Clinical and molecular genetics studies in Pendred's syndrome.

A large and highly inbred kindred including patients with incomplete and complete forms of Pendred's syndrome was studied. Blood samples were collected from 42 individuals (23 affected and 19 normal), and serum thyroid hormones, TSH, Tg, and anti-TPO autoantibodies were assayed. Thyroid function studies have indicated euthyroidism in all 42 individuals. The affected subjects, however, had significantly elevated serum Tg levels (19.4 +/- 6.8 ng/dL) as compared with normals (9.6 +/- 2.9 ng/dL). Nineteen subjects had clinical and or ultrasonographic evidence of a multinodular goiter. In addition, 13 individuals had impaired hearing with or without goiter. Computer axial tomography scan studies in six patients confirmed the presence of a defective cochlea (Mondini's cochlear defect) in three of these subjects. It has been suggested that thyroperoxidase (TPO) in patients with Pendred's syndrome might be defective for coupling but could be partially effective for iodide organification. We have investigated possible abnormalities in the TPO gene by Southern blot analysis. Genomic DNA was obtained from peripheral blood leukocytes of 40 subjects (22 affected and 18 normal). DNA samples were digested with five restriction enzymes and hybridized with the pM5 probe (831 bp). Polymorphic fragment patterns obtained with three of the five enzymes employed were equally distributed in normal and affected subjects of this kindred. Lod score analysis did not disclose any linkage of TPO gene polymorphisms with the phenotypic characteristics observed in this family. Our findings may be explained in two different ways. First one might have hitherto undetected mutations in the TPO gene, and, second, the pathology may in fact be due to a genetic defect lying elsewhere.