Hypothyroidism, Congenital

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DESCRIPTION

Abnormal thyroid function present at birth

EPIDEMIOLOGY

  • Increasing incidence worldwide due to stricter newborn screening thresholds, changing demographics
    • Overall incidence of primary congenital hypothyroidism: about 1 in 2,000 births
    • Severe congenital hypothyroidism: 1 in 3,000 to 4,000 births
    • Central (hypothalamic-pituitary) hypothyroidism: less common than primary hypothyroidism and may be more common than appreciated in the past (between 1 in 16,000 and 50,000 newborns)
  • Male-to-female ratio is 1:2 to 1:3 among severe cases and 1:1 among mild cases.
  • 70% dysgenesis; 30% dyshormonogenesis

ETIOLOGY

  • Dysgenesis: failure of normal thyroid gland formation. Includes:
    • Agenesis—absent thyroid gland
    • Ectopy—failure of gland to descend to normal position
    • Abnormally formed (e.g., hypoplastic) thyroid
  • Dyshormonogenesis
    • Defects in thyroxine (T4) synthesis, including in iodide transport and organification
  • Central hypothyroidism
    • Abnormal central control of thyroid function due to hypothalamic or pituitary defects
  • Transient hypothyroidism
    • Maternal treatment with antithyroid drugs (methimazole, propylthiouracil)
    • Transplacental transfer of maternal TSH receptor-blocking antibodies
    • Iodine deficiency or exposure to high levels of iodine (e.g., topical antiseptics, radiographic contrast)
    • Mild forms of dyshormonogenesis

RISK FACTORS

Genetics

  • Dysgenesis is usually sporadic.
    • Familial in 2–5%
    • Genetic differences reported in the thyrotropin (TSH) receptor (TSHR) and in thyroid transcription factors PAX8, NKX2.1, NKX2.5, and FOXE1.
  • Dyshormonogenesis is often inherited in autosomal recessive fashion, yet many cases do not have a defined genetic cause.
    • Most common mutated genes are thyroglobulin (TG), thyroperoxidase (TPO), DUOX2, and TSHR (relative distribution depends on ancestry background).
    • Pendred syndrome: Mutations in SLC26A4 cause a common syndromic form of deafness and a mild iodine organification defect that can cause hypothyroidism. Hypothyroidism usually presents later in childhood.
  • Central hypothyroidism
    • Multiple pituitary hormone deficiencies present in 75% of individuals with congenital central hypothyroidism
    • Isolated central hypothyroidism can be from mutations in TSH β-subunit, TRH receptor, IGSF1.

COMMONLY ASSOCIATED CONDITIONS

  • Infants with trisomy 21 have a significantly increased incidence of congenital hypothyroidism.
  • Newborns with congenital hypothyroidism have a slightly increased risk of congenital heart and kidney malformations.
  • Higher incidence of congenital hypothyroidism in infants with low birth weight (<2,500 g), preterm birth (<37 weeks)

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