Skip to main content
Public beta This website is in public beta – please give your feedback.
Endocrinology

Presentation: Patient with resistance to thyroid hormone

Resistance to thyroid hormone is characterised by defects in the thyroid hormone receptors due to pathogenic genetic variants, resulting in reduced responsiveness to the action of thyroid hormone.

Example clinical scenario

A 20-year-old male underwent routine blood tests when applying for the army. These revealed a mildly elevated fT4 level of 24.2pmol/L (normal range 10–22pmol/L), with a TSH of 3.7mIU/L (normal range 0.3–4.5mIU/L).

He was referred to endocrinology for assessment and management. His sample was tested on two different laboratory assays and the results remained the same. His fT3 level was 6.9pmol/L (normal range 3.1–6.8pmol/L). A circulating alpha subunit (part of the TSH molecule) was requested and was normal.

He went on to have a pituitary MRI scan, which was normal, and a thyrotropin-releasing hormone (TRH) test, which showed an exaggerated response; therefore, resistance to thyroid hormone (RTH) was suspected.

When to consider genomic testing

  • There are two forms of RTH to consider testing for:
    • RTHβ, due to loss-of-function pathogenic variants in THRB, which is the most common form; and
    • RTHα, due to loss-of-function pathogenic variants in THRA, which is much rarer.
  • Genomic testing for RTHβ should be considered for individuals with biochemical features of RTH – thyroid hormone excess with a non-suppressed thyroid-stimulating hormone (TSH) – where other causes have been excluded, including assay interference and TSHoma.
  • Genomic testing for RTHα should be considered for individuals with clinical features of hypothyroidism who have near-normal thyroid function tests.

What do you need to do?

  • Consult the National Genomic Test Directory. From this link you can access the Rare and Inherited Disease Eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • Select the appropriate test panel for your patient depending upon the clinical and biochemical picture:
    • THRB and THRA are included in:
      • R145 Congenital hypothyroidism: A panel that includes whole exome sequencing (WES) or a medium panel; and
      • R182 Hyperthyroidism: A small panel test.
    • THRA is also included in the following panels:
      • R21 Fetal anomalies with a likely genetic cause;
      • R412 Fetal anomalies with a likely genetic cause – non-urgent; and
      • R29 Intellectual disability – microarray and sequencing.
  • Generally, if considering the R21, R412 and R29 panel tests in the endocrinology clinic, a discussion with clinical genetics is advised
  • If a patient presents with RTH and has a family member with a genetic diagnosis in a relevant predisposition gene, single gene testing for that specific variant should be considered (R240).
  • These tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required and best stored at 4°C until posted to the genomic laboratory.
  • Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

Resources

For clinicians

Resources:

For patients

↑ Back to top
  • Last reviewed: 09/05/2025
  • Next review due: 09/05/2026
  • Authors: Dr Anna Mitchell
  • Reviewers: Dr Danielle Bogue, Dr Louise Izatt, Professor Márta Korbonits