Congenital hypothyroidism Exploration of biochemical and genetic perspectives

Open Access
Authors
  • P. Lauffer
Supervisors
  • A.S.P. van Trotsenburg
  • A. Boelen
Cosupervisors
  • N. Zwaveling-Soonawala
  • P. Henneman
Award date 23-09-2024
ISBN
  • 9789465063287
Number of pages 220
Organisations
  • Faculty of Medicine (AMC-UvA)
Abstract
This thesis explores the biochemical and genetic aspects of congenital hypothyroidism (CH), focusing on its diagnosis and the role of genetic factors, including hereditary forms of isolated central CH and CH in Down syndrome (DS).
Part A: Biochemical Considerations
The first section addresses the challenges in diagnosing central CH. It outlines a diagnostic algorithm for differentiating between transient conditions, like hypothyroxinemia of prematurity and non-thyroidal illness syndrome, and permanent conditions like central CH. Part A further emphasizes the need for establishing reliable reference intervals (RIs) for FT4 during the neonatal period and successfully establishes RIs for other thyroid hormones (T4, T3, and rT3) using liquid chromatography-tandem mass spectrometry.
Part B: Genetic Insights
This section delves into the genetic underpinnings of CH, highlighting the role of genetic testing in atypical cases. It discusses a case involving a sodium/iodide symporter defect and coexisting resistance to thyroid hormone beta (RTHβ). Part B further explores the TBL1X and IRS4 genes, which cause isolated central CH, and investigates a novel TSHB variant associated with a mild central CH phenotype.
Part C: Down Syndrome and Congenital Hypothyroidism
The final section examines the relationship between DS and CH. DNA methylation and gene expression changes in DS are investigated, contributing to a better understanding of the molecular mechanisms linking DS to thyroid dysfunction.
Document type PhD thesis
Note Chapter 3: This is the accepted version of the following article: “Analysis of serum FT4 concentrations in healthy term neonates underlines need for local and laboratory-specific reference interval: a systematic review and meta-analysis of individual participant data.”, which has now been formally published in final form at Thyroid at doi: 10.1089/thy.2023.0562. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions. - Chapter 5: This is the accepted version of the following article: “Defective Levothyroxine Response in a Patient with Dyshormonogenic Congenital Hypothyroidism Caused by a Concurrent Pathogenic Variant in Thyroid Hormone Receptor-β.”, which has now been formally published in final form at Thyroid at doi: 10.1089/thy.2021.0204. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions. - Chapter 6: This is the accepted version of the following article: “Further Delineation of Central Congenital Hypothyroidism due to Variants in TBL1X and IRS4.”, which has now been formally published in final form at Thyroid at doi: 10.1089/thy.2022.0675. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions. - Chapter 7: This is the accepted version of the following article: “Mild Isolated Congenital Central Hypothyroidism Due to a Novel Homozygous Variant in TSHB: A Case Report.”, which has now been formally published in final form at Thyroid at doi: 10.1089/thy.2021.0651. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions. - Chapter 8: This is the accepted version of the following article: “Meta-Analysis of DNA Methylation Datasets Shows Aberrant DNA Methylation of Thyroid Development or Function Genes in Down Syndrome.”, which has now been formally published in final form at Thyroid at doi: 10.1089/thy.2022.0320. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions.
Language English
Other links http://doi.org/10.1089/thy.2023.0562 http://doi.org/10.1089/thy.2021.0204 http://doi.org/10.1089/thy.2022.0675 http://doi.org/10.1089/thy.2021.0651 http://doi.org/10.1089/thy.2022.0320
Downloads
Thesis (complete) (Embargo up to 2026-09-23)
Chapter 4: Reference intervals for LC-MS/MS measured serum T4, T3 and rT3 concentrations in the first two weeks of life (Embargo up to 2026-09-23)
Chapter 9: Etiology of congenital thyroid dysfunction in Down syndrome: A multi-omics investigation (Embargo up to 2026-09-23)
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