Current loss-of-function mutations in the thyrotropin receptor gene: when to investigate, clinical effects, and treatment

In tro duc ti onCongenital hypothyroidism (CH) is the most common endocrine disorder in infancy.It shows a considerable variability in etiopathogenesis and clinical aspects.Among these various disorders, resistance to thyroid-stimulating hormone (TSH) has been defined as a genetic disease, characterized by TSH serum levels above the normal range, normal or reduced thyroid hormone concentrations, normal sized or hypoplastic thyroid gland, in absence of anti-thyroid antibodies.Recently, the OMIM database for genetic disease (at the website www.ncbi.nlm.nih.gov)classified TSH resistance among the six forms of nongoitrous CH (CHNG) and loss-of-function (LOF) mutations in the TSH receptor (TSHR) gene were identified as the most frequent cause of TSH resistance (Table 1) (1,2).This review will focus on the TSH resistance due to LOF TSHR gene mutations.Data about the spectrum of the TSHR gene mutations, genotype-phenotype correlation, phenotypic variability, and criteria for clinical work-up will be presented and discussed with the help of recent studies on TSHR gene analysis in large populations.TSHR Physiology TSHR encoded by the TSHR gene (chromosome 14q31) (3) is a G-protein-coupled receptor with a seven-transmembrane domain (TMD) activating the classical G-protein-coupled effectors, adenylatecyclase (AC) and phospholipase C (PLC) and a large extracellular domain (ECD) responsible for high-affinity hormone binding (Figure 1).TSHR ECD is encoded by the first 9 exons and part of exon 10, whereas TMD and intracellular domain are encoded by the exon 10. ABS TRACTThyroid-stimulating hormone receptor (TSHR) loss-of-function (LOF) mutations lead to a wide spectrum of phenotypes, ranging from severe congenital hypothyroidism (CH) 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 In this review data about genotype-phenotype correlation and criteria for clinical work-up will be presented and discussed.Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe not 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 the age but with a very variable pattern, free thyroxine (T4) concentrations are within the normal range and thyroid size can be normal or hypoplastic at ultrasound scan.An early substitutive treatment with L-T4 must be mandatory in all patients with severe CH due to complete uncompensated TSH resistance diagnosed at birth by neonatal screening.The usefulness of substitutive treatment appears 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.Together with standard criteria we recommend also an accurate clinical work-up to select patients who are candidates for a LOF TSHR mutation.