Genetic causes of congenital hypothyroidism due to dyshormonogenesis

Abstract

Purpose of review: Overview of congenital hypothyroidism caused by thyroid hormone synthesis defects, the current understanding of their pathophysiology, and clinical implications of molecular diagnoses.

Recent findings: Genetic defects in all known thyroid-specific factors required for thyroid hormone synthesis have been described. These include defects in iodide trapping (NIS), in the facilitated iodide efflux across the apical membrane (PDS), the organification of iodide within the follicular lumen (thyroid peroxidase, DUOX2, DUOXA2), the substrate for thyroid hormone synthesis (thyroglobulin) and the ability to recover and retain intrathyroidal iodine (iodotyrosine deiodinase). Clinical and biochemical evaluation aids in selecting the most appropriate candidate gene(s). A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic counseling and has prognostic value in differentiating transient from permanent congenital hypothyroidism and predicting the response of patients to iodine supplementation as adjunct or alternative treatment to L-T4 replacement.

Summary: Congenital hypothyroidism due to thyroid dyshormonogenesis is a heterogenic disorder that may be caused by mutations in any of the known steps in the thyroid hormone biosynthesis pathway. An exact molecular diagnosis allows genetic counseling and the identification of asymptomatic mutation carriers at risk of recurrent hypothyroidism, and provides a rationale for adjunct iodide supplementation.

Fig. 1. Schematic drawing of a follicular thyroid cell illustrating the key players involved in thyroid hormonogenesis

The distinct steps comprise 1) the active uptake of iodide from the blood circulation via the sodium-iodide symporter (SLC5A5); 2) the facilitated efflux of iodide into the colloid via an apical anion channel (SLC26A4); 3) iodination of tyrosine groups of thyroglobulin (TG) catalyzed by thyroid peroxidase (TPO); 4) subsequent coupling of iodinated tyrosines within TG via ether-bond formation to iodothyronines; steps 3 and 4 require hydrogen peroxide as co-substrate, which is provided by a hydrogen peroxide generating NADPH-oxidase constituted by dual oxidase 2 (DUOX2) and its maturation factor (DUOXA2); 5) following endocytosis, iodothyronines (T4>T3) are liberated by lysosomal degradation of the TG matrix protein; 6) concomitantly released iodotyrosines are dehalogenated by iodotyrosine deiodinase (IYD) allowing ‘recycling’ of iodide for further hormone synthesis.