Different Causes of Reduced Sensitivity to Thyroid Hormone: Diagnosis and Clinical Management

W. Edward Visser; Alies A. A. van Mullem; Theo J. Visser; Robin P. Peeters


Clin Endocrinol. 2013;79(5):595-605. 

In This Article

Abstract and Introduction


Normal thyroid hormone (TH) metabolism and action require adequate cellular TH signalling. This entails proper function of TH transporters in the plasma membrane, intracellular deiodination of TH and action of the bioactive hormone T3 at its nuclear receptors (TRs). The present review summarizes the discoveries of different syndromes with reduced sensitivity at the cellular level. Mutations in the TH transporter MCT8 cause psychomotor retardation and abnormal thyroid parameters. Mutations in the SBP2 protein, which is required for normal deiodination, give rise to a multisystem disorder including abnormal thyroid function tests. Mutations in TRβ1 are a well-known cause of resistance to TH with mostly a mild phenotype, while only recently, patients with mutations in TRα1 were identified. The latter patients have slightly abnormal TH levels, growth retardation and cognitive defects. This review will describe the mechanisms of disease, clinical phenotype, diagnostic testing and suggestions for treatment strategies for each of these syndromes.


Thyroid hormone (TH) is essential for normal development and for the physiological function of virtually all tissues. As a consequence, hypothyroidism affects multiple tissues resulting in a variety of symptoms such as fatigue, cold intolerance, constipation, congestive heart failure, and depression. The importance of TH for development is illustrated by the consequences of untreated congenital hypothyroidism, resulting in severe growth failure and permanent mental retardation.

The first report of patients with a familial syndrome of reduced sensitivity to TH at the tissue level was published in 1967.[1] These patients had high levels of TH without clinical symptoms of hormone excess or even with symptoms of TH deficiency in certain tissues.[2] After cloning of the T3 receptor isoforms TRβ1[3] and TRα1,[4] encoded by the THRB and THRA genes, respectively, it was demonstrated that this clinical syndrome of resistance to TH (RTH) was due to inactivating mutations in THRB (RTH-β).[5] Since then, more than 1000 patients with RTH have been published (see[6,7] for excellent reviews).

In recent years, other syndromes associated with a reduced sensitivity to TH have been recognized, involving a defect in transport of TH across the cell membrane,[8,9] a defect in the synthesis of selenoproteins, including TH-deiodinating enzymes resulting in an abnormal TH metabolism,[10] as well as a defect in the T3 receptor TRα1.[11,12] Thus, normal TH action requires both adequate serum TH concentrations and TH signalling at the cellular level of the target tissues. The current review focuses on the clinical diagnosis and management of all known different causes of a reduced sensitivity to TH.