The Genetic Aspects of Primary Congenital Hypothyroidism

  The TSH receptor gene (TSHR) encodes a transmembrane receptor present on the surface of follicular cells which mediates the effects of TSH secreted by the anterior pituitary and is critical for the development and function of the thyroid gland. The human TSHR gene is located on chromosome 14q31 and the extracellular domain of the receptor is encoded by nine exons, whereas the transmembrane and intracellular portions are encoded by a single large exon.

Organification defects leading to goitrous congenital hypothyroidism are now well known to have an autosomal recessive genetic basis.
More recently, there is growing evidence for the role of germline gene defects causing congenital hypothyroidism associated with thyroid dysgenesis. These include a role for the TSHR gene in non-syndromic congenital hypothyroidism, with evidence for its involvement in recessive disease, and possibly also heterozygous mutations in this gene in congenital or even acquired non-autoimmune hypothyroidism. Downstream of TSHR, defects in Gsa result in TSH resistance in Albright’s hereditary osteodystrophy. Defects in the transcription factors TITF-2 (cleft palate, spiky hair), TITF-1 (neonatal respiratory distress, involuntary movement), and Pax-8 (renal hemiagenesis) provide the basis for multisystem involvement in syndromic forms of congenital hypothyroidism. Finally, there is early evidence emerging for a third group of congenital hypothyroid conditions associated with defects in target tissue iodothyronine transporters, with devastating neurological features.

      Thyroid gland development begins normally, but follicle formation and thyroglobulin processing are abnormal in late gestation. The expression of several molecular markers essential for thyroid gland formation and function—namely TTF-1, Pax8, and TTF-2—is affected in the developing thyroid gland, with the consequence of altered expression of thyroid effector genes, including the thyroglobulin and TPO genes. Murine Nkx-2.5, a member of the homeobox gene superfamily that is related to the TITF1 (NKX-2.1), is expressed early during embryogenesis of both thyroid and myocardium, and accordingly represents a strong candidate in those 4% of cases of congenital hypothyroidism that are associated with cardiac defects.