Resistance to Thyroid Hormone alpha (RTHα) is characterised by tissue-selective hypothyroidism with near-normal thyroid function tests, and is due to thyroid receptor α gene mutations. We sought to correlate the clinical characteristics and response to thyroxine treatment of two RTHα patients with the properties of their defective TRα proteins.
Clinical, biochemical and physiological parameters were assessed in each patient at baseline and after thyroxine therapy.
Heterozygous THRA mutations were identified in a 17y.o male with mild pubertal and growth retardation (P1; A263V mutation), and a 15y.o male (P2; L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies and global developmental delay. Both exhibited typical features of RTHα; macrocephaly, delayed dentition, constipation, low T4/T3 ratio, low reverse T3 levels and mild anaemia.
In vitro, A263V mutant TRα1 was transcriptionally impaired and inhibited the function of its wild type counterpart at low (0.0110 nM) T3 levels, with higher T3 concentrations (100nM1nM) reversing dysfunction and dominant negative inhibition. In contrast, L274P mutant TRα1 was transcriptionally inert, exerting significant dominant negative activity, only overcome with 10nM T3. Normal expression of KLF9, a TH-responsive target gene, was achieved in A263V mutation-containing peripheral blood mononuclear cells (PBMCs) following 1nM T3 exposure, but reduced expression levels were seen in L274P mutation-containing PBMCs even with 10 nM T3. Following thyroxine therapy growth, BMI, dyspraxia and constipation improved in P1, whereas growth retardation and constipation in P2 were unchanged.
A milder clinical phenotype with favourable response to thyroxine therapy was evident in our patient (P1) with mutant TRα1 which exhibited partial, T3-reversible, loss-of-function in vitro. In contrast, a more severe clinical phenotype, refractory to hormone treatment, was evident in our patient (P2) with severe, virtually irreversible, dysfunction of mutant TRα1 in vitro. These differing clinical phenotypes and responses to treatment suggest a genotype-phenotype correlation exists amongst individuals with RTHα.
07 Nov 2016 - 09 Nov 2016