CLINICAL AND MOLECULAR-GENETICS STUDIES IN PENDREDS-SYNDROME

A large and highly inbred kindred including patients with incomplete a nd complete forms of Pendred's syndrome was studied. Blood samples wer e 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 individ uals. 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 evidenc e of a multinodular goiter. In addition, 13 individuals had impaired h earing 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 b e defective for coupling but could be partially effective for iodide o rganification. We have investigated possible abnormalities in the TPO gene by Southern blot analysis. Genomic DNA was obtained from peripher al blood leukocytes of 40 subjects (22 affected and 18 normal). DNA sa mples were digested with five restriction enzymes and hybridized with the pM5 probe (831 bp). Polymorphic fragment patterns obtained with th ree of the five enzymes employed were equally distributed in normal an d affected subjects of this kindred, Lod score analysis did not disclo se any linkage of TPO gene polymorphisms with the phenotypic character istics observed in this family. Our findings may be explained in two d ifferent ways. First one might have hitherto undetected mutations in t he TPO gene, and, second, the pathology may in fact be due to a geneti c defect lying elsewhere.