Recent advances in research on isolated congenital central hypothyroidism

Congenital central hypothyroidism (C-CH) is caused by defects in the secretion of thyrotropin-releasing hormone (TRH) and/or TSH, leading to an impairment in the release of hormones from the thyroid. The causes of C-CH include congenital anomalies of the hypothalamic-pituitary regions and several genetic defects. In terms of endocrinology, C-CH is divided into two categories: (1) accompanied by another pituitary hormone deficiency and called combined pituitary hormone deficiency, and (2) isolated C-CH, showing mainly TSH deficiency. For isolated C-CH, a mutation in the TSH gene (TSHB) encoding the β-subunit of the protein was first found in 1990 by Japanese researchers, and thereafter several mutations in TSHB have been reported. Mutations in the thyrotropin-releasing hormone receptor gene (TRHR), as well as genetic defects in immunoglobulin superfamily 1 (IGSF1), have also been identified. It was recently found that isolated C-CH is caused by mutations in transducin β-like 1 X-linked and insulin receptor substrate 4. It is noted that all patients with TSHB deficiency and some with IGSF1 deficiency show severe hypothyroidism soon after birth. Among the causes of C-CH, high frequency of mutations in IGSF1 is the most prevalent. This review focuses on recent findings on isolated C-CH.