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Thyroid Hormone Resistance N K Agrawal, R Goyal, a Rastogi, D Naik, S K Singh

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Thyroid Hormone Resistance N K Agrawal, R Goyal, a Rastogi, D Naik, S K Singh Downloaded from pmj.bmj.com on May 6, 2014 - Published by group.bmj.com Review Thyroid hormone resistance N K Agrawal, R Goyal, A Rastogi, D Naik, S K Singh Department of Endocrinology ABSTRACT or vice versa due to variable tissue resistance.2 The and Metabolism, Institute of Thyroid hormone resistance (THR) is a rare syndrome of euthyroid state is maintained by a compensatory Medical Sciences, Banaras reduced end organ sensitivity. Patients with THR have Hindu University, Varanasi, India increase in thyroid hormone concentrations. elevated serum free thyroxine (FT4), free triiodothyronine Pituitary thyroid hormone resistance (PTHR)—The Correspondence to: (FT3), but normal or slightly elevated serum thyrotropin patient presents with hyperthyroidism. The inap- Dr N K Agrawal, A-5 Krishna values. The characteristic clinical feature is goitre without propriately high pituitary TSH secretion causes Bag Apartments, N-1/69 C, Nagwa, Varanasi- 221005, India; symptoms and metabolic consequences of thyroid overproduction of T4 and T3, thus establishing a [email protected] hormone excess. THR can be classified on the basis of new equilibrium with high T4 and T3 together tissue resistance into pituitary, peripheral or generalised with a non-suppressed TSH. The signs and Received 12 March 2008 (both pituitary and peripheral) types. Mutations in the TRb symptoms are subjective; differentiating selective Accepted 29 June 2008 gene, cell membrane transporter and genes controlling pituitary resistance from generalised resistance can intracellular metabolism of thyroid hormone have been be difficult.2 implicated. THR is differentiated from thyroid stimulating Peripheral thyroid hormone resistance (PerTHR)—In hormone (TSH) secreting pituitary adenoma by history of this rare entity, the patient may present with THR in the family. No specific treatment is often required clinical hypothyroidism.45 The TSH value is for THR; patients with features of hypo- or hyperthyroid- normal. The sensitivity of peripheral tissues to ism are appropriately treated with levo-triiodothyronine (L- thyroid hormones is decreased relative to that of T3), levo-thyroxine (L-T4), dextro-thyroxine(D-T4) or 3,3,5 the pituitary. However, the distinction is unclear triiodo-thyroacetic acid (TRIAC). The diagnosis helps in as a variable degree of resistance can be found in appropriate genetic counselling of the family. pituitary and peripheral tissues of the same individual.6 Thyroid hormones regulate growth, basal meta- PATHOGENESIS bolic rate, myocardial contractility and functional a differentiation of the central nervous system. Their In humans there are two subtypes of TR, TR and b synthesis is stimulated by thyrotrophin releasing TR (encoded by genes on chromosomes 17 and 3, a hormone (TRH) and thyroid stimulating hormone respectively) and three main isoforms: TR 1 (most (TSH), and suppressed by its negative feedback abundant in the central nervous system, myocar- b effect. Thyroid hormones act on the carboxy- dium, and skeletal muscle), TR 1 (predominant in b terminal domain of steroid nuclear receptors called liver and kidney), and TR 2 (highly expressed in thyroid receptors (TR), which bind to thyroid the pituitary and hypothalamus) generated by alternate splicing. response elements (TRE) located in the promoter 2 regions of target genes. Although TR can bind TRE The THR usually is dominantly inherited. The as a monomer or homodimer, it usually interacts current estimate of de novo mutation is approxi- b preferentially as a heterodimer with the retinoid X- mately 22.5% in which TR gene mutation is receptor (RXR). Many promoters are repressed or excluded in the parents. Recessive transmission is very rare and was clearly demonstrated only in the ‘‘silenced’’ by unliganded receptor; hormone bind- 3 ing results in relief of repression and ligand first family reported by Refetoff. dependent activation of gene transcription. THR phenotype can result from TR and non-TR Reduced end organ response to circulating thyroid defects. The TRb mutations have been strongly 7 hormones or thyroid hormone resistance (THR) associated with THR. Genetic studies in 300 was first recognised in 1967 by Refetoff.1 Many families with this syndrome showed 122 different patients and families have since been identified. point mutations or frame shift mutations (inser- The present review highlights the classification, tions and deletions) localised to three mutation pathogenesis, clinical features, diagnosis and treat- clusters within the hormone binding domain of the ment for THR, with a view to enable appropriate receptor, except one which was having complete b 8 genetic