The resistance to TSH action is a genetic disease characterized by molecular defects hampering the adequate transmission of TSH stimulatory signal into thyroid cells. In principle the defect may affect every step along the cascade of events following the binding of TSH to its receptor (TSHR) on thyroid cell membranes. The phenotypic expressivity of TSH resistance is highly variable going from severe congenital hypothyroidism (CH) with thyroid hypoplasia to mild hyperthyrotropinemia (hyperTSH) associated with an apparent euthyroid state. More severe forms follow a recessive pattern of inheritance and occur in patients with biallelic mutations both causing a severe loss of TSHR function. Differential diagnosis in these cases includes the exclusions of other causes of isolated thyroid dysgenesis. Mildest forms may instead occur in patients with monoallelic TSHR defects following a dominant mode of inheritance. In these cases we described the dominant negative effect exerted by some mutants on the activity of the receptor encoded by the wild type allele. In these cases, differential diagnosis involves the exclusion of autoimmune thyroid disease or pseudohypoparathyroidism associated with defects at the GNAS locus. This review will focus on the variable clinical expression of this disease.
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