During embryogenesis, epithelial cells on the pharyngeal floor thicken to form a diverticulum. At about the fourth gestational week, the diverticulum elongates, and the primordial thyroid cells migrate caudally until they fuse with the ventral aspect of the fourth pharyngeal pouch. Two lobes connected by an isthmus are typically located anterior to the third tracheal cartilage. The thyroglossal duct that results from the migration normally involutes. Retention and growth of thyroid tissue at the lower end of the duct occasionally result in a pyramidal lobe. Thyroglobulin is produced by the eighth gestational week; trapping of iodine occurs by week 10, followed by iodination of tyrosine. Colloid formation and pituitary secretion of thyroid-stimulating hormone (TSH) occur by week 12. Fetal thyroid development is completely independent of the mother’s pituitary-thyroid axis because negligible amounts of maternal TSH or thyroxine (T₄) cross the placenta.

The secretion of T₄ is controlled by TSH, which is secreted by the pituitary gland. TSH secretion, in turn, is controlled by thyrotropin-releasing hormone (TRH), which is produced in the hypothalamus. The secretion of both TSH and TRH is modulated by serum levels of T₄ in a negative feedback loop. Circulating T₄ is predominantly bound by thyroxine-binding globulin and thyroxine-binding prealbumin. T₄ is deiodinated in peripheral tissues to the more bioactive hormone triiodothyronine (T₃). T₃ affects almost
every tissue in the body. T₃ binds to its receptors in the cell nucleus, and subsequent alteration of gene transcription by this complex leads to increases in the consumption of oxygen, formation of adenosine triphosphate, and cellular concentration of cyclic adenosine monophosphate.

Within 30 minutes after delivery, TSH levels in the normal neonate rapidly rise to about 80 μU per mL (80 mU/L) and then slowly decline during the next 3 days. In response, T₄ and T₃ levels rise dramatically by 24 hours of age, then slowly decline during the next few weeks.

The mental development of children with congenital hypothyroidism is related to the adequacy of treatment. Beginning treatment before 3 months of age improves the mental development of these children. Because of the paucity of early signs and symptoms in infants with congenital hypothyroidism (Table 17.1), early diagnosis and treatment were often delayed before the introduction of population screening.

Population screening for congenital hypothyroidism, by means of a T₄ radioimmunoassay of blood spots on filter paper, was begun in 1974 and combined with screening for phenylketonuria. Refinements in the initial screening program developed rapidly, and most industrialized nations now have such screening programs. In North America, the total T₄ level is measured in all newborns. Generally, if the T₄ level of a neonate falls within the lowest 10th percentile, both the T₄ and TSH levels are reassayed.

Newborn screening programs detect about one infant with congenital hypothyroidism for every 4000 live births. Up to five false-positive results may be obtained for every one confirmed case of congenital hypothyroidism. However, newborn screening programs are statistically unable to detect congenital hypothyroidism in about three infants for every 100,000 live births (about 12% of all infants with congenital hypothyroidism).

Of infants with congenital hypothyroidism:

Thyroid enzyme defects are inherited in an autosomalrecessive pattern.

Any infant in whom congenital hypothyroidism has been identified by a state screening program should immediately be examined by a physician for signs of congenital hypothyroidism (see Table 17.1). The infant’s serum free T₄ and TSH levels should be measured for confirmation. Infants with a deficiency of thyroxine-binding globulin are identified by state screening programs, but on confirmation testing, their free T₄ levels are found to be normal. The screening test results of infants whose mothers are receiving antithyroid medication also may be abnormal.

Therapy with levothyroxine should begin without delay after confirmatory blood tests have been obtained but before results become available. If the confirmatory tests show normal thyroid function, therapy is discontinued. The starting daily dose of levothyroxine is approximately 10 μg/kg.

Once treatment has been initiated, the T₄ and TSH levels should be followed monthly during the first year of life, every other month during the second year, and biannually thereafter. Dose increases of 0.0125 mg (one half of a 0.025-mg tablet) should be initiated when indicated, and measurements of T₄ and TSH should be repeated 1 month after the increase. The tablets are easily crushed and can be added to breast milk, formula, or water, or stirred into cereal. However, levothyroxine should not be mixed with soy-based formulas. Because the half-life of T₄ is about 6 days, a period of 4 weeks is required for serum T₄ values to reach a steady state. Normalization of elevated TSH levels may take even longer.

Even with adequate diagnosis and therapy, the intelligence quotient (IQ) of some children with congenital hypothyroidism is lower than predicted. Factors contributing to a decreased IQ include:

Occasionally, an infant appears to have congenital hypothyroidism on screening but has a normal T₄ value and a TSH value above 10 μU/mL (10 mU/L) on confirmatory testing. Some pediatric endocrinologists choose not to treat, but follow such infants carefully and treat them if the TSH levels increase with time. Alternatively, a cautious
approach is to treat these infants with levothyroxine until they are more than 2 years old. At this time, therapy can be stopped for 3 months and measurement of the T₄ and TSH levels repeated.

Causes of acquired hypothyroidism in children include:

A common cause of acquired hypothyroidism in children is autoimmune thyroiditis, which occurs in genetically predisposed persons. Clinical disease is triggered or aggravated by unidentified factors. The thyroid gland becomes enlarged but is usually not painful. Histologic changes include lymphocytic infiltration, formation of lymphoid follicles, and follicular cell hyperplasia. Antibodies to thyroid peroxidase (so-called microsomal antibodies) are characteristic of Hashimoto (chronic lymphocytic) thyroiditis. However, the antibodies are not responsible for the actual destruction of thyroid cells, which is probably caused by cytotoxic lymphocytes. Symptoms and signs of acquired hypothyroidism in children are listed in Table 17.2. The growth chart of an actual child with acquired hypothyroidism is shown in Figure 17.1.

Once a child is suspected of having hypothyroidism, the serum T₄ and TSH levels should be measured. If the T₄ level is low and the TSH level is high, the diagnosis of hypothyroidism is confirmed, and levothyroxine therapy should be started. Measuring the thyroid antibodies is unnecessary because the result of this test does not alter the treatment regimen.

In children with a goiter and normal T₄ and TSH levels, positive titers of microsomal thyroid antibodies confirm the diagnosis of Hashimoto thyroiditis and explain the thyromegaly. If a child or adolescent with Hashimoto thyroiditis has a noticeable goiter, treatment with levothyroxine may reduce it to some degree but usually does not eliminate it.