Development of the thyroid gland: lessons from congenitally hypothyroid mice and men.
Congenital hypothyroidism is the most common congenital endocrine disorder (one newborn in 3000) and represents the most common cause of preventable mental retardation. In 10-20% of cases, it is due to autosomal recessive functional disorders leading to goiter formation (thyroid dyshormonogenesis). In the remainder, it is due to thyroid dysgenesis, which comprises usually isolated defects in: (1) migration of the median thyroid anlage, leading to a round cluster of ectopic cells (usually in a sublingual position) with no other thyroid tissue present; (2) differentiation or survival of the thyroid follicular cells leading to athyreosis; and (3) growth of a thyroid with the normal bilobed shape and in the normal cervical position (orthotopic hypoplasia). Mouse knock-outs have demonstrated that thyroid transcription factor-1 (TTF-1) and PAX8 are required for the survival and proliferation of thyroid follicular cell precursors, TTF-2 for their downward migration and the thyrotropin receptor (TSHR) for post-natal thyroid growth. In humans, thyroid dysgenesis is generally a sporadic malformation but an affected relative is found in 2% of cases, a figure 15-fold higher than by chance alone. Pedigree analysis is most compatible with dominant inheritance with variable penetrance. However, mutations in TTF-1, TTF-2, PAX8 and TSHR are found in <10% of patients with congenital hypothyroidism and these predominantly have orthotopic thyroid hypoplasia, often associated with other malformations. This low yield and the discordance of >90% of monozygotic twin pairs suggests that isolated thyroid ectopy or athyreosis most often results from early somatic mutations, epigenetic modifications or stochastic developmental events.
Van Vliet
G
G
Department of Pediatrics, University of Montreal Endocrinology Service and Research Center, Sainte-Justine Hospital, Montreal, Quebec, Canada. gvanvliet@justine.umontreal.ca
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors; D006801:Humans; D007037:Hypothyroidism / Q000196:embryology / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000196:embryology* / Q000254:growth & development / Q000503:physiopathology; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D012097:Repressor Proteins; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators; D014157:Transcription Factors