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.

Familial forms of thyroid dysgenesis.

In many instances, the pathophysiology of thyroid dysgenesis (TD) remains as yet unclear and until relatively recently the disorder was usually regarded as occurring in a sporadic manner. However, over the past few years, a small but significant proportion of familial cases has been identified (2%) through the study of subjects with congenital hypothyroidism and more recent work has revealed an even higher proportion of familial TD in both symptomatic or asymptomatic individuals (7.9%). Together, these studies strongly point to a significant genetic component of this disorder. Moreover, detailed observations of members affected by different types of TD in the same family suggest that TD could be an entity with a common underlying mechanism for all the etiological groups. To date, molecular genetic studies have implicated four genes in thyroid development and some mutations have been reported in affected subjects. Three of these encode transcription factors while the forth encodes the thyrotropin hormone receptor. However, their involvement in the general TD population remains questionable, as only a few mutations have been reported so far and as linkage analysis has demonstrated the relevance of other genes. Therefore, further work is required to fully understand the pathophysiology of TD.

Analysis of physical and mental development of children with aplasia, hypoplasia and ectopy of the thyroid gland.

OBJECTIVE: Evaluation of clinical and biochemical differences between various forms of thyroid dysgenesia in children. METHODS: The study involved 102 children at the age between 4.8 and 14.2 years who were born with congenital hypothyroidism (CH), as diagnosed by neonatal screening examinations. In all the children diagnosis was settled and the levothyroxine (L-T4) administration was started by the 19th day of life. Out of the examined children, 79 were selected with following three forms of developmental thyroid disorders: Group I--athyroidism (thyroid aplasia or agenesis), Group II--thyroid hypoplasia, Group III--thyroid ectopy. On the basis of neonatal TSH (nTSH) levels obtained by screening and serum TSH, FT4 and Tg concentrations, the severity of hypothyroidism was determined at the time of diagnosis. Physical and mental development of the children was evaluated on the basis of growth and bone age indices and Wechsler's scale, respectively. RESULTS: Developmental disorders were diagnosed in 79 cases (77.4% CH) which included 45 cases (44.1%) of athyroidism, 31 cases (30.4%) of thyroid hypoplasia and 3 cases (2.9%) of thyroid ectopy. The physical and mental development in the studied groups was evaluated as normal. CONCLUSIONS: In the group of children with athyroidism, significantly lower growth indices and IQ values were found in comparison with respective values observed in the other study groups. However, the indices of physical and mental development in all the studied groups were within the normal values for children population. An early diagnosis and early administration of hormonal replacement therapy by L-T4 ensure normal development of children with CH, regardless of underlying causes and associated with them severity of congenital hypothyroidism.