At least six major steps are required for secreted thyroid hormone (TH) to exert 
its action on target tissues. Mutations interfering with three of these steps 
have been so far identified. The first recognized defect, which causes 
resistance to TH, involves the TH receptor beta gene and has been given the 
acronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 
affected subjects, from 339 families, have been identified. The gene defect 
remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced 
sensitivity to TH were recently identified. One, producing severe psychomotor 
defects in > 100 males from 26 families, is caused by mutations in the 
cell-membrane transporter of TH, MCT8; the second, affecting the intracellular 
metabolism of TH in four individuals from two families, is caused by mutations 
in the SECISBP2 gene, which is required for the synthesis of selenoproteins, 
including TH deiodinases.