Primary thyroid failure that is present at birth

Epidemiology

Incidence

• Worldwide: 1 in 3,000–4,000 births; in North America, 1 in 3,700
• Male/Female ratio is 1:2–1:3.
• 80% dysgenesis or agenesis; 20% dyshormonogenesis

• Racial differences: Prevalence in black infants ~1/3 that in whites
• Higher prevalence of congenital hypothyroidism in low–birth-weight (>2,000 g) and macrosomic (≥4,500 g) babies

Risk Factors

Genetics

• Dysgenesis is usually sporadic.
  • Familial occurrence in 2%
  • Mutations have been found in the TSH-receptor gene and in the transcription factors PAX-8, TTF-1, TTF-2 (FOXE1).
• Dyshormonogenesis is inherited in an autosomal recessive pattern. Most commonly:
  • Chromosome 2p: Mutations in the thyroid peroxidase gene result in partial or complete loss of iodide organification function.
  • Chromosome 19p: Mutations in the sodium-iodide symporter gene result in an inability to maintain the normal thyroid-to-plasma iodine concentration difference.
• Pendred syndrome (chromosome 7q): Mutations in PDS gene cause the most common syndromal form of deafness; a mild organification defect leads to goiter, usually in childhood.
• Down syndrome neonates have lower T₄ (left-shifted normal distribution) and mildly elevated TSH concentrations, suggesting a mild hypothyroid state.

Etiology

• Thyroid gland malformation:
  • Agenesis: Absent thyroid gland
  • Dysgenesis: Ectopic (e.g., sublingual) or incorrectly formed (e.g., hemigland) thyroid
• Dyshormonogenesis:
  • 15 known defects of thyroxine (T₄) synthesis, including those in iodide transport and iodide organification
• Transient hypothyroidism:
  • Maternal ingestion of antithyroid drugs
  • Transplacental transfer of maternal antithyroid antibodies (can be transient or permanent damage)
  • Exposure to high levels of iodine povidone, betadine in neonatal period