The effects of thyroid hormones (TH: thyroxine T4, triiodothyronine T3) on physiological processes are mediated principally by a nuclear thyroid receptor (TR; a member of the steroid/nuclear receptor superfamily of ligand-inducible transcription factors), which modulates target gene expression in different tissues. In humans, two highly homologous thyroid hormone receptors, denoted TRa and TRb, are encoded by separate genes on chromosomes 17 (THRA) and 3 (THRB) respectively, with alternate splicing generating three main isoforms (TRa1, TRb1, TRb2), which are widely expressed, but with differing tissue distributions: TRa1 is ubiquitously expressed, with particular abundance in the central nervous system (CNS), myocardium, gastrointestinal tract and skeletal muscle/skeleton; TRb1, which is also widely expressed, is the predominant isoform in liver and kidney; the TRb2 isoform is most highly expressed in the pituitary and hypothalamus, but is also found in the inner ear and retina. A fourth splice variant, TRa2, which is unable to bind thyroid hormone due to modification of its carboxyterminal region, is expressed in a variety of tissues (e.g. brain, testis), where it may act as a functional antagonist of TR signalling pathways.

Although loss-of-function mutations in human THRB have long been recognised as a cause of resistance to thyroid hormone (RTH), it is only within the last 18 months that subjects harbouring analogous defects in THRA have been identified. Comparing and contrasting the phenotypes of individuals with mutations in TRa or TRb affords a unique opportunity to better understand the tissue selective actions of TH in human physiology.

TRb RTH due to mutations in THRB: Resistance to TH action in the hypothalamic–pituitary–thyroid axis gives rise to the biochemical hallmark of this disorder, with pituitary TSH secretion driving T4 and T3 production, to establish a new equilibrium with high serum levels of TH together with a non-suppressed thyrotropin (TSH). The estimated prevalence of TRb RTH is approximately 1 in 40 000 live births, and over 700 cases (>250 families) have been described to date. The disorder is usually dominantly inherited and associated with variable clinical features. Many patients are either asymptomatic or have non-specific symptoms and may have a goitre, prompting testing of thyroid function, which suggests the diagnosis. In these individuals, classified as exhibiting generalized resistance (GRTH), the high TH levels are thought to compensate for ubiquitous tissue resistance, resulting in a euthyroid state. In contrast, a subset of individuals with the same biochemical abnormalities exhibit thyrotoxic features: in adults these may include weight loss, tremor, palpitations, insomnia, and heat intolerance; in children failure to thrive, accelerated growth, and hyperkinetic behaviour have also been noted. When the latter clinical entity was first described, patients were thought to have ‘selective’ or predominant pituitary resistance to thyroid hormone action (PRTH), with preservation of normal hormonal responses in peripheral tissues. However, a careful comparison of the clinical and biochemical characteristics of individuals classified clinically with either generalized or pituitary resistance to thyroid hormone indicates that there is significant overlap between these entities. Heterozygous TRb mutations in affected individuals generate non-functional mutant receptors, which inhibit wild type receptor action in a dominant negative manner.

 TRa RTH due to mutations in THRA: In contrast, mutations in human TRa1 mediate RTH with features of hypothyroidism in a different subset of tissues (e.g. CNS, gastrointestinal tract, myocardium, skeletal muscle, skeleton), but are not associated with a markedly dysregulated pituitary-thyroid axis. To date only a handful of individuals harbouring such mutations have been reported. Clinical features include growth and developmental retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels (resulting in a low T4:T3 ratio), together with subnormal reverse T3 levels; TSH levels are normal – indeed this more subtle biochemical signature may facilitate future identification of additional cases. Similar to TRb RTH, heterozygous TRa1 mutations yield non-functional mutant receptors that are capable of inhibiting wild type receptor action in a dominant negative manner. Current, albeit limited experience suggests that thyroxine (L-T4) therapy may be of limited benefit in TRa-mediated RTH, with hyperthyroidism in TRb-expressing tissues precluding high dose L-T4 treatment. Alternate therapeutic strategies could involve development of TRa1 subtype-selective hormone analogues or inhibition of histone deacetylase activity within the transcriptional repression complex recruited by mutant TRa.