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Endocrinology Genomics


Thyroid hormone resistance, also known as impaired sensitivity to thyroid hormone, is characterized by a reduced responsiveness of target tissues to thyroid hormone and is primarily caused by germline pathogenic variants in THRB, which encodes the thyroid receptor beta (TRbeta). The condition caused by THRB variants is known as resistance to thyroid hormone beta (RTHbeta). The mutant receptor has lower binding affinity for thyroid hormone and, as a consequence, serum thyroid-stimulating hormone (TSH) levels remain nonsuppressed despite elevated thyroid hormones. Patients with pathogenic variants in THRB also present with goitre and the absence of symptoms of thyrotoxicosis. Clinical phenotypes can be highly variable depending on the degree of tissue responsiveness to elevated thyroid hormone levels in a given individual; the same variant can result in different phenotypes in different patients, even within the same family. In general, heterozygous pathogenic variants in THRB are sufficient to cause disease, via a dominant negative effect. Patients homozygous for variants in THRB have a more severe phenotype than patients with heterozygous variants. Variants in THRB are found in ~86% patients with RTHbeta (Dumitrescu & Refetoff 2013 PMID: 22986150; Ortiga-Carvalho et al 2014 PMID: 25135573; Dumitrescu et al 2015 PMID: 25905294).

A smaller number of cases of thyroid hormone resistance are caused by heterozygous missense or truncating variants in THRA (thyroid hormone receptor alpha). This condition is known as RTHalpha. The phenotype is different to RTHbeta and includes growth retardation, skeletal dysplasia, intellectual disability, seizures, constipation, bradycardia and muscle weakness, consistent with the expression of the TRalpha in bone, brain, intestine, heart and muscle. Thyroid hormone tests reveal low reverse T3 (rT3), slightly low T4, relatively high normal T3 and normal TSH (Tylki-Szymanska et al 2015 PMID: 25670821).

Germline gain-of-function variants in the TSHR (thyroid-stimulating hormone receptor) gene cause autosomal dominant non-autoimmune hyperthyroidism. The disorder is characterised by low TSH levels and elevated thyroid hormone (T3 and T4) levels (Hebrant et al 2010 PMID: 20926595).

Autosomal recessive variants in SECISBP2 have been found to cause abnormal thyroid hormone metabolism in a small number of families. The SECISBP2 protein is required for synthesis of thyroid hormone deiodinases and its deficiency results in abnormal intracellular thyroid hormone metabolism. Patients exhibit growth delay, delayed bone maturation, muscle weakness, developmental delay and sensorineural hearing loss. Thyroid function tests show high total and free T4, low T3, high rT3 and slightly elevated serum TSH (Dumitrescu et al 2015 PMID: 25905294).

Allan-Herndon-Dudley syndrome is caused by loss-of-function variants in SLC16A2, which encodes the thyroid hormone transporter monocarboxylate transporter 8 (MCT8). The condition is X-linked; heterozygous females may have a milder phenotype. The clinical features include congenital hypotonia, severe neurodevelopmental defects, muscle weakness in males, and a specific pattern of abnormal thyroid hormone function consisting of high T3, low T4 and normal TSH. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, thought to be due to impaired thyroid hormone transport across the blood-brain barrier. (Schwartz & Stevenson 2007 PMID: 17574010; Sarret et al GeneReviews PMID: 20301789).

Familial dysalbuminaemic hyperthyroxinaemia is caused by heterozygous or homozygous missense variants in ALB, which result in the production of albumin with an increased affinity for thyroxine. Individuals with dysalbuminaemic hyperthyroxinaemia have elevated total T4, elevated or normal free T4 and normal TSH levels, and are asymptomatic. Recognition of the condition is important to avoid unnecessary investigations and/or treatment (Pappa et al 2015 PMID: 26522458).

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.

NHSE test directory code: R182 Hyperthyroidism. Testing criteria can be found on this webpage: https://www.england.nhs.uk/publication/national-genomic-test-directories/.

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