ABSTRACT: Resistance to thyroid hormone alpha (RTH?), a disorder characterized by tissue-selective hypothyroidism and near-normal thyroid function tests due to thyroid receptor alpha gene mutations, is rare but probably under-recognized. This study sought to correlate the clinical characteristics and response to thyroxine (T4) therapy in two adolescent RTH? patients with the properties of the THRA mutation, affecting both TR?1 and TR?2 proteins, they harbored.Clinical, auxological, biochemical, and physiological parameters were assessed in each patient at baseline and after T4 therapy.Heterozygous THRA mutations occurring de novo were identified in a 17-year-old male (patient P1; c.788C>T, p.A263V mutation) investigated for mild pubertal delay and in a 15-year-old male (patient P2; c.821T>C, p.L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies, and global developmental delay. Both individuals exhibited macrocephaly, delayed dentition, and constipation, together with a subnormal T4/triiodothyronine (T3) ratio, low reverse T3 levels, and mild anemia. When studied in vitro, A263V mutant TR?1 was transcriptionally impaired and inhibited the function of its wild-type counterpart at low (0.01-10?nM) T3 levels, with higher T3 concentrations (100?nM-1??M) reversing dysfunction and such dominant negative inhibition. In contrast, L274P mutant TR?1 was transcriptionally inert, exerting significant dominant negative activity, only overcome with 10??M of T3. Mirroring this, normal expression of KLF9, a TH-responsive target gene, was achieved in A263V mutation-containing peripheral blood mononuclear cells following 1??M of T3 exposure, but with markedly reduced expression levels in L274P mutation-containing peripheral blood mononuclear cells, even with 10??M of T3. Following T4 therapy, growth, body composition, dyspraxia, and constipation improved in P1, whereas growth retardation and constipation in P2 were unchanged. Neither A263V nor L274P mutations exhibited gain or loss of function in the TR?2 background, and no additional phenotype attributable to this was discerned.This study correlates a milder clinical phenotype and favorable response to T4 therapy in a RTH? patient (P1) with heterozygosity for mutant TR?1 exhibiting partial, T3-reversible, loss of function. In contrast, a more severe clinical phenotype refractory to hormone therapy was evident in another case (P2) associated with severe, virtually irreversible, dysfunction of mutant TR?1.
