Variable clinical presentation and outcome in pediatric patients with resistance to thyroid hormone (RTH)

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Resistance to thyroid hormone (RTH) is a rare endocrine disorder characterized by elevated thyroid hormone levels despite normal or elevated TSH.
• RTH is caused by mutations in the thyroid hormone receptor beta (TRβ) gene, leading to impaired hormone action.
• Clinical manifestations of RTH are highly variable, ranging from asymptomatic to severe symptoms.

Purpose of the Study:

• To describe the clinical and biochemical findings and long-term follow-up of children with RTH.
• To highlight the genetic basis and phenotypic diversity of RTH in affected families.
• To emphasize the importance of molecular diagnosis for accurate RTH identification.

Main Methods:

• Retrospective analysis of six children and four affected parents from five families with molecularly diagnosed RTH.
• Detailed clinical evaluation, including physical examination, symptom assessment, and thyroid function tests (T4, FT4, T3, TSH).
• Genetic analysis to identify mutations in the TRβ gene (exons 9 and 10) and assessment of hormone levels after T3 administration.

Main Results:

• Five distinct TRβ mutations (p.M313T, pN331D, p.L341P, p.L346F, p.P453L) were identified in affected individuals.
• Common clinical features included goiter, tachycardia, and learning disabilities, with significant variability in presentation.
• Biochemical profile showed elevated T4, FT4, T3, and normal TSH, with paradoxical decrease in SHBG after T3 administration in some patients.

Conclusions:

• RTH presents with a characteristic biochemical profile but highly variable clinical manifestations and outcomes.
• Molecular characterization of TRβ gene mutations is crucial to avoid misdiagnosis and guide appropriate management.
• Treatment for RTH should be individualized based on the patient's specific clinical requirements and symptom severity.