Molecular Defects in the Hypothalamic-Pituitary-Thyroid Axis Leading to Congenital Hypothyroidism

In recent years, the application of molecular techniques in the evaluation of patients with CH has made it possible to define the molecular basis in a number of cases. A prerequisite for molecular studies is the distinction between primary and secondary or central CH. In primary CH (disordered organogenesis of the thyroid gland or defective thyroxine synthesis), the genetic defects, thus far identified, include those of genes encoding the transcription factors TTF1, TTF2 and PAX8 or the TSHR, NIS, TG and TPO. In some of these molecular abnormalities (TTF2), CH may be associated with various morphogenetic defects. In central CH, the defect lies in the hypothalamic-pituitary axis: TRH synthesis, TRH receptor, synthesis of the TSH β subunit. The biochemical localization of the defect in such cases can be accomplished by a TRH test. Genetic defects in transcription factors involved in pituitary ontogenesis (HESX1, LHX3, Prop1, Pit1) can also result in CH. In such cases, low TSH occurs in association with other pituitary hormone deficiencies. It must be underlined that, in patients with CH, as in other genetically determined disorders, the localization of the molecular defect is very important for genetic counseling, antenatal diagnosis and delineation of prognosis.