Resistance to thyroid hormone caused by a new mutation (V336M) in the thyroid hormone receptor β gene

Resistance to thyroid hormone (RTH), usually caused by an inherited defect of the thyroid hormone receptor beta (TR beta), results in a reduced responsiveness of target tissues to thyroid hormone. Until now, more than 600 cases with RTH have been identified. Although usually linked to the TR beta gene, located on chromosome 3, RTH may also occur in the absence of mutations in the coding region of this gene. We report a 10-month-old boy who had laboratory findings typical of RTH. He was born prematurely on the 34th week of gestation and his thyrotropin (TSH) during neonatal screening was 121 mu U/mL, a value very high for RTH or prematurity. Direct sequencing of the TR beta gene from the patient's genomic DNA revealed a heterozygous substitution of the normal valine with a mutant methionine in codon 336 (V336M) that has not been previously reported. In vitro expression studies showed that this mutant TR beta has an impaired triiodothyronine (T-3)-dependent transactivation that reduces the activity of the wild-type TR beta (dominant negative effect). While the functional impairment of V336M is not unusual compared to other: TR beta gene mutations, the very high TSH value in this prematurely born infant suggests that fetuses with RTH have altered maturation of the hypothalamo-pituitary-thyroid axis or actually may suffer from hypothyroidism.