BACKGROUND: Six known steps are required for the circulating thyroid hormone 
(TH) to exert its action on target tissues. For three of these steps, human 
mutations and distinct phenotypes have been identified.
SCOPE OF REVIEW: The clinical, laboratory, genetic and molecular characteristics 
of these three defects of TH action are the subject of this review. The first 
defect, recognized 45years ago, produces resistance to TH and carries the 
acronym, RTH. In the majority of cases it is caused by TH receptor β gene 
mutations. It has been found in over 3000 individuals belonging to approximately 
1000 families. Two relatively novel syndromes presenting reduced sensitivity to 
TH involve membrane transport and metabolism of TH. One of them, caused by 
mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor 
defects. It has been identified in more than 170 males from 90 families. A 
defect of the intracellular metabolism of TH in 10 individuals from 8 families 
is caused by mutations in the SECISBP2 gene required for the synthesis of 
selenoproteins, including TH deiodinases.
MAJOR CONCLUSIONS: Defects at different steps along the pathway leading to TH 
action at cellular level can manifest as reduced sensitivity to TH.
GENERAL SIGNIFICANCE: Knowledge of the molecular mechanisms involved in TH 
action allows the recognition of the phenotypes caused by defects of TH action. 
Once previously known defects have been ruled out, new molecular defects could 
be sought, thus opening the avenue for novel insights in thyroid physiology. 
This article is part of a Special Issue entitled Thyroid hormone signaling.