New Developments in Clinical and Genetic Aspects of Thyroid Hormone Resistance Syndromes

The genetic etiology of thyroid hormone resistance syndromes is now well-established. Two clinical variants, generalized resistance to thyroid hormone (GRTH) and selective pituitary resistance to thyroid hormone (PRTH), are, in most cases, caused by heterozygous mutations in the ligand-binding domain of the c-erbAβ thyroid hormone receptor gene. No mutations have been found in the other related receptor gene, c-erbAα, associated with these syndromes. In resistant patients, the mutant β receptors act as dominant negative proteins and inhibit function of the normal β receptor (expressed from one allele) and the normal α receptor (expressed from two alleles). Patients homozygous for a dominant negative allele (the Refetoff patient) and without any β receptor (the Refetoff patient) have been described. GRTH and PRTH are both diagnosed by elevated serum free thyroid hormones and inappropriately 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 patients who have been classified as having GRTH and PRTH who harbor identical β mutations. Various mechanisms can explain the clinical heterogeneity seen in thyroid hormone resistance syndromes: overexpression of the mutant β receptor allele, additional contributory genes, and variable perturbations of the dimerization domain of the receptor that in turn affect DNA-binding affinity. These factors may modulate the magnitude of tissue resistance resulting in variable levels of circulating thyroid hormone and other differences in phenotype such as stature.