Neonatal Thyroid Disease

KEY POINTS

• 1.

  Thyroid hormone signaling is required for both normal fetal and pediatric development.

• 2.

  The identification of genes critical for thyroid gland development and migration and thyroid hormone metabolism, transport, and receptor function has revealed that derangement of local thyroid hormone signaling can impact development, even in the absence of primary thyroid disease.

• 3.

  The goal of thyroid hormone replacement in neonates is to optimize normal growth and development.

• 4.

  For many neonates, levothyroxine (LT4) replacement is anticipated to be lifelong; however, there is potential to discontinue LT4 in patients with transient congenital hypothyroidism.

• 5.

  In neonates with hyperthyroidism, there is a risk of acute morbidity and mortality as well as some evidence to suggest the potential for long-term adverse neurocognitive outcomes.

• 6.

  Further clinical research is needed to better understand the long-term consequences of fetal and neonatal hypothyroxinemia, as well as thyrotoxicosis, to better understand the potential benefits and risks of treatment.

Introduction

The incidence of congenital hypothyroidism (CH) is reported to be between 1 in 2000 and 1 in 4000 births, with the higher incidence associated with lowering of the thyroid-stimulating hormone (TSH) diagnostic level for diagnosis. The most common inheritable cause of primary CH is failure of normal thyroid gland development (dysgenesis) or failure of a eutopic thyroid gland (a gland located in its usual position, anterior to the second to fourth tracheal rings) to produce thyroid hormone normally (dyshormonogenesis). Thyroid dysgenesis accounts for approximately 85% of permanent CH, and thyroid ectopy is the most common cause of dysgenesis, with the ectopic thyroid tissue located anywhere along the path of migration, from the foramen cecum in the base of the tongue to the thyroid bed. The identified transcription factors critical for thyroid gland formation include NKX2-1 , FOXE1 , and PAX8 ; for thyroid folliculogenesis, NKX2-1 and PAX8 ; and for migration, FOXE1 and CDCA8 /Borealin. ^, Several of these transcription factors are also involved in nonthyroid related organogenesis. As an example, expression of NKX2-1 is critical in the development and function of interneurons in the central nervous system, surfactant producing cells in the lungs, and expression of thyroid peroxidase and thyroglobulin. Mutations in NKX2-1 are associated with brain-lung-thyroid syndrome, characterized by hereditary chorea, respiratory distress syndrome, and congenital hypothyroidism secondary to thyroid dysgenesis. Tables 26.1 and 26.2 review the genetic alterations and phenotypes for thyroid gland dysgenesis ( Table 26.1a ) and dyshormonogenesis ( Table 26.1b ).

Congenital central hypothyroidism is rare, with an incidence between 1 in 16,000 and 1 in 20,000. Because transcription factors regulate expression of multiple pituitary cell types, multiple pituitary hormone deficiencies are present in about 75% of infants with congenital central hypothyroidism ( Table 26.1c ).

Lastly, several extrinsic factors can cause hypothyroidism in neonates. Iodine deficiency remains the most common cause of neonatal hypothyroidism worldwide. Preterm infants are at increased risk of iodine-related thyroid dysfunction; iodine deficiency–associated hypothyroidism can occur due to low iodine content of preterm infant formulas and parenteral nutrition. Iodine excess can also cause hypothyroidism secondary to iodine-induced decreased synthesis of thyroid peroxidase, leading to decreased organification of iodine and production of thyroid hormone (called the Wolff-Chaikoff effect). The most common sources of excess iodine are exposure to topical iodine-based antiseptics, exposure to high content iodine medications such as amiodarone, radiographic contrast agents, ^, or high maternal dietary intake of iodine that is passed through breast milk. Other extrinsic causes include transplacental passage of antithyroid medications used to treat hyperthyroidism (methimazole, carbimazole, or propylthiouracil), transfer of maternal immunoglobulin G antibodies that block activation of the TSH receptor, and many additional medications that can alter thyroid hormone levels (see Table 26.2 ). ^,

Neonatal thyrotoxicosis (hyperthyroidism) is less common than congenital hypothyroidism; however, it can lead to significant morbidity and mortality if not promptly recognized and adequately treated. The majority of cases are transient, secondary to transplacental passage of maternal thyroid-stimulating immunoglobulin (maternal Graves disease, [GD]); however, neonatal hyperthyroidism can also occur secondary to activating mutations in the TSH receptor or activating mutations in the alpha subunit of stimulatory G proteins (GNAS) in McCune-Albright syndrome.

Pathophysiology