In 1942, Fuller Albright used the example of pseudohypoparathyroidism to introduce the concept of a hormone resistance syndrome (1). Over the last 50 yr, clinical, biochemical, and molecular studies of hormone resistance syndromes have flourished. In addition to resistance to PTH, there have been descriptions of insulin, GH, androgen, vitamin D, glucocorticoid, and thyroid hormone resistance syndromes. For each of these syndromes, receptor mutations have now been identified and new receptor mutations are reported in nearly every issue of the Journal.

In the face of these elegant molecular genetic studies, it is easy to lose sight of the fact that many years of clinical and biochemical experimentation laid the foundation for the more recent advances. Moreover, there is little value in defining mutations if they do not in some way help us to better understand pathophysiology or provide new approaches for the diagnosis or treatment of a disease. In the case of generalized resistance to thyroid hormone (GRTH), there has been a particularly rich interchange of information between the clinical and laboratory findings. It is helpful to retrace some of the clinical investigation that led to the discovery of mutations in the thyroid hormone receptor. Thyroid hormone resistance was first described in 1967 by Refetoff, DeWind, and DeGroot (2). They evaluated several siblings in a family with congenital deafness and dysgenetic stippled epiphyses. Initially, thyroid function tests were evaluated in this family to exclude hypothyroidism. Surprisingly, thyroid hormone levels were markedly elevated in the affected children. Because there were no signs or symptoms of thyrotoxicosis, the authors hypothesized the existence of target organ resistance to thyroid hormone to explain the clinical and laboratory findings. Since the original report of GRTH, more than 200 cases have been described. Individuals with GRTH are now characterized by having elevated free thyroid hormone levels and inappropriately normal or elevated TSH (assuming that other causes of inappropriate TSH