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Clin Genet. 2020 Jan;97(1):222-231. doi: 10.1111/cge.13627. Epub 2019 Aug 27.

Molecular defects in thyroid dysgenesis.

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Department of Medicine, University of Udine, Udine, Italy.
Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
Institute of Medical Genetics, Academic Hospital "Azienda Sanitaria Universitaria Integrata di Udine", Udine, Italy.


Congenital hypothyroidism (CH) is a neonatal endocrine disorder that might occur as itself or be associated to congenital extra-thyroidal defects. About 85% of affected subjects experience thyroid dysgenesis (TD), characterized by defect in thyroid gland development. In vivo experiments on null mice paved the way for the identification of genes involved thyroid morphogenesis and development, whose mutation has been strongly associated to TD. Most of them are thyroid-specific transcription factors expressed during early thyroid development. Despite the arduous effort in unraveling the genetics of TD in animal models, up to now these data have been discontinuously confirmed in humans and only 5% of TD have associated with known null mice-related mutations (mainly PAX8 and TSHR). Notwithstanding, the advance in genetic testing represented by the next-generation sequencing (NGS) approach is steadily increasing the list of genes whose highly penetrant mutation predisposes to TD. In this review we intend to outline the molecular bases of TD, summarizing the current knowledge on thyroid development in both mice and humans and delineating the genetic features of its monogenetic forms. We will also highlight current strategies to enhance the insight into the non-Mendelian mechanisms of abnormal thyroid development.


congenital hypothyroidism; next-generation sequencing; null mice; thyroid dysgenesis


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