Genetic disorders of thyroid development, hormone biosynthesis and signalling.
Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (T4, T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1, DIO2) converting T4 to the biologically active hormone T3. Thyroid hormones regulate expression of target genes via hormone-inducible nuclear receptors (TRα, TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired TSH receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of thyroid hormone signalling encompass conditions due to defects in membrane thyroid hormone transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to Thyroid Hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of thyroid hormone transport, metabolism and action. This article is protected by copyright. All rights reserved.