Current Loss-Of-Function Mutations in The Thyrotropin Receptor Gene: When to Investigate, Clinical Effects, and Treatment.

Background: TSHR LOF mutations lead to a wide spectrum of phenotypes, ranging from severe congenital hypothyroidism to mild euthyroid hyperthyrotropinemia. The degree of TSH resistance depends on the severity of the impairment of the receptor function caused by the mutation and on the number of mutated alleles. Objective: In this review, data regarding genotype-phenotype correlation and criteria for clinical work-up will be presented and discussed. Results: Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe non-syndromic CH and severe thyroid hypoplasia diagnosed at birth by neonatal screening. Partial forms of TSH resistance show a more heterogeneous hormonal and clinical pattern. In these cases, TSH serum levels are above the upper limit of normal range for age but show a very variable pattern, fT4 concentrations are within the normal range and thyroid size can be normal or hypoplastic at US scan. An early substitution treatment with L-thyroxine (L-T4) should be mandatory in all patients with severe CH due to complete uncompensated TSH resistance diagnosed at birth by neonatal screening. The usefulness of substitution treatment appears to be much more controversial in patients with subclinical hypothyroidism due to partial TSH resistance in whom the increased TSH concentration should be able to compensate the mild functional impairment of the mutant receptor. Conclusions: Together with standard criteria, we recommend also an accurate clinical work-up to select patients who are candidates for a LOF TSHR mutation testing