Possible non-Mendelian mechanisms of thyroid dysgenesis

Most research on the molecular mechanisms of thyroid dysgenesis over the past decade has focussed on the Mendelian mechanisms that may account for the few (5%) cases in which there is an affected relative. This chapter first reviews methodological issues in the imaging techniques used to classify thyroid dysgenesis into its various forms (ectopic thyroid, agenesis, orthotopic hypoplasia and hemiagenesis). It then reviews the evidence that non-Mendelian mechanisms must be involved in the vast majority of cases of this disease, for which the percentage of sporadic cases and of discordance between monozygotic twins exceeds 95%. Among the mechanisms reviewed are early somatic mutations and epigenetic changes in genes involved in thyroid development such as the thyroid transcription factors TTF-1, TTF-2 and PAX-8. The possible role of extrathyroid genes involved in the control of migration of the median thyroid bud during embryogenesis, such as adhesion molecules, and of vascular factors involved in the stabilization of the bilobed structure of the thyroid is also discussed.