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

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.