Familial MTC with RET exon 8 Gly533Cys mutation: origin and prevalence of second malignancy.

INTRODUCTION: High prevalence of RET p.Gly533Cys (c.1597G > T) has been found in familial MTC in Greece (exon 8 fMTC). We studied their origin and compared clinical characteristics with non-exon 8 fMTC. METHODS: 102 fMTC (FMTC and MEN2A) patients (31.4% males) were followed for 2.9-37 years (median 6 years). Fifty-one carried the RET exon 8 mutation; the remaining were non-exon 8 fMTC (exons 10, 11, 13, 14). Pre-, post-operative calcitonin, disease extent at diagnosis and follow-up and families' place of origin were recorded. RESULTS: Exon 8 fMTC were older (42.3 ± 13.3 vs 30.8 ± 17.8 years, P < 0.001), including index cases (P = 0.016). In index cases, the stage at diagnosis was more favorable in exon 8 fMTC compared to non-exon 8 fMTC (stage I and II: 65% vs 23.8%, stage III: 25% vs 57.1%, stage IV: 10% vs 19%, P = 0.025). More favorable outcome was noted in exon 8 fMTCs (remission: 72.5% vs 45.8%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 12.5%, P = 0.001). Exon 8 fMTC patients carried more frequently a second malignancy (25.5% vs 6.3%, P = 0.009); 69% of these were PTCs. Exon 8 fMTC patients were significantly older at diagnosis compared to non-exon 8 moderate-risk RET carriers and presented more favorable clinical outcome (remission: 72.5% vs 50%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 8.3%, P = 0.021). This difference remained when only index cases were analyzed. 'Hot spots' in the origin of exon 8 fMTCs families were recognized. No phenotype or outcome differences were found between the exon 8 families from the various regions. CONCLUSIONS: In exon 8 fMTCs' older age, favorable disease stage at diagnosis and favorable outcome suggest slow disease progression compared to non-exon 8 fMTC. Compared with moderate-risk RET mutation carriers, exon 8 fMTC patients have a more favorable clinical outcome. The higher prevalence of second malignancies, especially PTC, not previously reported, merits further investigation. Increased awareness for inherited disease is required for patients with apparently sporadic MTC originating from recognized 'hot spots', as the age at presentation is usually delayed.

Evidence for the founder effect of RET533 as the common Greek and Brazilian ancestor spreading multiple endocrine neoplasia 2A.

OBJECTIVES: About one-quarter of patients with medullary thyroid cancer (MTC) have inherited disease due to mutations in the RET gene. A rare mutation in exon 8 (G533C) of RET, previously described in a large Brazilian family with MEN2A, also appeared to be clustering in Greece, whereas it was rarely reported in other ethnic groups. The aim of this study was to identify a possible common ancestry between these carriers. PATIENTS AND METHODS: Twelve RET G533C mutation carriers, four randomly selected from the Brazilian cohort and eight from apparently unrelated Greek families, were studied for a possible common ancestral origin. RET flanking microsatellite markers at chromosome 10q (D10S197, D10S196, D10S1652 and D10S537) were used. RESULTS: Genomic DNA analysis using these markers showed that many of these apparently unrelated individuals shared a common haplotype indicating a common ancestral origin. CONCLUSION: Our data suggest that Brazilian and Greek patients with MTC carrying the G533C mutation in exon 8 of RET gene originate from a common ancestor. Due to historical reasons, we speculate that the more plausible explanation for the origin of this mutation is in Greece.

Hemodynamic markers and subclinical atherosclerosis in postmenopausal women with primary hyperparathyroidism.

CONTEXT: Recent evidence suggests that primary hyperparathyroidism (pHPT) is linked with hypertension and subclinical atherosclerosis. These associations have not been examined in postmenopausal women, in whom cardiovascular risk steeply rises after menopausal transition. OBJECTIVE: The objective of the study was to assess whether pHPT is associated with hemodynamic markers and subclinical atherosclerosis in postmenopausal women under a cross-sectional case-control design. METHODS: One hundred two postmenopausal women with pHPT and 102 women matched 1:1 for age and menopausal status were consecutively recruited. In all patients, flow-mediated dilatation, carotid-femoral pulse wave velocity, reflected waves, aortic blood pressures (BP), intima-media thickness, and the presence of plaques in the carotid and common femoral arteries were measured. RESULTS: Women with pHPT had higher aortic and peripheral BP (P < .05 for all), but no correlation was observed with subclinical atherosclerosis. After adjusting for possible confounders, pHPT was an independent determinant of peripheral and aortic diastolic BP (P < .05 for all). The association with systolic BP was lost after adjusting for C-reactive protein. Further adjustment for PTH and 25-hydroxyvitamin D levels revealed that PTH but not 25-hydroxyvitamin D was an independent determinant of all BP parameters. Both peripheral and aortic BP increased across PTH tertiles as compared with the control group, but this association lost significance after adjustment for C-reactive protein. CONCLUSIONS: These results suggest that pHPT may increase peripheral and aortic BP through PTH and inflammatory-mediated mechanisms. A direct impact of the disease on the arterial wall cannot be implicated despite the large number of markers of subclinical atherosclerosis measured in this study.

