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M Tonacchera, F Cetani, J Parma, J Van Sande, G Vassart and J Dumont

Toxic thyroid adenomas are well-encapsulated homogeneous neoplasia secreting thyroid hormones in the absence of a TSH stimulus. As the secreted hormones inhibit the pituitary thyrotrophs, TSH plasma levels decrease and the normal tissue becomes quiescent. Thyroid adenomas are monoclonal, i.e. are constituted by the progeny of one mutated cell, and therefore result from a single initial biochemical lesion.

Our group has demonstrated the mitogenic role of the cyclic AMP cascade in the thyroid (1, 2). Permanent stimulation of this cascade by a constitutive adenosine receptor (A2a) or a mutated Gs protein, which are coupled positively to adenylate cyclase in transgenic mice, leads to the formation of an autonomous hyperfunctioning adenoma involving the whole thyroid (3, 4). Gain-of-function activating mutations of the TSH receptor (TSH-R) or of the G protein (Gs), which stimulate adenylate cyclase, have been demonstrated in human autonomous thyroid adenoma (5–9). Activating germline mutations of the TSH receptor

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V Vanvooren, A Allgeier, M Nguyen, C Massart, J Parma, JE Dumont and J Van Sande

OBJECTIVE: The cyclic AMP (cAMP) cascade is the main regulatory pathway in thyrocytes. Whilst activating mutations in the TSH receptor or in the Gs alpha-subunit, which increase cAMP levels, have been shown to be responsible for 80% of the autonomous adenomas, no such mutations have been observed in the other types of thyroid tumors, suggesting that other mechanisms exist. The discovery of Epac ('exchange nucleotide protein directly activated by cAMP'), a novel cAMP-binding protein, which is strongly expressed in the thyroid, raised the possibility of a role for this protein in the generation of the unexplained cold thyroid follicular adenomas. Thus, we investigated whether activating mutations in either Epac or Rap (the downstream target of Epac) could be responsible for the generation of these thyroid nodules. DESIGN: Epac and Rap1 (Rap1A and Rap1B) cDNAs were sequenced in 10 patients. The sequencing of the cDNAs was realized on both strands in the cold nodule and the juxtanodular tissue of each patient. RESULTS: No mutations in either Epac or Rap1 cDNAs were found. For five patients, a polymorphism in Epac at codon 332 (Gly--Ser) was observed. CONCLUSIONS: In this report, we show that the cAMP--Epac--Rap1 signaling pathway in the thyroid gland does not play a major role in the generation of cold thyroid follicular adenomas, since no mutations in either Epac or Rap1 could be observed in the 10 nodules studied.

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A Ciccarelli, H Valdes-Socin, J Parma, SK Khoo, J Schoumans, A Colao, E Hamoir and A Beckers

OBJECTIVE: Atypical forms of hyperthyroidism represent a diagnostic challenge for clinicians. Struma ovarii is an ovarian teratoma and constitutes a rare cause of ectopic thyroidal hormonal production. We describe a case of struma ovarii that combined two different sources of hyperthyroidism in the same patient and report genetic studies in order to contribute a better understanding of the autonomy and tumorigenesis of the struma ovarii. CASE REPORT: A 73-year-old nulliparous woman presented a thyroid toxic adenoma that was successfully treated with 10 mCi radioiodine. Unexpectedly, a new onset of hyperthyroidism prompted us to look for a second etiology. A whole-body scan with (123)I detected a pelvic hyperfixation suggesting struma ovarii, and a thyroid differentiated left ovarian teratoma 3 cm in size was surgically removed. We screened for mutations of thyroid-stimulating hormone receptor and Gs-alpha protein genes, as these mutations are common in thyroid adenomas. We did not identify any mutations. Androgen receptor study demonstrated a monoclonal status. Comparative genomic hybridization did not reveal any chromosomal abnormality. However, loss of heterozygosity analysis showed several structural abnormalities, compared with the majority of benign ovarian teratomas, which show a normal karyotype. CONCLUSIONS: This is the first well-documented report of thyrotoxic struma ovarii revealed after treatment of a single thyroid toxic adenoma. We have shown in this case that struma ovarii originates from a single germ cell, and, albeit benign, this tumor presents several chromosomal abnormalities. Struma ovarii-induced hyperthyroidism is likely to be mediated by mechanisms different from those of the classical thyroid toxic adenoma.

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V Vanvooren, S Uchino, L Duprez, MJ Costa, J Vandekerckhove, J Parma, G Vassart, JE Dumont, J Van Sande and S Noguchi

OBJECTIVE: Constitutively activating mutations of the thyrotropin receptor (TSHR) have been found in the majority of autonomously functioning thyroid nodules (AFTNs) in European patients. The reported frequency of these mutations varies among reports but amounts to 50-80%. To date, only one such mutation responsible for AFTNs has been identified in the Japanese population and the pathogenic role of such mutations in Japanese AFTNs has been questioned. In the present study, we evaluated the frequency of activating mutations in the TSHR and G(alpha)s in 10 Japanese AFTNs. DESIGN: Genomic DNA was extracted from fresh frozen tissue. The TSHR and the almost entire sequence of the gene coding for the alpha subunit of Gs have been amplified and sequenced. RESULTS: In sequence analysis, four mutations in the TSHR (T632A, I486M, M453T and L512R) were found. To complete our analysis, we searched mutations in the gene coding for the alpha subunit of Gs, in the samples negative for TSHR mutations. In one case a mutation (R201H) affecting GTPase activity was found. CONCLUSIONS: If we focus on the solitary nodules, we obtain the same mutation proportion as in European patients (70%). The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions.