Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics
Open accessAbstract
BACKGROUND: Recently, the first patients with resistance to thyroid hormone alpha (RTHα) due to inactivating mutations in the thyroid hormone receptor alpha (TRα) were identified. These patients are characterized by growth retardation, variable motor and cognitive defects, macrocephaly, and abnormal thyroid function tests. The objective was to characterize a young girl (18 months old) with a mutation in both TRα1 and TRα2, and to study the effects of early levothyroxine (LT4) treatment. METHODS: The patient was assessed clinically and biochemically before and during 12 months of LT4 treatment. In addition, the consequences of the mutation for TRα1/2 receptor function were studied in vitro. RESULTS: At 18 months of age, the patient presented with axial hypotonia, delayed motor development, severe growth retardation, and abnormally elevated triiodothyronine (T3)/thyroxine (T4) ratios. RTHα was suspected, and concomitantly a c.632A>G/p.D211G missense mutation was identified, affecting both the TRα1 and TRα2 proteins. This mutation was also found in the girl's father. LT4 treatment was started, resulting in a marked improvement of her hypotonia, motor skills, and growth. Functionally, the missense mutation led to decreased transcriptional activity of TRα1, which could be overcome by higher T3 levels in vitro. The mutant TRα1 showed a moderate dominant negative activity on wild type (WT) TRα1. In contrast, WT TRα2 and mutant TRα2 had negligible transcriptional activity and showed no dominant-negative effect over TRα1. CONCLUSIONS: This report describes the phenotype of a young RTHα patient with a mild TRα mutation before and during early LT4 treatment. Treatment had beneficial effects on her muscle tone, motor development, and growth.
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In vitro analysis of the functional defects of mutant TRα1 proteins was consistent with the phenotype-genotype correlation described above.
“In vitro analysis of the functional defects of mutant TRα1 proteins was also consistent with the phenotype–genotype correlation described above, while all studies showed that wild-type and mutant TRα2 proteins were transcriptionally inactive and had no dominant-negative activity [67, 69, 72, 76].”
From Thyroid diseases and bone health (2018) · cites this paper as [72]
THRA mutations affecting both TRα1 and TRα2 have been described.
“More recently, THRA mutations affecting both TRα1 and TRα2 have been described [67, 69, 72, 76].”
From Thyroid diseases and bone health (2018) · cites this paper as [72]
No passage from our copy addresses whether the reported THRA mutation affects both TRα1 and TRα2. Searches for the two isoforms, THRA mutations, and receptor-alpha splice variants returned no relevant passage. (LLM, conf=0.70)
Experimental — accuracy not yet measuredAffected children and adults with THRA mutations affecting both TRα1 and TRα2 had a variable response to T4 treatment similar to that reported in individuals with mutations affecting TRα1 alone.
“Affected children and adults had a similar spectrum of abnormalities characteristic of the skeletal dysplasia and variable response to T4 treatment reported in individuals with mutations affecting TRα1 alone.”
From Thyroid diseases and bone health (2018) · cites this paper as [72]
Searches for skeletal dysplasia, variable T4 response, and comparisons with TRα1-only mutations found no matching full-text passage in our copy. The returned material was labeled Abstract and describes improvement in one girl, but does not establish variable responses across affected children and adults or the claimed comparison. (LLM, conf=0.68)
Experimental — accuracy not yet measuredAffected children and adults with THRA mutations affecting both TRα1 and TRα2 had a similar spectrum of abnormalities characteristic of the skeletal dysplasia to that reported in individuals with mutations affecting TRα1 alone.
“Affected children and adults had a similar spectrum of abnormalities characteristic of the skeletal dysplasia and variable response to T4 treatment reported in individuals with mutations affecting TRα1 alone.”
From Thyroid diseases and bone health (2018) · cites this paper as [72]
No passage from our indexed copy addresses whether mutations affecting both TRα1 and TRα2 produce skeletal abnormalities similar to those seen with TRα1-only mutations. Searches for TRα2, skeletal dysplasia, and related terms returned no relevant passage; the only returned text was bibliographic metadata (labelled Abstract, no page). (LLM, conf=0.72)
Experimental — accuracy not yet measuredWild-type and mutant TRα2 proteins were transcriptionally inactive and had no dominant-negative activity.
“In vitro analysis of the functional defects of mutant TRα1 proteins was also consistent with the phenotype–genotype correlation described above, while all studies showed that wild-type and mutant TRα2 proteins were transcriptionally inactive and had no dominant-negative activity [67, 69, 72, 76].”
From Thyroid diseases and bone health (2018) · cites this paper as [72]
Searches for TRα2 transcriptional activity and dominant-negative effects returned no body-text passage. The only matching material was labeled Abstract, which cannot serve as evidence under the supplied rubric; the claim therefore cannot be verified from the eligible passages of our copy. (LLM, conf=0.65)
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Cites
A Mutation in the Thyroid Hormone Receptor Alpha Gene
Bochukova, E., Schoenmakers, N., Agostini, M., Schoenmakers, E., Rajanayagam, O., Keogh, J. M., Henning, E., Reinemund, J., Gevers, E., Sarri, M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1110296 · Cited by 379 · see citing works
Bassett, J. H. D., Boyde, A., Zikmund, T., Evans, H., Croucher, P. I., Zhu, X., Park, J. W., Cheng, S.-Y., & Williams, G. R. (2014) · Endocrinology · doi:10.1210/en.2013-2156 · Cited by 50 · see citing works
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Thyroid diseases and bone health
Williams, G. R., & Bassett, J. H. D. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0753-4 · Cited by 276 · see citing works
Thyroid hormone resistance: mechanisms and therapeutic development
Yao, B., Yang, C., Pan, C., & Li, Y. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111679 · Cited by 26 · see citing works
- Authors
- van Gucht, A. L. M., Meima, M. E., Zwaveling-Soonawala, N., Visser, W. E., Fliers, E., Wennink, J. M. B., Henny, C., Visser, T. J., Peeters, R. P., & van Trotsenburg, A. S. P.
- Affiliations
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
- Erasmus MC (NL)
- Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
- Amsterdam UMC Location University of Amsterdam (NL)
- Sint Lucas Andreas Hospital (NL)
- Practice of Pediatric Physiotherapy, Sport Medical Center, Amsterdam, The Netherlands.
- Corresponding author
- Peeters, Robin P.
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2016-03
- Volume
- 26
- Issue
- 3
- Pages
- 338-346
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W2287640117
- Cited by
- 67
- References
- 2
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 9 · 2019: 10 · 2018: 5 · 2017: 8 · 2016: 6
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- thyroid hormone receptor alpha, thyroid hormone receptor alpha 1, TRα2, levothyroxine therapy, growth retardation, hypotonia, motor delay, dominant negative effect, transcriptional activity, pediatric patients
- MeSH terms
- Cell Line, Child Development, DNA Mutational Analysis, Female, Humans, Infant, Male, Pedigree, Phenotype, Thyroid Function Tests, Thyroxine, Transfection, Treatment Outcome, Thyroid Hormone Resistance Syndrome, Genetic Predisposition to Disease, Mutation, Missense, Thyroid Hormone Receptors alpha
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