Part of “CHAPTER 32 – THYROID HORMONE RESISTANCE SYNDROMES“

Generalized resistance to thyroid hormone is a genetic disease. Most reported cases belong to families with multiple affected members, and inspection of these pedigrees reveals that, in all but the original Refetoff kindred, the abnormal trait is transmitted dominantly.2 Compelling evidence that generalized resistance to thyroid hormone is a disease of the c-erbAβ thyroid-hormone receptor gene has come from linkage studies.2,5,6 Restriction fragment length polymorphisms (RFLPs) have been used to establish tight linkage between the β receptor gene and the syndrome of generalized resistance to thyroid hormone. Given the dominant inheritance pattern of pedigrees of generalized resistance to thyroid hormone, it was originally postulated that resistance occurred because mutant β receptors inhibited the activity of the normal β and α1 receptors (from one and two alleles, respectively).6 This hypothesis was convincingly proved in humans from the recessive kindred that has been extensively studied by Refetoff and coworkers.7,8 Sixty-five different mutations in the c-erbAβ gene have been identified in 115 families with either generalized or selective pituitary resistance to thyroid hormone9 (Fig. 32-2). These mutations exist as single (i.e., heterozygous) alleles, except in the Refetoff and Bercu patients.7,8,10,11 The majority of the c-erbAβ mutations is located in the penultimate and final exons of the gene and reduce T₃-binding affinity; these mutations cluster within two hot spots in the T₃-binding domain between amino acids 310-353 and 429-461.2,9

Presently, only one exception exists to the c-erbAβ rule. A kindred has been reported in whom the resistance phenotype is not linked to the c-erbAβ gene and who has no c-erbAβ1 or c-erbAβ2 defect.12 These data suggest that other factors that mediate thyroid hormone action may be defective, resulting in thyroid hormone resistance.