Diagnostic Utility of Genetic Testing in Hyperthyroxinemia With Non-Suppressed TSH

Area of Science:

• Pediatric Endocrinology
• Clinical Genetics
• Molecular Diagnostics

Background:

• Hyperthyroxinemia with non-suppressed TSH presents diagnostic challenges in children.
• Inherited causes include resistance to thyroid hormone beta (RTHβ) and familial dysalbuminemic hyperthyroxinemia (FDH), an assay interference.
• Distinguishing these conditions is crucial for appropriate management.

Purpose of the Study:

• To characterize clinical, laboratory, and molecular features of pediatric patients with elevated FT4 and non-suppressed TSH.
• To identify parameters aiding in the differential diagnosis of RTHβ and FDH.
• To evaluate the utility of genetic testing in this cohort.

Main Methods:

• Retrospective observational study of 25 children from 19 families with elevated FT4 and non-suppressed TSH.
• Review of clinical history, anthropometrics, physical exams, vital signs, and laboratory results.
• Sequencing of THRB and ALB genes to identify pathogenic variants.

Main Results:

• Pathogenic THRB variants (RTHβ) identified in 33.3% of tested patients; tachycardia noted in 50% of these.
• Hotspot ALB variants (FDH) found in 46.2% of tested patients; no tachycardia or thyroid dysfunction signs observed.
• FT4 and TSH levels were similar between groups, but FT3 tended to be lower in FDH.

Conclusions:

• Molecular testing is essential for accurate diagnosis of elevated FT4 with non-suppressed TSH.
• Hotspot analysis of the ALB gene is recommended as a first-line test, especially for asymptomatic individuals.
• Accurate diagnosis prevents unnecessary medical interventions.