Endocrine Abstracts

Generalised resistance to thyroid hormone (GRTH), a subset of the syndrome of resistance to thyroid hormone (RTH), is characterised by variable reduced target tissue responsiveness to circulating thyroid hormones. Plasma thyroid hormone levels are raised and TSH levels inappropriately non-suppressed. We describe a 54-year-old female with GRTH diagnosed from the finding of raised fT4 and fT3 levels coincidental with non-suppressed TSH levels. A thyrotropin (TRH) test resulted in an attenuated response.

On examination she was of short stature, lean with a small nodular goitre. Previous medical history revealed behavioural problems. Obstetric history included one stillbirth, one miscarriage and two neonatal deaths. Thyroid function tests (TFTs) on her mother and two of her three offspring also suggested GRTH. Gene analysis of the thyroid hormone beta receptor (TRβ) in her and one of her offspring with abnormal TFTs confirmed a novel heterozygous missense substitution mutation, D351G, located in the second mutation cluster. This corresponds to a transition of adenine for guanine at codon 351 coding for glycine (GGC) rather than aspartic acid (GAC). No other amino acid substitutions at the same codon have been described to date. Functional analyses have not been performed on D351G. Abnormal TFTs in the patient and other family members suggest that D351G is causative and pathogenic and not a simple polymorphism.

The patient exhibited a 30% higher than predicted basal metabolic rate. A DEXA scan confirmed osteoporosis. TFTs reveal a rise in thyroid hormones coincidental with a fall in TSH over a number of years indicating autonomous thyroid hormone secretion from her nodular goitre with progression to hyperthyroidism.

This patient presents a difficult management problem as she has the coincidental combination of the very rare GRTH with the common condition toxic nodular goitre. To our knowledge this combination has not previously been described.