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.