replacing valine 138 by phenylalanine (V138F). Conclusions: All patients included in this study presented with the classic Pendred syndrome triad and molecular analysis revealed pendrin mutations a s the underlying cause. The identification of three novel mutations, one of them of complex structure, expands the spectrum of mutations in the PDS ge ne and emphasizes that they display marked allelic heterogeneity.