Resistance to Thyroid Hormone Beta: A Focused Review

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Resistance to thyroid hormone (RTH) is a genetic disorder characterized by insensitivity to thyroid hormones (TH).
• The most common form, RTH beta (RTHβ), results from mutations in the thyroid hormone receptor beta (THRB) gene.
• Affected individuals typically present with elevated serum TH levels without suppressed thyrotropin, often appearing clinically euthyroid despite biochemical abnormalities.

Purpose of the Study:

• To provide a concise update on RTHβ, including its genetic basis and biochemical profile.
• To discuss less recognized associations of RTHβ with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease.
• To summarize current evidence and controversies regarding the phenotypic variability of RTHβ and review management strategies for associated symptoms.

Main Methods:

• Literature review focusing on RTHβ, THRB gene mutations, and associated thyroid disorders.
• Analysis of existing evidence on phenotypic variability and management approaches.
• Inclusion of emerging research on variants of unknown significance and epigenetic effects of intrauterine TH exposure.

Main Results:

• RTHβ exhibits significant phenotypic variability due to diverse THRB mutations and differential expression of mutant TRβ protein.
• Management strategies are individualized based on specific symptoms of TH excess or deprivation.
• Emerging areas include the clinical relevance of variants of unknown significance and the transgenerational inheritance of epigenetic effects from intrauterine TH exposure.

Conclusions:

• RTHβ is a complex syndrome with variable clinical manifestations, necessitating personalized management.
• Further research is needed to understand the implications of genetic variants and epigenetic factors in RTHβ.
• Current therapeutic approaches focus on symptom management rather than correcting the underlying TRβ defect.