counselling. deletion of the TR gene. Affected individuals are heterozygous for mutations in the TRb gene; this occurs in approximately 10% of sporadic cases. The CLASSIFICATION same receptor mutation can result in PTHR in THR is characterised by elevated concentrations of some individuals and GTHR in others within a 9 free thyroxine (FT4) and free tri-iodothyronine single family or unrelated kindreds. Another (FT3), with inappropriately normal thyrotropin reported family had the father with mosaicism in (TSH). On the basis of tissue response to thyroid some cell lineages, including his germline for hormones, THR has been classified into general- R338W mutation, but not in the fibroblasts. This ised, pituitary and peripheral resistance.23 mosaicism is without apparent TRb gene muta- Generalised thyroid hormone resistance (GTHR)— tions.10 In a few cases there may be limited The patient is clinically euthyroid. There may be expression of somatic TRb1 mutation which is low IQ without an effect on bone (normal stature) undetectable in peripheral blood leucocyte DNA. Postgrad Med J 2008;84:473–477. doi:10.1136/pgmj.2008.069740 473 Downloaded from pmj.bmj.com on May 6, 2014 - Published by group.bmj.com Review THR phenotype could also result from non-TRb defects. In mutations elude discovery by lacking dominant negative activity, some families or sporadic cases, mutations in TR locus have therefore being clinically and biochemically silent. The ability to been excluded, raising the possibility of new, non-receptor exert a dominant negative effect within the hypothalamic– mechanisms to produce THR phenotype called non-TR THR.11 pituitary–thyroid axis is a key property of mutant TRs which So far 29 affected subjects from 23 different families have been characteristically generates abnormal thyroid function tests, identified.312 They are clinically similar to subjects with TRb leading to the identification of the disorder. gene mutations but have a high female-to-male ratio (2.5:1) and 3 high prevalence of sporadic cases. Genetic and clinical studies CLINICAL FEATURES have highlighted two novel defects giving rise to THR. The first THR was first described in two clinically euthyroid siblings one involves transport of thyroid hormone and the second with high circulating thyroid hormone concentrations and other defect lies in its intracellular metabolism (SECISBP2 gene abnormalities including deaf mutism, delayed bone maturation, 13 mutation affecting synthesis of selenoproteins). The psycho- stippled femoral epiphyses, short stature, dysmorphic facies, motor abnormalities in males have been associated with X winging of the scapulae and pectus carinatum.1 In some cases, 14 15 linked monocarboxylate transporters (MCT8) mutation. hypothyroid features such as growth retardation, delayed The location of an abnormality in the hormone binding dentition or bone age occurred in children, whereas in adults domain of the mutant receptor determines the strength of T3 fatigue and hypercholesterolaemia may coexist with thyrotoxic binding affinity to the receptor and its ability to activate or symptoms in the same individual. Nevertheless, the presence or repress target genes. A subset of receptor mutations that involve absence of thyrotoxic symptoms, suggesting either generalised residues critical for mediating TRb interaction with co- or pituitary resistance to thyroid hormone, is a useful guide to activators result in notably reduced transcriptional function treatment. with normal hormone binding. The prevalence of THR is approximately 1 in 40 000.6 Table 1 In the first documented family with THR, which was enumerates the clinical features and their frequency of recessively inherited, the two affected siblings were homozy- occurrence. 16 gous for complete deletion of the TRb receptor gene. The clinical phenotypes may be attributable to variable Significantly, their heterozygous parents harbouring a deletion peripheral resistance in different individuals, as well as in of one TRb allele were completely normal. In the dominantly different tissues within a single subject. This may be due to inherited THR, mutant receptors are not only functionally variable distribution of TR isoforms in different tissues. As impaired but can also cause inhibition of wild type receptor hypothalamus, pituitary and liver express predominantly TRb 17 (dominant negative inhibition). A case of compound effect of whereas TRa is mainly expressed in the myocardium, TRb two dominant negative mutant receptors has been reported in a mutations are likely to be associated with pituitary and liver child with severe biochemical resistance, pronounced develop- resistance, as exemplified by normal sex hormone binding mental delay, growth retardation, and cardiac hyperthyroidism globulin (SHBG) and non-suppressed TSH concentrations with which was fatal due to heart failure following
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