In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

A 50-yr-old woman with Addison's disease from the age of 14 yr was diagnosed as empty sella turcica in 1974 (Rev Clin Esp 139: 183, 1975). She subsequently continued with hyperpigmentation in spite of adequate hormone substitution therapy which permitted her to lead a normal life. When studied she showed an extreme elevation of plasma ACTH (1500--2000 pg/ml), and with dexamethasone (2 and 8 mg/day) continued to have levels of 900 pg/ml. With 60 mg hydrocortisone daily, effects of overdosage were observed (swelling and Cushingoid facies) associated with depigmentation. However, she continued to manifest levels of plasma ACTH of 700 pg/ml and an absence of circadian rhythm. It seems likely that this patient represents a case of pituitary ACTH secretory adenoma (corticotropinoma) secondary to the preexisting Addison's disease. The circulating levels of other pituitary hormones were normal.

A technique is described for stem cell autotransplantation in rats. First we obtain autologous bone marrow-derived stem cells. Second, we inject the cells in the pancreas of the donor rat. This approach can be applied to experimental diabetes and other pancreatic processes.

In order to assess the association between empty sella (ES) and primary autoimmune hypothyroidism, and the possibility of a common pathogenesis. We retrospectively studied all patients with presumed ES diagnosed in the last 20 years, most of whom were treated by our Endocrinology Department. Subjects with a known etiology were excluded. Incomplete records or those with a doubtful diagnosis were also excluded. A total of 56 subjects were included in the study. ES was diagnosed by pituitary MRI. The measurement of free T4, TSH, and antithyroid antibodies (TPOAb and TgAb) was assayed using commercial kits. The cases of hypothyroidism obtained were compared with those in another group of similar patients, diagnosed with diabetes mellitus type 2, through chi2 test. A total of 15 (26.78%) patients of 56 with ES had autoimmune thyroid disease (subclinical or clinical hypothyroidism). Primary hypothyroidism with negative antithyroid autoantibodies was found in a further 13 patients (23.21%). The 46.42% of ES had primary hypothyroidism; this result had obtained a statistically significant difference when compared to the ratio obtained in the group of diabetes mellitus type 2 (P < 0.0029). There is an important association between ES and autoimmune thyroid disease, which reached 26.78% in our series. We suggest the possibility of a common pathogenesis for certain cases of ES and autoimmune thyroid disease, with the end point of ES in the pituitary, and atrophy in the thyroid gland.

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