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 human mutations have yet been described in the other related receptor gene, c-erbAα. 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 a receptor (expressed from two alleles). Patients homozygous for a dominant negative allele (the Bercu patient) and without any β receptor (the Refetoff patient) have been described. Patients with GRTH and PRTH both present with elevated free thyroxine and triiodothyronine and inappropriately normal thyroid-stimulating hormone, but the former patients are clinically euthyroid, whereas the latter patients have symptoms and signs of hyperthyroidism. However, in some cases, different patients who have been classified as having GRTH and PRTH have been found to have identical P mutations. A recent study of the level of pituitary resistance in a large kindred with GRTH (ARG-320-HIS mutation) indicated a contributory gene in the regulation of thyroid hormone action. Relative overexpression of the mutant PRO-453-HIS receptor at the level of messenger RNA in patient fibroblasts (kindred A) was associated with short stature. Finally, an ARG-316-HIS mutation (kindred G-H) was associated with relatively weak dominant negative activity and perturbed DNA-binding properties. In summary, multiple genetic factors, allelic-specific expression, and altered receptor dimerization properties may play a role in affecting the level of thyroid hormone resistance in various tissues.
© Lippincott-Raven Publishers.