Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq
Open accessAbstract
Context: Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (TRH) receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood. Objectives: Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms. Design: All family members were phenotyped with thyroid hormone profiles, pituitary magnetic resonance imaging, TRH tests, and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB, and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling. Results: A homozygous missense mutation in TRHR (c.392T > C; p.I131T) was identified in an 8-year-old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; –0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq. Conclusions: A unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.
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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 [30]
The Abstract describes two patients referred at ages 9 and 11 with short stature and symptoms including lethargy and fatigue; a third was diagnosed at two months. The Discussion says the paper’s 8-year-old patient was overweight, but came to medical attention because of abnormal thyroid tests at a routine checkup, not because of overweight. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEven 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 [30]
The Abstract (page unavailable) reports moderate hypothyroidism in three patients with severely impaired TRHR signaling, all missed by TSH-based neonatal screening. The Discussion (page unavailable) says previously described mutations had no residual activity. These observations are consistent with the main point, but the paper does not establish that complete resistance never causes severe neonatal hypothyroidism, and the cited passages do not report prolonged neonatal jaundice in a female patient. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn central hypothyroidism patients with high immunoreactive TSH, TSH elevations are similar to those generally found in subclinical or mild primary hypothyroidism and may lead to misdiagnosis.
“In these cases, TSH elevations are similar to those generally found in subclinical or mild primary hypothyroidism and may lead to misdiagnosis [14-17, 30, 42].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [30]
The Results report mild TSH elevation with normal FT4 in several family members, and the Discussion warns that central hypothyroidism can go undiagnosed when TSH is normal or elevated. The paper does not compare those elevations with subclinical or mild primary hypothyroidism or report misdiagnosis as primary hypothyroidism. The available passages have no page numbers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHeterozygous relatives were reported to have hyperthyrotropinemia in 1 family.
“Interestingly, heterozygous relatives were reported to have hyperthyrotropinemia in 1 family [30].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [30]
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 [30]
Blunted TSH and PRL responses to TRH testing suggest TRHR involvement, though normal responses have also been reported when TRHR function is not completely disrupted.
“Blunted TSH and PRL responses to TRH testing suggest TRHR involvement [11], though normal responses have also been reported when TRHR function is not completely disrupted [30].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [30]
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References 43 · Cited by 33
Research works printed but not linked: 1
- [25]Zubiaur Cantalapiedra A, Zapico Alvarez-Cascos MD, Ruiz Pérez L, Sanguino López L, Sánchez Serrano FJ, Alfayate Guerra R, Sánchez-Paya J, Guirao Carratalá MD, Pico Alfonso A, Flores Serrano J. Iodine nutritional status in the school-aged population in Alicante (Spain). An Pediatr (Barc). 2007;66(3):260–266. [DOI] [PubMed] [Google Scholar]
- Authors
- García, M., González de Buitrago, J., Jiménez-Rosés, M., Pardo, L., Hinkle, P. M., & Moreno, J. C.
- Affiliations
- Hospital Universitario La Paz (ES)
- Department of Pediatrics, San Pedro de Alcántara Hospital, 10003 Cáceres, Spain
- Computational Medicine Laboratory, Biostatistics Unit, Autonomous University of Barcelona, 08193 Barcelona, Spain
- Universitat Autònoma de Barcelona (ES)
- University of Rochester Medicine (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2017-04-17
- Volume
- 102
- Issue
- 7
- Pages
- 2433-2442
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5505191
- OpenAlex
- W2607288296
- Cited by
- 33
- References
- 43
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 8 · 2017: 1
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048823)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- thyrotropin-releasing hormone receptor, Gq coupling, hyperthyrotropinemia, TSH receptor, consanguinity, short stature, pituitary gland
- MeSH terms
- Child, Computer Simulation, Congenital Hypothyroidism, Humans, Male, Pedigree, Thyroid Function Tests, Thyrotropin, Transcriptional Activation, Receptors, Thyrotropin-Releasing Hormone, Genetic Predisposition to Disease, Mutation, Missense, Rare Diseases, GTP-Binding Protein alpha Subunits, Gq-G11
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