What genetic testing and antibody testing are recommended for diagnosing thyroid hormone resistance syndrome, including specific tests such as Thyroid Peroxidase Antibodies (TPOAb) and Thyrotropin Receptor Antibodies (TRAb) and sequencing of the Thyroid Hormone Receptor Beta (THRB) gene?

Diagnostic Testing for Thyroid Hormone Resistance Syndrome

For diagnosing thyroid hormone resistance syndrome, genetic testing for mutations in the thyroid hormone receptor beta (THRB) gene is the gold standard, while antibody testing should include thyroid peroxidase antibodies (TPOAb) and thyrotropin receptor antibodies (TRAb) to rule out autoimmune thyroid disorders.

Initial Laboratory Evaluation

• The characteristic laboratory finding in thyroid hormone resistance syndrome is elevated free T3 (FT3) and free T4 (FT4) with normal or non-suppressed TSH levels 1, 2
• This pattern distinguishes it from primary hyperthyroidism, where TSH would typically be suppressed 3
• Initial laboratory testing should include:
  • Complete thyroid function panel (TSH, FT4, FT3) 1, 4
  • Thyroid antibody testing to exclude autoimmune thyroid disorders 3, 4

Antibody Testing

• Thyroid Peroxidase Antibodies (TPOAb) should be ordered to rule out Hashimoto's thyroiditis, which is the most common cause of hypothyroidism in industrialized nations 5
• Thyrotropin Receptor Antibodies (TRAb) should be tested to exclude Graves' disease, which could present with similar laboratory findings 5
• Negative antibody results in the presence of elevated thyroid hormones with non-suppressed TSH strongly suggest thyroid hormone resistance syndrome 4

Genetic Testing

• Direct DNA sequencing of the THRB gene is the definitive diagnostic test for thyroid hormone resistance syndrome 6
• Approximately 85% of patients with thyroid hormone resistance have identifiable mutations in the THRB gene 4
• The genetic testing should specifically target:
  • Exons 7-10 of the THRB gene, which encode the ligand-binding domain where most pathogenic mutations occur 3, 6
  • Particular attention to cluster 3 of the ligand-binding domain, a region frequently associated with resistance to thyroid hormone 6

Additional Diagnostic Tests

• Somatostatin suppression test may be performed to differentiate thyroid hormone resistance from TSH-secreting pituitary adenomas 1, 4
• Thyroid ultrasound to evaluate for goiter, which is present in approximately 31.8% of patients with thyroid hormone resistance 2
• MRI of the sellar region to rule out TSH-secreting pituitary adenoma 1, 4

Interpretation of Results

• A confirmed diagnosis requires:
  • Laboratory evidence of elevated FT3 and FT4 with non-suppressed TSH 1, 2, 4
  • Identification of a pathogenic variant in the THRB gene 3, 6
  • Absence of thyroid autoantibodies or other causes of thyroid dysfunction 4

Common Pitfalls to Avoid

• Misdiagnosis as hyperthyroidism is common, occurring in approximately 18.2% of cases, leading to inappropriate treatments such as thyroidectomy or antithyroid medications 2, 3
• Failure to consider thyroid hormone resistance when TSH is not suppressed despite elevated thyroid hormone levels can lead to unnecessary treatments 3, 6
• DNA-based diagnosis is more reliable and economical compared to traditional biochemical tests for confirming thyroid hormone resistance syndrome 6

Family Testing

• Once a mutation is identified in the index patient, targeted genetic screening should be offered to all first-degree relatives, as thyroid hormone resistance follows an autosomal dominant inheritance pattern 2, 4
• Family screening can identify affected individuals before inappropriate treatment is initiated 2, 6