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Whether hyperthyroidism influences the birth characteristics of children born several years after treatment is unknown.The objective of the study was to compare birth characteristics in singleton newborns delivered by women previously treated for Graves' disease (GD), toxic nodular goiter (TNG), or nontoxic goiter (NTG).This was a nested case-control design within a national cohort registry study from 1950 through 2006.The study was conducted at a university and a hospital center in collaboration.The birth characteristics of newborns (n = 3421) delivered in a cohort of 43 633 women treated for GD or toxic nodular goiter by radioiodine or surgery (exposed group) at least 1 year prior to pregnancy were compared with newborns (n = 2914) of 45 655 mothers, previously operated for NTG (unexposed group).The primary outcome was birth weight, length, and head circumference. The secondary outcome was malformations, gestational age, and type of hyperthyroidism.The birth weight of exposed children was 3431 ± 607 g (mean ± SD) compared with the unexposed, 3520 ± 641 g (P.001). The cumulative odds ratio (OR) for lower birth weight was 1.29 [95% confidence interval (CI) 1.16-1.43]. The average birth length for the exposed children was 50.0 ± 2.7 cm compared with the unexposed of 50.4 cm ± 2.6 cm (P.01) [cumulative OR 1.25 (95% CI 1.13-1.37)]. The head circumference was 34.5 ± 1.9 cm among exposed and 34.7 ± 1.8 cm, respectively (P.001), with an OR of 1.24 (95% CI 1.13-1.35). No differences in birth characteristics were observed between children born after maternal GD or toxic nodular goiter.Previous GD or TNG may influence the birth characteristics several years after radioiodine or surgical treatment.

Previous randomized trials have suggested an association between radioiodine treatment for Graves' hyperthyroidism and thyroid-associated ophthalmopathy (TAO).The aim of the study was to compare the occurrence of worsening or development of TAO in patients who were treated with radioiodine or antithyroid drugs.We conducted a randomized trial (TT 96) with a follow-up of 4 yr. PATIENTS, SETTING, AND INTERVENTION: Patients with a recent diagnosis of Graves' hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with T(4) was given in both groups.Worsening or development of TAO was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P0.001).The risk for de novo development of TAO was greater in patients treated with iodine-131 (53 patients) than with medical treatment (23 patients). However, worsening of TAO in the 41 patients who had ophthalmopathy already before the start of treatment was not more common in the radioiodine group (10 patients) than in the medical group (nine patients). Smoking was shown to influence the risk of worsening or development of TAO, and smokers treated with radioiodine had the overall highest risk for TAO. However, in the group of smokers, worsening or development of TAO was not significantly associated with the choice of treatment for hyperthyroidism.Radioiodine treatment is a significant risk factor for development of TAO in Graves' hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective of treatment modality.

The Ras effector NORE1A (RASSF5A) is a putative tumor suppressor and is inactivated in several human cancers. NORE1A has not been studied in thyroid cancer.The objective of this study was to investigate whether NORE1A is involved in follicular thyroid cancer (FTC) development.We analyzed NORE1A expression in 25 FTCs, eight follicular thyroid adenomas, and seven normal thyroid tissues by TaqMan quantitative RT-PCR. The results were evaluated in relation to RASSF1A expression, RAS mutations, and PAX8-PPARgamma fusions assessed in the same material. NORE1A promoter methylation was assessed by the combined bisulfite restriction endonuclease assay.Although the NORE1A mRNA levels of the majority of the tumors were similar to those in the normal controls, the cases harboring a PAX8-PPARgamma translocation (n = 6) exhibited dramatically reduced NORE1A expression (P0.001). In contrast, RAS mutations (n = 5) and NORE1A down-regulation were mutually exclusive. A significant reduction in the expression of the NORE1A homolog and the bona fide tumor suppressor gene RASSF1A was observed, but with weak correlation to the respective NORE1A values. No NORE1A promoter methylation was detected in the 32 thyroid tumors analyzed.Our experiments demonstrate the suppression of NORE1A, a known Ras effector, in PAX8-PPARgamma carrying FTCs.

