Thyroid hormone has many effects on the human body. It plays an essential role in growth and development, thermogenesis, oxygen consumption, and the metabolism of carbohydrates, lipids, and proteins. Although thyroid hormone is essential for the normal function of many tissues, thyroid dysfunction is frequently insidious and may be missed.

The hypothalamic-pituitary-thyroid axis is finely tuned to maintain stable levels of thyroid hormone in the body. Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and stimulates the production and secretion of thyroid-stimulating hormone (TSH) by the anterior pituitary gland.¹ Through binding of the thyroid-stimulating hormone receptor (TSHR), TSH leads to production and release of the thyroid hormones, thyroxine (T4) and triiodothyroxine (T3), as well as thyroid cell growth. Thyroid hormones feedback on the anterior pituitary and hypothalamus, decreasing secretion of TSH and TRH, respectively, allowing for tight regulation of thyroid hormone concentrations. The predominant form of hormone secreted by the thyroid is T4, which then undergoes peripheral conversion to T3 by types I and III deiodinases. T3, the metabolically active hormone, and exerts its effects by binding nuclear receptors and influencing DNA transcription. T4 may also be converted into the inactive reverse T3 (rT3) by deiodinase type III. Increased rT3 is commonly seen in the fetus and in severely ill patients.¹

The majority of thyroid hormone circulates bound to thyroid-binding globulin (TBG) and to a lesser extent, other serum proteins. The remainder circulates unbound (free) and is metabolically active. Estrogen decreases TBG clearance, leading to higher levels of total thyroid hormone. As a result, oral contraceptive pill use or pregnancy will lead to elevated total T4 levels, but the free amount of thyroid hormone remains normal.

The maturity level of the hypothalamic-pituitary-thyroid axis must be considered to correctly interpret thyroid function tests in newborns and children. At birth, an acute surge in TSH occurs in response to exposure to the cold extrauterine environment, resulting in a rise in T4 and T3 levels. TSH remains elevated for 3 to 5 days after birth while the T4 and T3 levels gradually decline over the first 2 to 4 weeks of life.² During childhood, there is a progressive decrease in TSH and thyroid hormone levels until approximately age 15 to 16 years, when adult levels are reached (Table 69-1).

HYPOTHYROIDISM

Congenital Hypothyroidism

Congenital hypothyroidism, defined as thyroid hormone deficiency present at birth, occurs in approximately 1:2000 to 1:4000 newborns and is one of the leading causes of preventable intellectual disability.² The clinical manifestations are often subtle and usually not present at birth. Symptoms include lethargy, difficulty feeding, constipation, a hoarse cry, and prolonged jaundice. Physical examination may show a wide posterior fontanel, macroglossia, coarse facies, umbilical hernia, and hypotonia. Placental transfer of maternal thyroid hormone protects the developing fetus.³ Due to newborn screening, infants are usually identified before they develop clinical signs or symptoms of hypothyroidism.

Acquired Hypothyroidism

Hashimoto thyroiditis or autoimmune hypothyroidism is the most common cause of acquired hypothyroidism in children. The presentation is variable as the child may be euthyroid, hypothyroid, or transiently hyperthyroid at diagnosis. Children may complain of neck swelling, fatigue, constipation, cold intolerance, and in pubertal girls, menstrual irregularities. 70% to 80% of children with hypothyroidism will present with a goiter, which is typically symmetric and nontender.⁴ Other exam findings include bradycardia, proximal muscle weakness, delayed deep tendon reflexes, and growth failure (Figure 69-1). Hypothyroidism produces poor linear growth with preservation of normal weight gain, and these children may be relatively overweight for their height, but contrary to popular belief, hypothyroidism generally does not cause obesity.

Autoimmune hypothyroidism has a female predominance (2:1) and 40% to 50% of patients will have a positive family history of autoimmune thyroid disease.⁴ It can be associated with other autoimmune disorders, including type 1 diabetes mellitus, primary adrenal insufficiency (Addison disease), and celiac disease. Autoimmune thyroiditis is also more common in patients with certain chromosomal disorders, such as Down syndrome and Turner syndrome.

HYPERTHYROIDISM

Neonatal Hyperthyroidism

Neonatal thyrotoxicosis (neonatal Graves disease) is a rare disorder, occurring in only 1% to 1.4% of pregnancies affected by maternal Graves disease (autoimmune hyperthyroidism).⁵ It is most commonly due to transplacental passage of TSH receptor-stimulating antibodies from a mother with Graves disease, leading to increased thyroid hormone production in the fetus. The hyperthyroidism persists until the maternal antibodies are cleared from the infant’s circulation, which can take up to 3 to 4 months. Thyrotoxicosis may be suspected due to fetal tachycardia and intrauterine growth restriction. Clinical symptoms in the neonate are variable and may not occur until several days after birth due to antithyroid medications taken by the mother during pregnancy. Neonates may present with irritability, tachycardia, jaundice, poor weight gain, and exophthalmos.⁵ Affected infants need to be admitted to a neonatal intensive care unit for close monitoring of vital signs and frequent testing of thyroid labs, as neonatal hyperthyroidism can result in high-output cardiac failure and even death. A pediatric endocrinologist should be consulted immediately if neonatal hyperthyroidism is suspected. Untreated infants that survive may develop advanced bone age, craniosynostosis, and intellectual disability.

Graves Disease

The most common cause of hyperthyroidism in children is Graves disease (autoimmune hyperthyroidism), occurring in 1:10,000 children in the United States.⁶ There is a female predominance and peak incidence is during adolescence. Graves disease is an autoimmune disorder in which antibodies against the TSH receptor (also known as thyroid-stimulating immunoglobulins) cause the overproduction and secretion of thyroid hormone. The symptoms are often insidious and the rarity of the disorder and its nonspecific symptoms often result in a delay in diagnosis. Children may present with fatigue, weight loss, palpitations, increased bowel movements, irritability, and difficulty sleeping. Parents may report that their child has deteriorating school performance and decreased concentration.⁶ On examination, the thyroid is generally diffusely enlarged, and the patient may have tachycardia, hypertension, hyperreflexia, and a fine tremor. Ophthalmopathy (thyroid eye disease) may occur in children, but less commonly than in adults.

Thyroid storm in children is extremely rare, but is a medical emergency. It consists of acute hyperthermia, tachycardia, and encephalopathy in a patient with hyperthyroidism. Heart failure can result from the tachycardia. Thyroid storm may be precipitated by infection, surgery, or noncompliance with antithyroid medications.

HYPOTHYROIDISM

Congenital Hypothyroidism

Congenital hypothyroidism can be permanent or transient and is classified as primary, due to an inherent defect of the thyroid gland or thyroid hormone production or secretion, or secondary (central), due to defects in the pituitary/hypothalamus. Eighty-five percent of primary congenital hypothyroidism is caused by thyroid gland dysgenesis.² The gland may be ectopically located, hypoplastic, or absent. In some parts of the world, iodine deficiency is an important cause of congenital hypothyroidism; however, this condition is almost nonexistent in the United States. Isolated TSH deficiency is very rare and central congenital hypothyroidism occurs more commonly in the presence of other pituitary deficits. The presence of midline defects, micropenis, and/or hypoglycemia in a neonate suggests the possibility of hypopituitarism, which could be due to anatomical defects of the pituitary or septo-optic dysplasia, a disorder in which pituitary deficiencies may also occur later in life.