ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 3.10 | DOI: 10.1530/ey.16.3.10


To read the full abstract: J Med Genet. 2018;55:693–700.

This genetic study identified, by whole exome sequencing, mutations in the insulin receptor substrate 4 gene (IRS4) in 5 families with isolated central congenital hypothyroidism. Thus, the authors add a fifth genetic cause of isolated congenital hypothyroidism to the previously known genes: TSHB, TRHR, IGSF1, and TBLX1. Interestingly, as for IGSF1 and TBLX1, IRS4 is also located in the X-chromosome, resulting in X-linked inheritance. While detailed clinical phenotyping of affected male patients revealed all elements of central hypothyroidism, such as mildly decreased FT4 in the context of inadequately normal TSH, decreased basal, pulsatile and total TSH secretion over 24 hours, the phenotype could not be reproduced in IRS4 knock-out mice. The general molecular role of the IRS family of proteins (IRS1-6) is to interact with tyrosine kinase receptors such as insulin, leptin, and insulin-like growth factor 1 (IGF-1) receptors and it is well known that starvation modifies (e.g. by leptin levels) the activity of the central regulation of the thyroid axis. However, the detailed mechanism how IRS4 regulates the hypothalamo-pituitary-thyroid axis remains to be described.

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