Congenital Hypothyroidism

The thyroid forms as a midline outpouching from between the first and second pharyngeal pouches and descends into the neck just above the developing lung bud between 4 and 7 weeks gestation. The parathyroid glands condense from the third and fourth pharyngeal pouches and move into the migrated thyroid tissue. C cells are derived from separate neuroectodermal tissue in the ultimobranchial body. These events are under the control of a series of transcription factors and ‘patterning’ genes that can be mutated to produce maldevelopment at any stage of descent. However, it is rare for there to be associated hypoparathyroidism as the derivation of the tissue is separate. The gland may fail to develop or may be an abnormal midline structure anywhere from the base of the tongue (see Fig. 1.85) to the upper thorax. During fetal life the thyroid starts to produce thyroid hormone from 20 weeks onwards, stimulated by pituitary thyroid stimulating hormone (TSH) secretion. Thyroxine (T4) is first primarily metabolized to inactive reverse triiodothyronine (rT3) by the placenta, and only after 30 weeks does the active T3 level starts to rise. It was thought for many years that maternal T4 does not cross the placenta, but there is now good evidence that some bioactive and necessary T4 can pass to the fetal circulation as mothers with borderline hypothyroidism have infants with slightly, but significantly, lower developmental quotients. The majority of release of thyroid hormones from the thyroid gland is in the form of T4 that is de-iodinated to T3 in the peripheral tissues or deactivated by the formation of rT3 and then further de-iodinated. Most of the activity of the hormones is mediated by the action of T3 on intranuclear receptors. Most T4 circulates bound to a specific protein, thyroxine binding globulin (TBG), and albumin. Assays of total T4 are strongly influenced by states that affect this binding such as drugs, liver disease, and pregnancy. Modern assays of free T4 (FT4) and T3 (FT3) are largely free of interference from other conditions, although some antiepileptic drugs do speed up the conversion of FT4 to FT3 and can alter circulating levels in the assay. Normal levels of thyroid hormones in infancy and childhood are given in the Appendix; there is an immediate postnatal surge in TSH, and FT4 levels are higher in the neonatal period than later in life. Congenital hypothyroidism can be divided into primary and secondary–tertiary forms. Primary hypothyroidism is caused either by embryonic defects (agenesis, dysgenesis, ectopia), accounting for 90% of cases, or by dyshormonogenesis – this category comprises several enzyme deficiencies, which are usually transmitted as an autosomal recessive trait and are commoner in some ethnic subpopulations and with consanguinity. Secondary or tertiary hypothyroidism is usually associated with other pituitary hormone deficiencies and accounts for only 1–2% of cases. Down syndrome is associated with an increased incidence of thyroid agenesis.