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.

Familial immunoglobulin superfamily member 1 deficiency as a cause of isolated congenital central hypothyroidism

“…Finally, there is no clearly established link between IGSSF1 mutations and causation of neurodevelopmental disorders, although attention deficits, difficulties with gross motor skills and structural brain abnormalities on magnetic resonance imaging have been reported in some cases. 6,8 The index case in this report is receiving speech and language therapy input for expressive language delay. His difficulty with pronouncing words is thought to be related to his macroglossia.…”

A novel variant of <i>IGSF1</i> in siblings with congenital central hypothyroidism whose diagnosis was prompted by school health checkups

“…The severity of hypothyroidism varies among patients with an IGSF1 deficiency. Accordingly, the time of diagnosis and chief complaint also vary, including some cases with jaundice and failure to thrive from infancy, asymptomatic cases accidentally detected during family screening of the proband ( 16 ). IGSF1 deficiency, diagnosed based on increased BMI observed during a school health checkup, seems to be relatively mild.…”

Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain

“…Genetic variants in TSH-releasing hormone receptor (TRHR) and TSH have been found in isolated CCH ( 97 ). Recently, de novo or inherited mutations in TBL1X were found in isolated CCH cases in pediatric patients ( 98 ). Six missense mutations in TBL1X were identified from 6 families with CCH individuals, including c.1510C-T (H453Y), c.1526A-G (Y458C), c.1246A-T (N365Y), c.1249G >A (A366T), c.1258T > C (W369R), and c.1312-1G > A (splice) ( 99 ).…”