Introduction: Thyroid hormones act via receptors encoded by different genes (THRA and THRB) generating receptor subtypes (TRα1, TRβ1, TRβ2) with differing, tissue-specific expression. Resistance to Thyroid Hormone due to THRB defects is well recognised, but no THRA mutations have yet been reported. We describe the first case of human TRα-mediated thyroid hormone resistance due to a dominant negative THRA mutation.
Results: A 6-year-old female presented with lower segmental growth retardation (height <10th centile), skeletal dysplasia (delayed bone age, femoral epiphyseal dysgenesis, delayed fusion of cranial sutures) and severe constipation. Thyroid function tests showed low/low-normal free T4 (fT4), high/high-normal free T3 (fT3), low reverse T3 (rT3) and normal TSH resulting in a markedly subnormal fT4/fT3 ratio. Heart rate, blood pressure (BP) and basal metabolic rate (BMR) were subnormal, but serum sex hormone binding globulin concentrations (SHBG), a hepatic marker of thyroid hormone action, were elevated. Whole exome sequencing identified a heterozygous nonsense mutation (E403X) in THRA, generating a carboxyterminally truncated receptor protein which binds corepressors aberrantly and inhibits wild type receptor action in a dominant-negative manner. Thyroxine treatment suppressed TSH and normalised BMR with a further rise in SHBG; but heart rate, BP, growth retardation and intestinal dysmotility remained refractory.
Conclusions: This patient exhibits tissue-specific hypothyroidism paradoxically associated with only borderline abnormal thyroid hormone levels, synonymous with findings in TRα mutant mice. Some parameters (TSH, SHBG) responded to thyroxine treatment, but cardiac, gastrointestinal and skeletal tissues remained refractory. Such differential tissue sensitivity to thyroid hormone action, reflects preserved hormone responsiveness in TRβ-expressing tissues (e.g. hypothalamus, pituitary and liver) but resistance in TRα-expressing tissues (skeleton, gastrointestinal tract and myocardium). Recognition of hypothyroid features, but associated with a distinctive biochemical profile (subnormal fT4/fT3 ratio, low rT3), may enable future identification of additional cases.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: This work was supported by The Wellcome Trust (grant numbers 082390 and 080237) and the MRC Centre for Obesity and Related Metabolic Disease, the Great Ormond St Childrens Charity and the National Institutes of Health Research Cambridge Biomedical Research Centre.