The fetal hypothalamic-pituitary-thyroid system develops independently of the mother's pituitary-thyroid axis. During embryogenesis, primordial thyroid cells arise from epithelial cells on the pharyngeal floor; they then migrate caudally to fuse with the ventral aspect of the fourth pharyngeal pouch by 4 weeks' gestation. The thyroid continues to develop anteriorly to the third tracheal cartilage. Thyroglobulin is produced by 8 weeks' gestation. Trapping of iodine occurs by 10-12 weeks' gestation, followed by the synthesis of iodothyronines. Colloid formation and pituitary secretion of thyrotropin, also termed thyroid-stimulating hormone (TSH), occur by the 12 weeks' gestation.
The primary function of the thyroid gland is synthesis of thyroxine (T4) and triiodothyronine (T3). Pituitary thyrotropin regulates thyroid hormone production. TSH synthesis and secretion are stimulated by thyrotropin-releasing hormone (TRH), which is synthesized by the hypothalamus and is secreted into the hypophyseal portal vasculature for transport to the anterior pituitary gland. Serum T4 concentration modulates secretion of both TRH and TSH by means of a classic negative feedback loop.
Circulating T4 is predominantly bound to T4-binding globulin (TBG). T4 is deiodinated in peripheral tissue to T3, the more bioactive thyroid hormone. T3 carries 3-4 times the metabolic potency of T4, freely enters cells, and binds to receptors of the hormone into the cell nucleus. Thyroid hormone exerts profound effects on the regulation of gene transcription. Some major clinical phenomena of thyroid hormone action include differentiation of the CNS and maintenance of muscle mass. Thyroid hormone also controls skeletal growth and differentiation and metabolism of carbohydrates, lipids, and vitamins.
Thyroid hormone synthesis absolutely requires iodine. Dietary iodine deficiency is endemic in several areas of the world, particularly high mountain plateaus. In the United States, supplementation of salt with iodine has nearly eliminated dietary deficiency of this essential element. The recommended dietary allowance of iodine is 40-50 mcg daily in infants, 70-120 mcg daily for children, and 150 mcg daily for adolescents and adults. The daily intake in North America varies from 240 mcg to more than 700 mcg.
In the thyroid gland, iodide is trapped, transported, and concentrated in the follicular lumen for thyroid hormone synthesis. Before trapped iodide can react with tyrosine residues, it must be oxidized by thyroidal peroxidase. Iodination of tyrosine forms mono-iodotyrosine and di-iodotyrosine. Two molecules of di-iodotyrosine combine to form T4, and one molecule of mono-iodotyrosine combines with one molecule of di-iodotyrosine to form T3. Formed thyroid hormones are stored within thyroglobulin in the lumen of the thyroid follicle until release. TSH stimulates uptake and organification of iodide as well as liberation of T4 and T3 from thyroglobulin.
Hypothyroidism is among the most common endocrine diseases. Congenital hypothyroidism most commonly results from agenesis, dysplasia, or ectopy of the thyroid; however, it is also caused by autosomal recessive defects in the organification of iodine (thyroid hormone synthesis) and defects in other enzymatic steps in T4 synthesis and release. In older children and adults, acquired hypothyroidism is most commonly caused by autoimmune destruction (Hashimoto thyroiditis). 
Congenital hypothyroidism has a frequency of 1 case per 1500-3000 live births. 
Hypothyroidism can be congenital. Thyroid dysgenesis affects 1 per 4000 newborns worldwide. Hypothalamic or pituitary insufficiency, which results in secondary or tertiary hypothyroidism, respectively, affects 1 per 60,000-140,000 newborns worldwide.
Hypothyroidism can be acquired. Depending on the criteria used for diagnosis, as many as 10% of young females are estimated to have some signs of autoimmune thyroid disease, usually chronic lymphocytic thyroiditis (CLT). Not all cases progress to frank hypothyroidism; however, these patients remain at an increased risk compared with the general population.
Untreated congenital hypothyroidism in early infancy results in profound growth failure and disrupted development of the CNS, leading to developmental cognitive delay (cretinism). Untreated hypothyroidism in older children leads to growth failure as well as slowed metabolism and impaired memory.
In descending order, thyroid dysgenesis occurs more frequently in Hispanics than in whites, followed by blacks.
Thyroid dysgenesis occurs more frequently in females than in males, with a female-to-male ratio of 2:1. CLT also has a 4:1 female-to-male preponderance in childhood.
Congenital hypothyroidism can present with goiter at birth or with the gradual development of symptoms over the first several months of life.  The age of symptom onset is unpredictable in a child who has thyroid dysgenesis with a hypoplastic and/or ectopic thyroid gland because initial increases in TSH may be able to initially overcome the relative insufficiency of the thyroid gland. CLT typically presents during adolescence; however, it may present any time in life.
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