Genetic causes and neonatal diagnosis of congenital isolated central hypothyroidism

Research output: PhD ThesisPhd-Thesis - Research and graduation internal

Abstract

Congenital hypothyroidism (CH) is the most common cause of preventable mental retardation. While CH is usually caused by abnormalities of the thyroid gland (primary CH), it may also be caused by abnormalities of the hypothalamus or pituitary, i.e. central CH. This thesis a) studies the genetic etiology of isolated central CH, b) describes the clinical characteristics of earlier described phenotypes, and c) establishes reference intervals for thyroid hormone concentrations in the neonatal period to provide cut-off values for the diagnosis of central CH.
Genetic analysis in affected families detected mutations in two genes located on the X-chromosome: transducin β-like protein 1, X-linked (TBL1X), an essential subunit of the NCoR/SMRT corepressor complex, and insulin receptor substrate 4 (IRS4), an interface between tyrosine kinase receptors and their intracellular pathways. A single mutation in the transducin β-like protein 1, X-linked receptor 1 (TBL1XR1) causes Pierpont syndrome, suggesting that despite their close homology, TBL1X and TBL1XR1 do not have identical functions. IGSF1 mutations cause a phenotype including central hypothyroidism, adult macroorchidism, a delayed and disharmonious puberty, and prolactin deficiency. Despite the marked macroorchidism in males, fertility is unaffected.
Finally, neonatal day-to-day reference intervals for FT4 and TSH based on an independent data meta-analysis show that commonly used cut-off values for TSH are adequate, while commonly used FT4 cut-off values are probably too low. Based on our findings, FT4 cut-off values during the first two to three weeks of life should be increased to allow for more sensitive testing.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Supervisors/Advisors
  • Fliers, Eric, Supervisor
  • van Trotsenburg, Adrianus, Supervisor
  • Hennekam, Raoul, Co-supervisor
  • Boelen, Anita, Co-supervisor
Award date10 Oct 2018
Print ISBNs9789402809589
Publication statusPublished - 2018

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