Resistance to thyroid hormone alpha associated with a novel THRA ligand-binding domain variant: familial clinical, biochemical, skeletal, and exploratory cerebral FDG-PET/CT metabolic findings
6 affiliations
- 1Laboratorio de Glicobiología Humana y Diagnóstico Molecular, Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico
- 2Departamento de Genética, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de Mexico, Mexico
- 3Departamento de Endocrinología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán., Ciudad de Mexico, Mexico
- 4Departamento de Medicina Nuclear, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de Mexico, Mexico
- 5Departamento de Radiología e Imagen, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de Mexico, Mexico
- 6Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica, Ciudad de Mexico, Mexico
Abstract
Background: Thyroid hormones (TH) regulate skeletal development, central nervous system maturation, and energy homeostasis, primarily through the nuclear receptors TRα and TRβ, encoded by the THRA and THRB genes. Pathogenic variants in THRA lead to resistance to thyroid hormone alpha (RTHα), a rare and diagnostically challenging condition.
Methods: A 36-year-old woman and her 12-year-old son were studied to characterize the clinical, biochemical, radiological, and exploratory cerebral metabolic findings associated with a previously unreported, likely pathogenic variant in THRA. Both individuals underwent a comprehensive clinical evaluation. Thyroid function tests included TSH, fT4, fT3, TT3, TT4, and rT3, along with additional biochemical assessments.
Molecular analysis included whole-exome sequencing in proband 1, which identified a variant in THRA (NM_199334.5:c.662T>C; p.Ile221Thr), subsequently confirmed in the second case. Additionally, the adult patient underwent brain positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET) to assess regional cerebral metabolism with exploratory visual and ROI-based comparison with an age- and sex-matched control subject.
Results: Both patients exhibited a phenotype consistent with RTHα, characterized by hypotonia, macrocephaly, dysmorphic features, chronic constipation, and normocytic anemia. The fT3/fT4 ratio was elevated (high-normal), and rT3 levels were decreased in both cases. The THRA variant was located in the ligand-binding domain and segregated with the familial phenotype. Exploratory brain ^18F-FDG PET assessment in Proband 1 showed symmetrically higher FDG uptake in the prefrontal cortex, basal ganglia, and lateral temporal cortex compared with the control subject, with consistently higher SUVmax values across the evaluated ROIs. These findings represent an exploratory single-subject comparison and have not previously been reported in RTHα.
Conclusions: This study expands the clinical, biochemical, radiological, and metabolic spectrum associated with THRA variants and suggests that cerebral metabolic evaluation may provide additional diagnostic insights in RTHα. Further studies, including larger cohorts and functional analyses, will be necessary to confirm the proposed mechanisms and the clinical relevance of the observed metabolic findings.
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BibTeX
@article{matasalgado2026resistance,
title = {{Resistance to thyroid hormone alpha associated with a novel THRA ligand-binding domain variant: familial clinical, biochemical, skeletal, and exploratory cerebral FDG-PET/CT metabolic findings}},
author = {Denisse Mata-Salgado and Juan José Morales-Suárez and Alfredo Adolfo Reza-Albarrán and Rodrigo Hernández-Ramírez and Miguel Angel Corza-Ayala and José Antonio Cienfuegos-Alvear and Ana María González-Jaimes and Iván Martínez-Duncker and Carmen Alaez-Verson},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1891019},
url = {https://doi.org/10.3389/fendo.2026.1891019},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Resistance to thyroid hormone alpha associated with a novel THRA ligand-binding domain variant: familial clinical, biochemical, skeletal, and exploratory cerebral FDG-PET/CT metabolic findings
AU - Denisse Mata-Salgado
AU - Juan José Morales-Suárez
AU - Alfredo Adolfo Reza-Albarrán
AU - Rodrigo Hernández-Ramírez
AU - Miguel Angel Corza-Ayala
AU - José Antonio Cienfuegos-Alvear
AU - Ana María González-Jaimes
AU - Iván Martínez-Duncker
AU - Carmen Alaez-Verson
PY - 2026
DA - 2026/10/12
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1891019
UR - https://doi.org/10.3389/fendo.2026.1891019
AB - Background: Thyroid hormones (TH) regulate skeletal development, central nervous system maturation, and energy homeostasis, primarily through the nuclear receptors TRα and TRβ, encoded by the THRA and THRB genes. Pathogenic variants in THRA lead to resistance to thyroid hormone alpha (RTHα), a rare and diagnostically challenging condition. Methods: A 36-year-old woman and her 12-year-old son were studied to characterize the clinical, biochemical, radiological, and exploratory cerebral metabolic findings associated with a previously unreported, likely pathogenic variant in THRA. Both individuals underwent a comprehensive clinical evaluation. Thyroid function tests included TSH, fT4, fT3, TT3, TT4, and rT3, along with additional biochemical assessments. Molecular analysis included whole-exome sequencing in proband 1, which identified a variant in THRA (NM_199334.5:c.662T>C; p.Ile221Thr), subsequently confirmed in the second case. Additionally, the adult patient underwent brain positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET) to assess regional cerebral metabolism with exploratory visual and ROI-based comparison with an age- and sex-matched control subject. Results: Both patients exhibited a phenotype consistent with RTHα, characterized by hypotonia, macrocephaly, dysmorphic features, chronic constipation, and normocytic anemia. The fT3/fT4 ratio was elevated (high-normal), and rT3 levels were decreased in both cases. The THRA variant was located in the ligand-binding domain and segregated with the familial phenotype. Exploratory brain ^18F-FDG PET assessment in Proband 1 showed symmetrically higher FDG uptake in the prefrontal cortex, basal ganglia, and lateral temporal cortex compared with the control subject, with consistently higher SUVmax values across the evaluated ROIs. These findings represent an exploratory single-subject comparison and have not previously been reported in RTHα. Conclusions: This study expands the clinical, biochemical, radiological, and metabolic spectrum associated with THRA variants and suggests that cerebral metabolic evaluation may provide additional diagnostic insights in RTHα. Further studies, including larger cohorts and functional analyses, will be necessary to confirm the proposed mechanisms and the clinical relevance of the observed metabolic findings.
SN - 1664-2392
ER -