Thyroid Hormone Resistance, Selective Pituitary

A number sign (#) is used with this entry because of evidence that selective pituitary resistance to thyroid hormone is caused by mutation in the thyroid hormone receptor gene (THRB; 190160). Generalized resistance to thyroid hormone (GRTH), autosomal dominant (188570) and autosomal recessive (274300), is also caused by mutation in the THRB gene.

Clinical Features

In 3 generations of a family, Rosler et al. (1982) found 6 females who had hyperthyroidism due to chronic overstimulation of the thyroid by pituitary thyroid-stimulating hormone (TSH). Complete remission was achieved and maintained with continuing therapy with triiodothyronine (T3). The authors suggested that the inappropriate TSH secretion was due to partial unresponsiveness of the thyrotrophic cells of the pituitary to thyroid hormone. Possibly the unresponsiveness was due to deficiency of pituitary T4 monodeiodinase which converts T4 to T3 or the thyrotrophic cells may have a reduced sensitivity to T3 so that they are shut off only when serum T3 is raised to high levels. Gershengorn and Weintraub (1975) described an 18-year-old woman with clinical and laboratory features of hyperthyroidism despite persistently elevated serum levels of immunoreactive TSH. They proposed the designation 'inappropriate secretion of TSH.' Spanheimer et al. (1982) reported 3 cases, the youngest a 4-year-old girl with goiter and symptoms of hyperthyroidism. The syndrome was attributed to selective pituitary insensitivity to thyroid hormone. Hamon et al. (1988) observed the disorder in a 15-month-old boy. Aguilar Diosdado et al. (1991) observed the disorder in mother and sister of a 12-year-old girl who presented with hyperthyroidism.

Molecular Genetics

Geffner et al. (1993) described an arg311-to-his mutation in the thyroid hormone receptor beta gene (THRB; 190160.0018) in a patient with PRTH, but the mutation did not fully explain the phenotype inasmuch as the father and a half sister who were clinically clinically unaffected had the same mutation. Geffner et al. (1993) indicated that the original patient with PRTH described by Gershengorn and Weintraub (1975) had been found to have a common mutation of the THRB gene (R338W; 190160.0023) (Mixson et al., 1993).

Adams et al. (1994) analyzed 20 cases of generalized resistance to thyroid hormone and 9 cases of selective pituitary resistance to thyroid hormone, sporadic or dominantly inherited. All affected individuals were heterozygous for single nucleotide substitutions in the THRB gene, except for one case of a 7-nucleotide insertion. In this series, 9 individuals exhibited a marked preponderance of thyrotoxic signs and symptoms leading to a diagnosis of PRTH. Adams et al. (1994) documented a dominant mode of inheritance in 4 PRTH families with cosegregation of mutations and thyroid dysfunction. Sporadic mutations were recorded with approximately equal frequency in GRTH and PRTH. Both GRTH and PRTH phenotypes were observed in different families harboring the same mutation and could coexist in affected members of a single kindred. Even in a single individual, thyrotoxic symptoms were variable. Although Adams et al. (1994) did not find a clear association between particular mutations and PRTH, it was noteworthy that the R338W mutation was associated with PRTH in 4 out of 5 of their kindreds as well as in 2 other cases reported in the literature (Mixson et al., 1993; Sasaki et al., 1993).