Recently, a translocation t(2; 3)(q13;p25), involving the fusion of PAX8 and peroxisome proliferator-activated receptor gamma (PPAR gamma) was suggested to arise only in follicular thyroid carcinomas. In this study, a group of 87 thyroid tumors were analyzed to determine the involvement of the PAX8/PPAR gamma fusion gene in these tumors, and also to determine whether this rearrangement can be used as a diagnostic marker for the differentiation between follicular thyroid carcinoma and adenoma. The PAX8/PPAR gamma rearrangement was detected by RT-PCR, fluorescence in situ hybridization, and/or Western analysis in 10 of 34 (29%) follicular thyroid carcinomas and in one of 20 (5%) atypical follicular thyroid adenomas, but not in any of the 20 follicular thyroid adenomas or 13 anaplastic thyroid carcinomas studied. In addition, seven of the 87 thyroid tumors exhibited involvement of PPAR gamma alone. Our findings suggest that PAX8/PPAR gamma occurs frequently in follicular thyroid carcinomas, and the presence of this rearrangement is likely to prove highly suggestive of a malignant tumor. Lack of the PAX8/PPAR gamma rearrangement in the anaplastic thyroid carcinoma group suggests that the tumorigenic pathway in these tumors is likely to be independent of this fusion. Furthermore, the results suggest that other rearrangements, involving PPAR gamma and other unidentified genes, may be involved in follicular thyroid tumorigenesis.

To analyze the benefits and risks of three common treatments, we randomly assigned 179 patients with Graves' hyperthyroidism as follows: 60 patients, 20-34 yr of age (young adults), received antithyroid drugs for 18 months (medical) or subtotal thyroidectomy (surgical), and 119 patients, 35-55 yr of age (old adults), received medical, surgical, or radioiodine (iodine-131) treatment. The follow-up time was at least 48 months. Antithyroid drugs, surgery, or iodine-131 treatment normalized the mean serum hormone levels within 6 weeks. The risk of relapse was highest in the medically treated young and old adults (42% vs. 34%), followed by that in those treated with iodine-131 (21%) and that in the surgically treated young and old adults (3% vs 8%), respectively. Elevated TSH receptor antibodies at the end of medical therapy or increasing TSH receptor antibodies values after medical or surgical treatment increased the probability of relapse. Development or worsening of ophthalmopathy was not associated with relapse per se. Ninety percent of the subjects in all groups were satisfied with the treatment they received. No significant difference in sick-leave due to Graves' or other diseases was seen during the first 2 yr after initiation of therapy. The increased risk of ophthalmopathy in patients with high serum T3 levels, especially when treated with iodine-131, and the relatively high frequency of relapse after treatment with antithyroid drugs are important factors to consider when selecting therapy for Graves' disease.

The hereditary multiple endocrine neoplasia syndromes types 2A and B (MEN 2A and B) were recently linked to germline mutations in the RET proto-oncogene, altering one of five cysteine residues in exon 10 or 11 (MEN 2A), or substituting a methionine for a threonine at codon 918 in exon 16 (MEN 2B). The latter mutation also occurs somatically in some sporadic medullary thyroid carcinomas (MTC), and has in a previous study been correlated with a less favorable clinical outcome. In the present study, 46 MTCs were selected for investigation of the codon 918 mutation. The mutation was found in 29 tumors (63%), and was significantly correlated with a poor outcome, with regard to distant metastasis or tumor recurrence (p < 10(-4)). Two tumors showed multifocal growth and C-cell hyperplasia, and these patients were therefore also investigated for germline mutations in exons 10, 11 and 16. The codon 918 mutation was found only in the tumors, thus of somatic origin. The RET codon 918 mutation may have prognostic impact, and therefore preoperative assessment may influence decision-making in the treatment of patients suffering from MTC.