Thyroid Hormone Receptor beta (Gene Sequence Analysis)

Clinical Use
Suspected Resistance to Thyroid Hormone.

1 Resistance to Thyroid Hormone
The syndrome of resistance to thyroid hormone is characterized by elevated circulating FT4 and FT3 levels, failure to suppress pituitary TSH secretion and variable peripheral tissue refractoriness to hormone action. The disorder is inherited in an autosomal dominant manner in 75% of families but sporadic cases are described (15-20%). RTH is associated with diverse, heterozygous, loss-of-function mutations in the thyroid hormone ? receptor gene. Patients with RTH can present in two ways: some individuals are asymptomatic and identified when thyroid function tests (TFTs) are undertaken for other reasons; in other cases, patients may experience thyrotoxic symptoms (failure to thrive in childhood; anxiety, tachycardia, weight loss) which prompt thyroid investigation.
The differential diagnosis of hyperthyroxinaemia with non-suppressed TSH levels is broad. Quantitative abnormalities in serum binding proteins can be excluded by measurement of free thyroid hormones. Two-step and equilibrium dialysis assays can be helpful in excluding interference with FT4 and FT3 measurement and dilution studies (see below) can help exclude interference with TSH measurement. Other causes (e.g. non thyroidal illness, amiodarone or heparin treatment) can usually be excluded from the clinical context. The major alternative diagnosis to RTH is a TSH-secreting pituitary tumour (TSHoma). An elevated molar ratio of pituitary glycoprotein alpha subunit to TSH, an abnormality on pituitary MRI imaging, or an impaired TSH response on dynamic testing (TRH stimulation, T3 suppression) is suggestive of TSHoma. Conversely, normal levels of serum sex hormone binding globulin (SHBG), a hepatic marker of thyroid hormone action, or abnormal TFTs in first degree relatives favours a diagnosis of RTH. In ~15% of RTH cases, an abnormality in the TR? gene cannot be identified, raising the possibility that defects in other genes mediating thyroid hormone action could result in a similar biochemical picture.

2 Interference in thyroid assays
Interference with thyroid hormone and TSH measurement (e.g. antiiodothyronine or antiTSH antibodies) is much commoner than resistance to thyroid hormone or TSHoma, so it is advisable to first exclude such interference. We offer two different free thyroid hormone and TSH assays to check local thyroid function test results, plus a total T4 assay that can be useful where displacement from binding proteins is a problem. We also offer measurement of TSH following serial dilution of serum, as non-linearity in this test is indirect evidence for assay interference.

Patient Preparation
Thyroid hormone receptor gene sequence analysis is a genetic test. Before taking any blood sample it is essential that the patient receives appropriate counselling . It is the responsibility of the clinician caring for the patient to ensure that this is done and samples are only accepted on the basis that patients have been counselled and consent to the analysis.

Sample Preparation
Before requesting sequencing, it is strongly recommended that other causes of hyperthyroxinaemia with non-suppressed TSH have been excluded. Provision of a summary of the clinical background of the case is valuable. Please include results of thyroid function tests and other relevant investigations undertaken locally and any medication which could influence TFTs.
Send 5 mL of whole blood in EDTA tubes to the SAS laboratory by first class post.
Send 3.0 mL serum if exclusion of interference in thyroid hormone or TSH assays is required.

Reference Ranges
Please contact SAS laboratory.

Quality Assessment
No EQAS is available. Strict internal QC procedures are followed and we operate a sample exchange system with other SAS labs for biochemical tests.

Centre offering this assay
Cambridge Addenbrooke’s Hospital Endocrine Laboratory
Cardiff UHW Hormone and Steroid Laboratory

Chatterjee VKK.& Gurnell M. Resistance to thyroid hormone in Oxford Textbook of Endocrinology and Diabetes (Eds JAH Wass and S.M.Shalet) Oxford University Press, 2002

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