Does the presence of thyroid antibodies affect the course and outcome of pregnancy in type 1 diabetic women?

OBJECTIVE: The aim of the study was to evaluate the significance of the presence of thyroid peroxidase autoantibodies (anti-TPO Abs) in type 1 diabetes mellitus (DM1) pregnant women relative to the course of pregnancy and, especially, with regard to metabolic control, thyroid function, maternal complications and neonatal outcome. METHODS: In a prospective observational study of 91 DM1 women with singleton pregnancies, anti-TPO, anti-thyroglobulin, thyroid-stimulating hormone (TSH), and free thyroxine index (T4/thyroid binding capacity) were measured in each trimester. At each visit, HbA1c, body mass index, and units of insulin per kilogram were recorded, as were complications and pregnancy outcome. RESULTS: Twenty-one (27%) of the 78 women who met the inclusion criteria presented with positive anti-TPO Abs. There were no differences regarding glycemic control (HbA1c) or insulin dose. First-trimester TSH levels were significantly higher in the anti-TPO-positive group than in the anti-TPO-negative group. Finally, no differences were observed regarding diabetic or obstetric complications and neonatal outcome. CONCLUSION: One fourth of DM1 pregnant women presented with positive anti-TPO Abs. However, the presence of anti-TPO Abs does not seem to be related with worse metabolic control or adverse pregnancy outcome. Further investigation is needed; meanwhile, the effort for early treatment of thyroid dysfunction and strict metabolic control in all DM1 women should be continued.

Medullary thyroid carcinoma: the influence of policy changing in clinical characteristics and disease progression.

OBJECTIVE: Medullary thyroid carcinoma (MTC) has varying clinical course. We assessed trends in MTC presentation during the last 34 years. DESIGN: Retrospective study. METHODS: One hundred and fifty one patients (44.4% males) were followed for 0.934 years. Patients were classified according to year of diagnosis: group 1, 1977-2000 (n=53) and group 2, 2001-2011 (n=98). Extent of disease at diagnosis, during follow-up, number of surgeries, and pre- and postoperative calcitonin levels were recorded. RESULTS: In total, 48.34% reported family history of MTC. Group 1 had larger tumors (median 1.70 (intraquartile range (IQR) 1.7) vs 1.1 (1.2) cm, P=0.045, Mann-Whitney), they presented less frequently micro-MTCs (27.8 vs 46.1%, P=0.045), and underwent more multiple surgeries (63.3 vs 20.0%, P<0.001). Group 1 had more frequently progressive disease (35.8 vs 12.2%, P=0.003) and distant metastasis at follow-up (39.7 vs 17.4%, P=0.017). Chronological group (HR 0.15, 95% CI 0.03-0.68, P=0.015) and distant metastases at follow-up (HR 0.07, 95% CI 0.015-0.30, P=0.001) were independently associated with 10-year disease progression (P<0.001). In sporadic cases, cervical lymph node invasion and distant metastases at diagnosis were more frequent in group 1 (72.7 vs 45.5%, P=0.032 and 27.3 vs 5%, P=0.019 respectively); disease stage at diagnosis was more advanced (P=0.004). They underwent more multiple surgeries (P<0.001), presented more frequently distant metastasis at follow-up (67.7 vs 20.0%, P=0.002), had less frequently remission, and more frequently progressive disease (21.4 vs 58.0% and 64.3 vs 14.0% respectively, P<0.001). Postoperative calcitonin levels were higher (P=0.024). CONCLUSIONS: Recently, an increase in micro-MTCs is observed, while indices of invasiveness and persistence of disease are better. Increased awareness in familial cases, routine calcitonin measurements, and improved surgical procedures could be responsible.

Efficient testing of the RET gene by DHPLC analysis for MEN 2 syndrome in a cohort of patients.

BACKGROUND: Multiple Endocrine Neoplasia type 2 (MEN 2) is an autosomal dominant inherited syndrome characterized by a strong predisposition for developing endocrine tumors. MEN 2 is caused by germline mutations in the ret proto-oncogene. We investigated the feasibility of using the DHPLC technique in mutation detection of the ret gene in members of MTC families. We compared DHPLC analysis with direct sequencing with regard to sensitivity, reliability, cost and time. MATERIALS AND METHODS: Exons 10 and 11 were amplified with PCR from forty-three samples in seventeen unrelated Greek families and were analyzed for mutations by DHPLC and DNA sequencing. RESULTS: Eight PCR amplicons showed a distinct non-wild-type DHPLC profile. Sequence analysis confirmed different nucleotide variations: six of them were localized in exon 10 and two in exon 11. Mutations were detected in five out of seventeen families tested (29%). CONCLUSION: None of the alterations detected by direct sequencing was missed by DHPLC. We conclude that DHPLC is a fast, sensitive, cost-efficient and reliable method for the scanning of ret germline mutations.