Endocrine Abstracts

Hypothyroidism is the most frequent innate endocrine disorder, reaching a prevalence of 1 in 1200 newborns. Defects causing hypothyroidism occur at any level of the hypothalamus-pituitary-thyroid axis, but also at peripheral tissues, where alterations of intracellular transport, deiodination or nuclear action of thyroid hormone have been described in humans.

In recent decades, molecular research found evidence that hypothyroidism is a genetic disease. Defects in more than 20 genes have been associated with different types of hypothyroidism. However, environmental conditions like iodine deficiency also cause hypothyroidism. Indeed, iodine shortage may influence the phenotype of genetically-determined hypothyroidism, especially that of partial dyshormonogeneses. Furthermore, the deficiency of iodotyrosine deiodinase (DEHAL1), the enzyme that recycles iodide within the thyroid, exemplifies the close genetic-environmental interplay in the expression of hypothyroidism.

Congenital hypothyroidism (CH) can be permanent or transient. Recently, we learned that transitory CH is not only originated by immune or iatrogenic factors, but rather that it is also a genetic disease, caused by haploinsufficiency of DUOX2, the main component of the thyroidal H₂O₂-generation system.

All known cases of human genetic hypothyroidism are monogenic diseases inherited in classical Mendelian fashion, but they only represent a minority among CH population. The majority of CH cases are sporadic, and do not follow Mendelian inheritance. Moreover, monozygotic twins are discordant for CH. This calls for a paradigm change when understanding the pathogenesis of hypothyroidism, including that, in certain instances, it may be a multigenic disease. This hypothesis was proven correct in Pax8 and Titf1 double heterozygous KO mice, but is not shown in humans. Other non-Mendelian mechanisms that could be involved are the occurrence of (early) somatic mutations together with germline defects (in a "two-hit" model) and alterations of the epigenetic modification of DNA and histones, and both represent attractive challenges for future translational research of hypothyroidism.