ESPE Abstracts (2014) 82 S4.3

University of Cambridge Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK

Resistance to thyroid hormone mediated by defective TRβ (RTHβ) or TRα(RTHα).

Separate genes (THRA, THRB) undergo alternate splicing, generating nuclear receptors (TRα1, TRβ1, TRβ2) with distinct tissue distributions, which mediate thyroid hormone action; the function of a non-hormone binding protein (α 2), derived from the THRA locus, is unknown.

RTHβ a dominantly-inherited disorder associated with ~150 different heterozygous THRB mutations, is characterised by elevated thyroid hormones, with non-suppressed TSH levels. Features in childhood can include failure to thrive and attention deficit hyperactivity disorder. The adult RTHβ phenotype is characterised by features of both hyperthyroidism (e.g. tachycardia, raised metabolic rate, low bone mineral density) and hypothyroidism (elevated cholesterol), reflecting either resistance or retention of hormone sensitivity in TRβ versus TRα-expressing peripheral tissues.

Recently, the first patients with THRA defects have been identified. Features in childhood include growth (lower segment) retardation, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), constipation, motor dyspraxia and variable cognitive impairment. Whilst these features suggest hypothyroidism in specific tissues, patient’s thyroid function tests (low/low-normal T4, high/high-normal T3, normal TSH) are near-normal; however, low T4/T3 ratio, subnormal reverse T3 and raised muscle CK levels with mild anaemia in these cases, provide a biochemical signature for the disorder. Four patients harbour highly deleterious heterozygous mutations in TRα1, abolishing its function; three further cases have a milder, missense mutation involving both TRα1 and α2 proteins, with no readily-discernible added phenotype attributable to mutant α2. Thyroxine therapy may be beneficial in this disorder, suggesting that early identification of cases will be important.

The contrasting phenotypes of RTHβ and RTHα exemplify the differing importance of receptor subtypes in tissues, providing a rational basis for development of receptor-specific hormone analogues.

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