Identification of a novel mutation in the gene encoding the β‐triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone

Abstract

OBJECTIVE We investigated whether the first patient (L‐F3) reported as having selective pituitary resistance had a mutation in the hTRβ gene. We compared the clinical parameters of this case with those of patients with generalized resistance to thyroid hormone. DESIGN The patient, L‐F3, was part of a study at the NIH to identify mutations by sequencing the hTRβ gene in kindreds with thyroid hormone resistance. The clinical data of L‐F3 as well as patients with generalized resistance to thyroid hormone were compared and analysed retrospectively. MEASUREMENT We amplified by the polymerase chain reaction and then sequenced exons 5 to 10 of the hTRβ gene in L‐F3 and a normal control. Upon finding the mutation in L‐F3, we measured the affinity constant of this mutated hTRβ receptor. Criteria developed previously were used to assess tissue responsiveness to thyroid hormone of L‐F3. RESULTS We identified a C to T transition at base 1297 in codon 333 of the hTRβ gene in the first patient (L‐F3) reported as having apparent selective pituitary resistance. This base substitution resulted in more than a fourfold decrease in T3‐binding affinity for the hTRβ 1 receptor. The mutation of L‐F3 occurred in the dimerization domain of exon 9, a region where the majority of mutations of kindreds with generalized thyroid hormone resistance have been found. Furthermore, the nucleotide substitution at base 1297 found in the apparent selective pituitary resistant case, L‐F3, was the same as in an unrelated patient (K‐T3) with generalized resistance to thyroid hormone. As a result, we compared the clinical parameters of both patients and found that they had similar patterns of resistance in several tissues. Besides the bone resistance present in both kindreds, the apparent selective pituitary resistance case also had liver and neuromuscular resistance. CONCLUSIONS These findings suggest that apparent selective pituitary resistance and generalized resistance to thyroid hormone are not qualitatively different syndromes. Nevertheless, identification of selective pituitary resistance is a useful clinical distinction since such patients with clinical and biochemical features of hyperthyroidism appear to benefit from reduction in serum thyroid hormone concentrations. In contrast, patients with more conventional forms of thyroid hormone resistance require no treatment or may benefit from increased concentrations of thyroid hormone.