Resistance to thyroid hormone due to defective thyroid receptor alpha

Thyroid hormones act via nuclear receptors (TR alpha 1, TR beta 1, TR beta 2) with differing tissue distribution; the role of alpha 2 protein, derived from the same gene locus as TR alpha 1, is unclear. Resistance to thyroid hormone alpha (RTH alpha) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic fades, 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 TR alpha 1 alone or both TR alpha 1 and alpha 2, with no discernible phenotype attributable to defective alpha 2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTH alpha, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTH alpha and its optimal management remain to be elucidated. (C) 2015 The Authors. Published by Elsevier Ltd.