Congenital isolated central hypothyroidism: Novel mutations and their functional implications

Handb Clin Neurol. 2021:180:161-169. doi: 10.1016/B978-0-12-820107-7.00010-0.


Congenital hypothyroidism is the most frequent endocrine disorder in newborns, occurring in 1 per 3000-4000 newborns. In the Netherlands, the neonatal screening program is based primarily on heel prick thyroxine (T4). In contrast to thyroid-stimulating hormone-based programs, this approach allows for the detection of both primary and central congenital hypothyroidism. Over the past decade, the identification of families with isolated congenital central hypothyroidism enabled the identification of novel genetic causes of this condition, in addition to mutations in the TSHβ-subunit gene and thyrotropin-releasing hormone receptor gene reported earlier. In 2012, loss-of-function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene, were reported as a genetic cause of a syndrome including X-linked congenital central hypothyroidism and adult macroorchidism. IGSF1 encodes a hypothalamic plasma membrane glycoprotein. Mutations in IGSF1 represent the most prevalent genetic cause of isolated central hypothyroidism to date. In 2016, mutations in the transducin β-like 1X (TBL1X) gene were identified in patients with a combination of mild central hypothyroidism and sensorineural hearing loss. TBL1X is an essential subunit of the NCoR/SMRT corepressor complex and expressed in many tissues including the human hypothalamus and pituitary. In 2018, mutations in the insulin receptor substrate 4 (IRS4) gene were reported in cases of familial isolated central hypothyroidism. IRS4 encodes a hypothalamic protein that is part of the insulin and leptin signaling cascade. These recent developments will broaden our understanding of the role of the hypothalamus in hypothalamus-pituitary-thyroid axis regulation and will help to improve diagnosis and treatment of isolated central hypothyroidism.

Keywords: Coactivator; Corepressor; Hypothalamus; Hypothyroidism; Neonatal screening; Pituitary; TRH; TSH; Thyroid.

Publication types

  • Review

MeSH terms

  • Adult
  • Congenital Hypothyroidism* / genetics
  • Humans
  • Immunoglobulins
  • Infant, Newborn
  • Membrane Proteins / genetics
  • Mutation / genetics
  • Netherlands
  • Receptors, Thyrotropin-Releasing Hormone / genetics
  • Thyrotropin


  • IGSF1 protein, human
  • Immunoglobulins
  • Membrane Proteins
  • Receptors, Thyrotropin-Releasing Hormone
  • Thyrotropin