title: Development of the thyroid gland: lessons from congenitally hypothyroid mice and men.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Montreal Endocrinology Service and Research Center, Sainte-Justine Hospital, Montreal, Quebec, Canada. gvanvliet@justine.umontreal.ca
authors.forename: G
authors.initials: G
authors.lastname: Van Vliet
mesh_terms: 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
chemical_list: 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