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Disorders of the thyroid are one of the most common reasons for pediatric endocrinology consultations in the newborn period. Physical symptoms of thyroid disease are often absent, but the effects of thyroid dysfunction in the neonatal period could result in significant deleterious health effects later in life. This chapter reviews disorders of the thyroid most likely to be encountered in the newborn nursery and neonatal intensive care unit (NICU).


Prenatal Development of the Hypothalamic-Pituitary-Thyroid Axis

The hypothalamic-pituitary-thyroid system develops during the first trimester of gestation. The hypothalamus forms from the neural plate by gestational week 6.1 The anterior pituitary is derived from oral ectodermal tissue that becomes Rathke’s pouch. Studies have demonstrated formation of the pouch as early as 8.5 days and separation from the ectodermal tissue by 12.5 days of gestation.2, 3 Several transcription factors are responsible for formation of the anterior pituitary cells, including HESX1, sonic hedgehog (SHH), SIX3, ZIC1, and others. HESX1 mutations have been reported in septo-optic dysplasia, which results in pituitary hypoplasia.4 Mutations in SHH, SIX3, and ZIC1 are associated with holoprosencephaly.5, 6, and 7 Pit1 is a major transcription factor responsible for formation of thyrotrophs (thyroid-stimulating hormone-producing cells), somatotrophs (growth hormone-producing cells), and lactotrophs (prolactin-producing cells).8 This factor interacts with the promoter regions of genes responsible for production of the β subunit of thyroid-stimulating hormone (TSH) and the thyrotropin-releasing hormone (TRH) receptor and is involved in thyroid hormone receptor formation.9, 10

The thyroid gland is derived from components of the pharyngeal floor and the fourth pharyngobronchial pouch.1 Follicular cells migrate from the pharyngeal floor along the thyroglossal duct until they merge with the parafollicular C cells formed from the fourth pharyngobronchial pouch. The thyroid is fully formed and located in its normal position in the anterior neck by 50 days’ gestation.1, 11 Morphologic errors that occur during these 50 days can result in ectopic thyroid tissue anywhere along the migratory tract, including sublingually, high in the neck, or even in the mediastinum or the heart.1 Rarely, thyroid tissue may be found in a thyroglossal duct cyst, when the thyroid does not migrate appropriately and the thyroglossal duct simultaneously does not appropriately degenerate.

Multiple homeobox genes and transcription factors are involved in normal development and migration of the thyroid. Thyroid transcription factor 1 (TTF-1 or Nkx2.1) is necessary for survival and proliferation of primitive thyroid cells.1 Thyroid transcription factor 2 (TTF-2 or FOXE-1) is responsible for proper migration of thyroid tissue to its normal position in the neck.12, 13 Pax8 is important for follicular cell development.13, 14 Other genes, such as various Hox, Hex, FOXE-2, and Eya subtypes, interact with TTF-1, TTF-2, and Pax8 to form the ...

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