Recent advances in research on isolated congenital central hypothyroidism

Abstract

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.

Keywords: TBL1X; TRHR; congenital central hypothyroidism (C-CH); immunoglobulin superfamily 1 (IGSF1).

Fig. 1.

Schema of IGSF1 and mutations/deletions. Immunoglobulin superfamily 1 (IGSF1) has 12 immune loops. The protein is cleaved at N- and C-terminal domains between immunoglobulin loops 5 and 7. Whereas the C-terminal domain moves to the cell membrane, the N-terminal domain remains in the endoplasmic reticulum. Deletions, nonsense, frameshift, missense, and splicing mutations reported are summarized.

Fig. 2.

Mechanism of C-CH: Mutations in TBL1X. (a) In the absence of T3, NCoR/SMRT complexes bind thyroid hormone receptor β (TRB) with RXR (as a heterodimer). These complexes bind to the thyroid hormone response element in the promoter region of thyroid hormone (TH) targeting genes and repress the transcription of these genes. (b) When T3 binds TRBs, the dissociation of the repressor complex and the recruitment of coactivator (CoA) occur, thus activating the transcription of TH target genes. (c) Several in vitro studies showed that cotransfection of NCoR/SMRT with TRBs conversely stimulates the transcription of TSHB and TRH in the absence of T3. The ligand-independent thyroid hormone receptor-mediated stimulation of TSHB and TRH promoters was enhanced by TBL1X. (d) TBL1X (shaded box) mutants of N365Y and Y458C impaired the stimulating effect. TBL1X, transducin β-like 1 X-linked; NCoR, nuclear receptor repressor; SMRT silencing mediator of retinoid and thyroid receptors; TRB, thyroid hormone receptor β; RXR, retinoid X receptor; CoA, coactivator; TH, thyroid hormone.