Thyroid Dysgenesis: Multigenic or Epigenetic … or Both?

With about 1/3200 newborn affected, congenital hypothyroidism is a significant public health issue that, in developed countries, has been addressed by efficient neonatal screening programs. In about 15% of the cases, the cause can be traced to a defect in one of the many genes implicated in thyroid hormone synthesis (thyroglobulin, thyroperoxidase, sodium-iodide symporter, pendrin, Thox2, iodotyrosine dehalogenase) (1). Dyshormonogeneses, as these situations are called, are transmitted as classical autosomal recessive mendelian traits. Thyroid dysgenesis, referring to developmental defects, encompasses the remaining 85% of the cases and can be further subdivided into agenesis, hypoplasia, ectopy, and hemiagenesis. Whereas about 5% of these cases have been shown to result from mutations in one of three thyroid developmental genes (TITF1, PAX8, FOXE1/TITF2) or the TSH receptor, the great majority present as sporadic (2). As such, thyroid dysgenesis represents one of the remaining enigma in the pathophysiology of thyroid diseases. Over the past 20 yr, research conducted essentially by the group of Roberto Di Lauro (2) has lead to the identification of the role of these three developmental genes, both in the regulation of expression of thyroid-specific genes, and embryonic development of the thyroid anlagen. Knockout mice provided the first animal models of human thyroid dysgenesis. From the beginning, however, there have been difficulties in comparing the mode of transmission between mouse and man. For titf1, homozygous knockout mice are nonviable, with athyreosis and major central nervous system anomalies (3). In human, no homozygous case has been identified yet, but heterozygotes display minor thyroid problems, with variable respiratory problems and progressive development of extrapyramidal symptoms in relation with developmental anomalies of the brain (4–6). Interestingly, and contrary to what is reported in the paper of Amendola et al. in this issue (7), upon reinvestigation, the heterozygous titf1 knockout mice, initially considered wild type, demonstrated mild thyroid anomalies (slightly elevated TSH), together with limited trouble of motor coordination (4). For pax8, the mode of transmission is different: recessive in mice, with failure of follicular cell development in homozygotes (8), and dominant in human in whom heterozygotes display thyroid hypoplasia with variable penetrance and expressivity (9–13). For foxe1/titf2, there seems to be agreement between recessive transmission in mice (agenesis or ectopy) and the limited number of human cases (agenesis) (14, 15).