title: Resistance to thyroid hormone due to defective thyroid receptor alpha.
abstract: Thyroid hormones act via nuclear receptors (TRα1, TRβ1, TRβ2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated.
authors: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. Electronic address: cm682@medschl.cam.ac.uk.
authors: Carla
authors: C
authors: Moran
authors: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. Electronic address: kkc1@medschl.cam.ac.uk.
authors: Krishna
authors: K
authors: Chatterjee
mesh_terms: D006801:Humans; D009154:Mutation; D010641:Phenotype; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000378:metabolism
chemical_list: D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones
keywords: corepressor; dominant negative inhibition; resistance to thyroid hormone; thyroid receptor α