LETTER
Resistance to Thyroid Hormone
Leslie J. DeGroot, MD
1 October 1996 | Volume 125 Issue 7 | Page 623
TO THE EDITOR:
Historians have recognized that history is a collection of impressions that can be presented in many ways. Voltaire said that "in all nations, history is disfigured by fable" and "history proves that anything can be proved by history." However, the sequence of recognition of thyroid hormone receptor mutations as a cause of resistance to thyroid hormone is not as suggested in the editorial by Dr. Sawin [1].
The first patients with resistance to thyroid hormone were observed in 1964 by Dr. Loren T. DeWind and were initially studied at the Good Samaritan Hospital in Los Angeles. Characterization of their syndrome as being caused by resistance to thyroid hormone came from studies that were done at Massachusetts General Hospital and Massachusetts Institute of Technology in 1965-1966 (published in 1967 [2]) and at Massachusetts Institute of Technology in 1966 and the University of Chicago in 1969 (published in 1972). Dr. Samuel Refetoff and I subsequently worked on this problem until the cause became elucidated two decades later. It was impossible at first to get closer to the cause because the concept of receptors was just developing (thyroid hormone receptors were first recognized by Oppenheimer and colleagues in 1972). We studied the receptors in the original patients by using fibroblasts and showed in 1978 that the receptors of these patients were abnormal [3].
Further understanding awaited cloning of the ß-receptor by Weinberger and colleagues in 1986. We subsequently cloned the 
-receptor in 1988. Also in 1988, Usala and coworkers showed a link between the phenotype of resistance to thyroid hormone and the thyroid hormone receptor gene on chromosome 3. Sequencing of the receptor led us to submit a paper on 21 August 1989 [4]; this paper reported that a mutated receptor causes thyroid hormone resistance. In 1992, our laboratory reported the second cause of thyroid hormone resistance, homozygous deletion of thyroid hormone receptor-ß [5].
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Author and Article Information
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University of Chicago Medical Center, Chicago, IL 60637
1. Sawin CT. When hormones fail to act [Editorial]. Ann Intern Med. 1995; 123:625-7.
2. Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab. 1967; 27:279-94.
3. Bernal J, Refetoff S, DeGroot LJ. Abnormalities of triiodothyronine binding to lymphocyte and fibroblast nuclei from a patient with peripheral tissue resistance to thyroid hormone action. J Clin Endocrinol Metab. 1978; 47:1266-72.
4. Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seino S, et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor ß. Proc Natl Acad Sci U S A. 1989; 86:8977-81.
5. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor ß gene. J Clin Endocrinol Metab. 1992; 74:49-55.
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