Different forms of resistance to thyrotropin (TSH) Action

More than 30 years ago, a child presenting with congenital hypothyroidism and normal/low basal thyroid radioiodine uptake was reported (1). Since thyroid gland was not enlarged and uptake did not increase after exogenous TSH administration, a diagnosis of congenital hypothyroidism due to TSH unresponsiveness was formulated. Thereafter, other similar cases were reported (2-6) and alterations in the receptor (TSHR), or in other downstream elements transducing the stimulatory signal in thyroid cells, were suggested as possible explanations for such clinical condition. It is in the mid 90s, soon after the cloning of TSHR (7-10), that inactivating mutations of TSHR were reported to cause TSH resistance in mouse and man (11,12). Nowadays, several other cases of TSH resistance due to loss-of-function TSHR mutations have been reported (13-24). Nevertheless, patients with clinical and biochemical features of TSH resistance but lacking mutations in TSHR gene are still currently reported (24-28). It is now evident that resistance to TSH action is a heterogeneous condition. Heterogeneity is reflected by the wide spectrum of clinical and subclinical manifestations, depending on the degree of thyroid tissue refractoriness to TSH stimulation, and by the different molecular mechanisms that may be involved in cases with normal TSHR gene.