Endocrine Abstracts (2002) 3 P300

Determining the molecular causes of hyperthyroidism

F Al-Khafaji, G Baker & M Ludgate

Department of Medicine, University of Wales College of Medicine, Cardiff, UK.

Hyperthyroidism is a common disorder, most usually caused by Graves' Disease (GD), in which thyroid-stimulating antibodies (TSAB) mimic thyrotropin. Since the diagnosis of GD is made clinically and its signs and symptoms are indistinguishable from those of patients harboring an activating germline thyrotropin receptor (TSHR) mutation, incorrect diagnoses have been made. Point mutations in more than 30 residues, predominantly in exon 10, of the TSHR cause constitutivity making it highly amenable to activation by this mechanism.

We aim to determine the proportion of hyperthyroidism due to GD or to gain of function TSHR mutation.

We have studied 270 consecutive outpatients with a diffuse goitre and a history of thyrotoxicosis (TSH <0.02 mIU\/L, FT4 >23.1 pmol\/L). All the patients have been treated. TSAB were measured using an in-house luminescent bioassay, in all patients who were either negative or had not been

tested for thyrotropin binding inhibiting immunoglobuline (TBII) in a commercial assay.

119/270 patients were positive for TSAB, 90 for TBII and 61 were TSAB/TBII negative. Since treatment could produce false negatives, TSAB measurements have so far been repeated, using samples from a different time point, in 41 of the patients, 18 tested positive. 9 of the negative patients had either a strong family history or instances of repeated relapse, making them candidates for mutational analysis. This has been commenced in 3, with extraction of genomic DNA and amplification/ sequencing of exon 10. We have identified a D727E polymorphism in one case, a silent polymorphism at codon 459 in the second and no abnormality in exon 10

in the third. Sequencing of the remaining exons is in progress.

Preliminary results suggest that a proportion of patients diagnosed as GD may have activating TSHR mutations requiring genetic counselling and more aggressive treatment for their thyrotoxicosis.

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