Thyroid defects due to Pax8 gene mutations.

Congenital hypothyroidism (CH) occurs in 1 in 3000– 4000 newborns. Early diagnosis and therapy are absolutely critical because, when untreated, hypothyroid subjects develop severe and irreversible mental retardation. Thyroid dysgenesis (agenesis, ectopic location or hypoplasia) is the most common cause of CH. Tissue-specific transcription factors play a major role in organogenesis and cell differentiation. Therefore, defects of thyroid-specific transcription factors may be responsible for thyroid dysgenesis. Three transcription factors whose expression is restricted to the thyroid follicular cell (TFC) and few other cell types have been identified so far: the thyroid transcription factors-1 and -2 (TTF-1 and TTF-2) and Pax8 (1–2). In addition to the developing and mature thyroid gland, TTF-1 is expressed in lung and in several regions of developing brain (3), TTF-2 in the Rathke’s pouch (2) and Pax8 in developing kidney (4). Recent data, obtained in mice by the gene inactivation technique, have demonstrated the importance of TTF-1, TTF-2 and Pax8 in thyroid organogenesis (5–7) (Fig. 1). As expected, the search for mutations of genes coding for TTF-1, TTF-2 and Pax8 in subjects with thyroid dysgenesis has revealed that defects in these factors are responsible for several cases of CH (8–11). TTF-1 gene inactivation in mice, in addition to severe defects in lung and forebrain, gives rise to absence of the thyroid gland, indicating a critical role of this factor in early events of organogenesis (5). The lung defects are not compatible with life; this is probably why no CH due to TTF-1 gene mutations has been found in humans (8). Recently, however, a subject in which a heterozygous deletion of TTF-1 gene was associated with respiratory failure and raised serum thyrotropin (TSH) concentration was described (9). TTF-2 gene inactivation has revealed that this factor is absolutely required for the downward migration of the thyroid gland primordium which occurs from 9.5 to 15.5 days post-conception (p.c.), as well as for palate closure (6). Newborn mice show either ectopy or absence of the thyroid gland, associated with cleft palate. In accord, a family in which thyroid agenesis, cleft palate and choanal atresia are associated with homozygous TTF-2 gene mutation has been recently described (10). Pax8 gene mutations elicit also thyroid defects in both mice and humans. The reported data, however, reveal a complex picture suggestive for future development in the field, therefore deserving a detailed comment.