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S Miedlich, K Krohn, P Lamesch, A Muller and R Paschke

OBJECTIVES: Investigation of small numbers of parathyroid tumours by X-chromosome inactivation analysis suggests that the majority of them are monoclonal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identified in 12-17% of solitary parathyroid tumours in patients with sporadic primary hyperparathyroidism, and they may be the precipitating genetic defect leading to monoclonal cell proliferation in these tumours. DESIGN: To determine the prevalence of MEN1 gene mutations in monoclonal parathyroid neoplasias we investigated 33 parathyroid tumours of patients with primary hyperparathyroidism for clonality and mutations in the MEN1 gene. METHODS: X-chromosome inactivation analysis was used to assess the clonal status of the tumours, direct sequencing of the complete coding region was applied to identify mutations in the MEN1 gene. RESULTS: Twenty-eight female patients (26 patients with solitary adenoma, 2 patients with hyperplasia) were informative for the polymorphism of the androgen receptor on the X-chromosome and could be tested for inactivation pattern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Somatic mutations in the MEN1 gene were identified in nine cases. Six of them were found in the relatively large second exon of the MEN1 gene (A49D, 193del36, 402delC, 482del22, 547delT, W126X). One was found in exon 5 (904del9), one in exon 7 (Y327X) and one in exon 9 (R415X). Of the monoclonal tumours, 5 out of 19 (26%) harboured a somatic MEN1 gene mutation. CONCLUSIONS: In summary, 73% of the solitary parathyroid adenomas were monoclonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has been identified. However, for 74% of monoclonal tumours of the parathyroids the underlying genetic defects are still not known.

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M Bluher, K Krohn, H Wallaschofski, LE Braverman and R Paschke

OBJECTIVE: Apoptosis via the Fas pathway is a potential mechanism for thyroid tissue destruction leading to clinical hypothyroidism in Hashimoto's thyroiditis (HT). Recent studies reported contradictory results regarding the regulation of Fas/Fas ligand (FasL) expression by cytokines in vitro. We therefore determined the Fas and FasL gene expression in the BioBreeding/Worcester (BB/W) rat thyroiditis model, which can be regarded as a model for HT. METHODS: In order to obtain BB/W rats with spontaneous, iodine-induced or without lymphocytic thyroiditis (LT), rats were divided into 3 groups: 55-day-old rats after 24 days of iodine administration, 75-day-old rats after 45 days of iodine administration, and 101-day-old rats respectively. The gene expression of Fas, FasL, and interleukin (IL)-1beta was determined by Genescan fragment analysis using reverse polymerase chain reaction. Serum thyroglobulin (TG) antibody concentrations were measured and the extent of lymphocytic infiltration of one thyroid lobe was histologically graded. RESULTS: Fas and FasL gene expression was significantly higher in rats with LT and correlated with the extent of lymphocytic infiltration and the TG antibody level. There was no evidence that the expression of IL-1beta or other cytokines is related to the expression of Fas or its ligand. CONCLUSIONS: The increased expression of Fas and FasL in LT of BB/W rats suggests the involvement of the Fas pathway in the pathogenesis of LT in BB/W rats. However, in contrast to results of recent in vitro studies, in the BB/W rat Fas/FasL expression is not regulated by IL-2, -4, -6, -10, -12, interferon gamma, and tumor necrosis factor alpha.

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G Aust, K Krohn, N G Morgenthaler, S Schröder, A Schütz, J Edelmann and E Brylla

Objective: To report on the rare simultaneous occurrence of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) in monozygotic twins.

Design: We compared the pattern of thyroid tissue-derived cDNAs to gain insight into previous and ongoing immune destruction and reconstruction processes using microarrays. The results were confirmed by immunohistology and real-time PCR.

Results: Destruction of thyroid tissue in HT reduced levels of thyrocyte-related cDNAs and cDNAs encoding extracellular matrix components, but increased levels of proteases involved in extracellular matrix degradation compared with GD. Lymphocytic infiltrates forming ectopic follicles replaced the thyroid tissue almost completely in HT. Thus, lymphocyte-related cDNA levels were higher in HT than in GD. The same was true for many chemokines and their receptors, which not only enable migration towards the thyroid but also maintain the lymphocytic infiltrate. HT also showed increased levels of cDNAs encoding molecules related to apoptosis than did GD. Surprisingly, the Th1- and Th2-specific cytokine profiles suggested for HT and GD respectively could not be confirmed. cDNAs encoding factors and receptors involved in angiogenesis were increased in GD compared with HT.

Conclusions: Comparison of gene expression reflects the cellular differences between the two types of autoimmune thyroid disease in twins with identical genetic and similar environmental background.