Synthesis, storage, secretion, delivery, action, and metabolism of the thyroid hormones involve a complex sequence of molecular events, for which a number of the genes involved are known. Thyroid diseases may result from impairments at many steps in this process. Defects may be classified as resulting from anomalies within the thyroid gland (dyshormonogenesis), in the development of the thyroid anlage (thyroid dysgenesis), in the transport of thyroid hormones, in target tissues of thyroid hormones (thyroid hormone resistance), or in the regulatory hypothalamo-pituitary circuit.
Defects involving genes expressed in the thyroid gland may be responsible for a series of different phenotypes. Gain of function mutations of the thyrotropin receptor cause autosomal dominant toxic thyroid hyperplasia, or sporadic (neonatal) toxic thyroid hyperplasia, depending on whether the mutation is transmitted from one parent or is a new mutation. Loss-of-function mutations in any of the genes encoding proteins implicated directly or indirectly in thyroid hormone synthesis, cause hypothyroidism, usually associated with goiter secondary to hyperstimulation by thyrotropin (congenital goiter). Mutations of this type have been found in the sodium-iodide symporter (trapping defects), thyroglobulin (coupling defects), and thyroperoxidase and pendrin (organification defects). In all these instances, transmission is autosomal recessive and, except for the last one, the disease is nonsyndromic. Mutations of pendrin cause hypothyroidism associated with sensorineural deafness. Additional mutations are expected to be found in the genes responsible for H2O2 generation (an additional cause of organification defect), and in iodotyrosine deiodinase.
Inadequate regulation of thyroid function by thyrotropin causes a decrease in thyroid function (synthesis and secretion of thyroid hormone) and growth (thyroid hypoplasia). This may result from defects at the hypothalmo-pituitary level (central hypothyroidism), secondary to mutations in a series of developmental genes (PIT1, PROP1) required for normal growth and function of thyrotrophs. Mutations directly affecting the TRH receptor or thyrotropin beta genes also cause congenital hypothyroidism with thyroid hypoplasia. Similarly, but at the thyroid level, loss-of-function mutations of the TSH receptor gene cause variable levels of resistance to thyrotropin, the more severe cases presenting with congenital hypothyroidism and thyroid hypoplasia.
Thyroid dysgenesis is responsible for the majority of cases with congenital hypothyroidism (85%). It encompasses a series of developmental defects affecting the thyroid gland, whose common characteristic is an inadequate amount of functional thyroid tissue. The situation is anatomically (and probably genetically) heterogeneous, presenting as thyroid aplasia (agenesis), hypoplasia, ectopy, or hemiagenesis. Most cases are sporadic (~1/3500 newborn) which poses the unresolved problem of the genetic or environmental cause of the disease. In a handful of cases, a mutation has been identified in genes implicated in the development of the gland: PAX8 and TTF2 . In the latter, hypothyroidism is part of a complex syndrome with choanal atresia, cleft palate, and kinky hairs (Bamforth syndrome), reflecting the multiple sites of normal TTF2 expression.
Since only free thyroid hormones are responsible for the effects on target tissues (including the hypothalamus and the thyrotrophs), mutations in the proteins implicated in the transport of thyroid hormones in the blood (thyroid binding globulin (TBG); transthyretin; albumin) are responsible only for anomalies of the concentration of circulating thyroxine or triodothyronine, without any other biological or clinical sign of thyroid dysfunction. Mutations have been described leading to quantitative (complete/partial TBG deficiency, TBG excess) or qualitative anomalies in thyroxin binding globulin, the most frequent situation being defective production of the protein secondary to loss-of-function mutations in this X-linked gene. Increase in serum total thyroxine is observed in patients with mutations resulting in the production of transthyretin with increased affinity for the hormone. Similarly, variant albumin molecules have been described and the mutations identified, with increased affinity for iodothyronines, the result being euthyroid hyperthyroxinemia or hyper-triodothyroninemia. Values of thyroid hormones may reach extremely high values in some cases.
Resistance to thyroid hormone of variable severity and tissue distribution has been identified. In the majority of cases it is caused by mutations in the thyroid hormone receptor beta gene. The more common form is inherited dominantly because the mutant receptors, with decreased ligand binding or abnormal interaction with transcription cofactors, interfere with the function of the normal receptor. Resistance caused by receptor deletion is inherited recessively while a third form, without thyroid hormone receptor abnormalities, may be caused by defects in any of the cofactors involved in the mediation of thyroid hormone action.