Endocrine Abstracts

Thyroid hormones act via receptor subtypes (TRα1, TRβ1, TRβ2) with differing, tissue-specific expression. We describe two unrelated cases of Resistance to Thyroid Hormone mediated by defective TRα1. Proband one (P1 female, age 6yrs) 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. Proband two (P2, female, age 46yrs) also has disproportionate short stature (height <0.4th centile) and is dysmorphic (macrocephaly, coarse facies, multiple skin tags) with chronic constipation. Childhood cognitive impairment and epilepsy persist into adult life.

Many biochemical and physiological parameters were similar in P1 and P2: both exhibited low/low-normal FT4, high/high-normal FT3, low reverse T3 (rT3) and normal TSH levels; their resting heart and metabolic rates (BMR) were subnormal; circulating IGF1 levels were reduced; red blood cell mass was reduced with macrocytosis, but with normal haematinic and haemolytic indices.

Heterozygous mutations in THRA, resulting in carboxyterminally truncated TRα1 mutant proteins were identified in each subject ((P1: E403X; P2: fs388X). Both E403X and fs388X mutant TRα1 are transcriptionally inactive, fail to dissociate from corepressors, unable to recruit coactivators and inhibit wild type receptor action in a dominant-negative manner. T3-dependent target gene (KLF9) induction in peripheral blood mononuclear cells from patients is markedly attenuated.

Thyroxine treatment readily suppressed TSH and raised BMR and circulating IGF1 levels in both patients; serum SHBG levels rose and raised muscle CK normalised (P2); resting heart rates remained subnormal. General alertness, constipation and growth (P1) improved. These treatment responses reflect preserved hormone sensitivity in TRβ-expressing tissues (eg hypothalamus, pituitary, liver) and resistance in TRα-expressing tissues (e.g. myocardium).

This disorder exemplifies the existence of tissue-selective hypothyroidism, uncoupled from a dysregulated pituitary-thyroid axis, in humans.

Declaration of funding

This work was supported by the Wellcome Trust (grant number 095564) and the NIHR Cambridge Biomedical Research Centre.