A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene1
Abstract
Isolated central hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder. We report a boy in whom isolated central hypothyroidism was diagnosed at 9 yr of age. Complete absence of TSH and PRL responses to TRH led us to speculate that he had an inactivating mutation of the TRH receptor gene. The patients' genomic DNA was isolated, and the entire coding region of the TRH receptor was amplified by the PCR and sequenced directly. Confirmation of the mutations and haplotyping of the family was performed using restriction enzymes. The biological activity of the wild-type and mutated TRH receptors was verified by evaluating the binding of labeled TRH and stimulation by TRH of total inositol phosphate accumulation in transfected HEK-293 and COS-1 cells. The patient was found to be a compound heterozygote, having inherited a different mutated allele from each of the parents; both mutations were in the 5'-part of the gene. Mutated receptors were unable to bind TRH and to activate total inositol phosphate accumulation. Our report is the first description of naturally occurring inactivating mutations of a G protein-coupled receptor linked to the phospholipase C second messenger pathway. The prevalence and phenotypic spectrum of TRH receptor mutations in isolated central hypothyroidism remain to be established.
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In children, L-T4 treatment promotes acceleration of growth velocity allowing attainment of target height.
“In children, L-T4 treatment was reported to promote an acceleration of growth velocity allowing attainment of target height [11, 28, 43].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [28]
Even complete TRH resistance does not cause severe neonatal hypothyroidism.
“Though prolonged neonatal jaundice was reported in 1 female, even complete TRH resistance does not cause severe neonatal hypothyroidism.”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [28]
The diagnosis in 3 of 4 probands with biallelic TRHR mutations was made during childhood because of delayed growth accompanied by lethargy and fatigue or by overweight.
“The diagnosis in 3 of 4 probands with biallelic TRHR mutations was made during childhood because of delayed growth accompanied by lethargy and fatigue or by overweight.”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [28]
Defective TRH action due to biallelic mutations in the TRHR gene has, to date, been described in few families.
“Defective TRH action due to biallelic mutations in the TRHR gene has, to date, been described in few families [11, 28-30].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [28]
In children with central hypothyroidism, LT4 therapy is accompanied by acceleration of growth velocity, allowing attainment of target height.
“In CeH children, LT4 therapy was accompanied by an acceleration of growth velocity thus allowing the attainment of target height (9, 30, 47).”
From The diagnosis and management of central hypothyroidism in 2018 (2019) · cites this paper as [30]
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- Authors
- Collu, R., Tang, J., Castagné, J., Lagacé, G., Masson, N., Huot, C., Deal, C., Delvin, E., Faccenda, E., Eidne, K. A., & Van Vliet, G.
- Affiliations
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Medical Research Council (GB)
- Corresponding author
- Collu, Robert
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1997-05
- Volume
- 82
- Issue
- 5
- Pages
- 1561-1565
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2160221952
- Cited by
- 207
- References
- 16
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 13 · 2015: 10 · 2014: 10 · 2013: 6 · 2012: 11
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01dk042792-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK42792)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- thyrotropin-releasing hormone receptor, loss-of-function mutations, compound heterozygosity, G protein-coupled receptors, phospholipase C signaling, inositol phosphate accumulation, TSH deficiency, prolactin response, receptor binding, pediatric hypothyroidism
- MeSH terms
- Cell Line, Child, DNA, Haplotypes, Humans, Hypothyroidism, Male, Mutation, Pedigree, Prolactin, Thyrotropin, Thyrotropin-Releasing Hormone, Sequence Analysis, DNA, Receptors, Thyrotropin-Releasing Hormone
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