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Identification of Constitutively Activating Somatic Thyrotropin Receptor Mutations in a Subset of Toxic Multinodular Goiters¹

Department of Internal Medicine III, University of Leipzig (H.-P.H., D.F., P.W., W.A.S., R.P.), D-04103 Leipzig; and the Department of Surgery, Israelitisches Krankenhaus Hamburg (G.W.), Hamburg, Germany

Address all correspondence and requests for reprints to: Prof. Dr. R. Paschke, Department of Internal Medicine III, University of Leipzig, Ph.-Rosenthal-Strasse 27, D-04103 Leipzig, Germany.

Constitutively activating mutations in the TSH receptor (TSHR) gene and in the G_s gene are frequent molecular causes for solitary toxic nodules of the thyroid. However, the etiology of toxic multinodular goiter is still largely unknown. Therefore, DNA from nodular and quiescent surrounding tissue of six patients with toxic multinodular goiters was screened for mutations in exons 9 and 10 of the TSHR gene and exons 7–10 of the G_s gene by direct automated sequencing.

In one patient, two different somatic TSHR mutations were identified in two different toxic nodules (L632I and F631L). In another patient, two different toxic nodules harbored the same TSHR mutation (I630L), whereas only one TSHR mutation (F631L) was identified in one of the two toxic nodules of an additional patient. In the other three patients, no mutations could be found in exons 9 and 10 of the TSHR gene or in exons 7–10 of the G_s gene.

Our results demonstrate that not only solitary toxic adenomas but also toxic multinodular goiters can be caused by constitutively activating mutations of the TSHR. In addition to mutations in the TSHR and possibly in G_s, there are probably other still unknown mechanisms that cause hot nodules in toxic multinodular goiters.

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