Congenital hypothyroidism is the most common neonatal metabolic disorder and 
results in severe neurodevelopmental impairment and infertility if untreated. 
Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis 
is familial, and congenital hypothyroidism caused by organification defects is 
often recessively inherited. The candidate genes associated with this 
genetically heterogeneous disorder form two main groups: those causing thyroid 
gland dysgenesis and those causing dyshormonogenesis. Genes associated with 
thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital 
hypothyroidism, and Gsalpha and the thyroid transcription factors (TTF-1, TTF-2, 
and Pax-8), associated with different complex syndromes that include congenital 
hypothyroidism. Among those causing dyshormonogenesis, the thyroid peroxidase 
and thyroglobulin genes were initially described, and more recently PDS (Pendred 
syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene 
defects. There is also early evidence for a third group of congenital 
hypothyroid conditions associated with iodothyronine transporter defects 
associated with severe neurological sequelae. This review focuses on the genetic 
aspects of primary congenital hypothyroidism.