NEW DEVELOPMENTS IN CLINICAL AND GENETIC-ASPECTS OF THYROID-HORMONE RESISTANCE SYNDROMES

The genetic etiology of thyroid hormone resistance syndromes is now we ll established. Two clinical variants, generalized resistance to thyro id hormone (GRTH) and selective pituitary resistance to thyroid hormon e (PRTH), are, in most cases, caused by heterozygous mutations in the ligand binding domain of the c-erbA beta thyroid hormone receptor gene . No mutations have been found in the other related receptor gene, c-e rbA alpha, associated with these syndromes. In resistant patients, the mutant beta receptors act as dominant negative proteins and inhibit f unction of the normal beta receptor (expressed from one allele) and th e normal alpha receptor (expressed from two alleles). Patients homozyg ous for a dominant negative allele (the Bercu patient) and without any beta receptor (the Refetoff patient) have been described. GRTH and PR TH are both diagnosed by elevated serum free thyroid hormones and inap propriately normal TSH, but in the former case patients are clinically euthyroid whereas in the latter case patients have symptoms and signs of hyperthyroidism. Interestingly, there are examples of different pa tients who have been classified as having GRTH and PRTH who harbor ide ntical beta mutations. Various mechanisms can explain the clinical het erogeneity seen in thyroid hormone resistance syndromes: overexpressio n of the mutant beta receptor allele, additional contributory genes, a nd variable perturbations of the dimerization domain of the receptor t hat in turn affect DNA binding affinity. These factors may modulate th e magnitude of tissue resistance resulting in variable levels of circu lating thyroid hormone and other differences in phenotype such as stat ure.