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  • Author: Sarka Dvorakova x
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Barbora Pekova, Sarka Dvorakova, Vlasta Sykorova, Gabriela Vacinova, Eliska Vaclavikova, Jitka Moravcova, Rami Katra, Petr Vlcek, Pavla Sykorova, Daniela Kodetova, Josef Vcelak and Bela Bendlova

There is a rise in the incidence of thyroid nodules in pediatric patients. Most of them are benign tissues, but part of them can cause papillary thyroid cancer (PTC). The aim of this study was to detect the mutations in commonly investigated genes as well as in novel PTC-causing genes in thyroid nodules and to correlate the found mutations with clinical and pathological data. The cohort of 113 pediatric samples consisted of 30 benign lesions and 83 PTCs. DNA from samples was used for next-generation sequencing to identify mutations in the following genes: HRAS, KRAS, NRAS, BRAF, IDH1, CHEK2, PPM1D, EIF1AX, EZH1 and for capillary sequencing in case of the TERT promoter. RNA was used for real-time PCR to detect RET/PTC1 and RET/PTC3 rearrangements. Total detection rate of mutations was 5/30 in benign tissues and 35/83 in PTCs. Mutations in RAS genes (HRAS G13R, KRAS G12D, KRAS Q61R, NRAS Q61R) were detected in benign lesions and HRAS Q61R and NRAS Q61K mutations in PTCs. The RET/PTC rearrangement was identified in 18/83 of PTCs and was significantly associated with higher frequency of local and distant metastases. The BRAF V600E mutation was identified in 15/83 of PTCs and significantly correlated with higher age of patients and classical variant of PTC. Germline variants in the genes IDH1, CHEK2 and PPM1D were found. In conclusion, RET/PTC rearrangements and BRAF mutations were associated with different clinical and histopathological features of pediatric PTC. RAS mutations were detected with high frequency in patients with benign nodules; thus, our results suggest that these patients should be followed up intensively.

Open access

Louise Vølund Larsen, Delphine Mirebeau-Prunier, Tsuneo Imai, Cristina Alvarez-Escola, Kornelia Hasse-Lazar, Simona Censi, Luciana A Castroneves, Akihiro Sakurai, Minoru Kihara, Kiyomi Horiuchi, Véronique Dorine Barbu, Françoise Borson-Chazot, Anne-Paule Gimenez-Roqueplo, Pascal Pigny, Stephane Pinson, Nelson Wohllk, Charis Eng, Berna İmge Aydoğan, Dhananjaya Saranath, Sarka Dvorakova, Frederic Castinetti, Patocs Attila, Damijan Bergant, Thera P. Links, Mariola Peczkowska, Ana O Hoff, Caterina Mian, Trisha Dwight, Barbara Jarzab, Hartmut P H Neumann, Mercedes Robledo, Shinya Uchino, Anne Barlier, Christian Godballe and Jes Sloth Mathiesen

OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations, and have been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.

DESIGN AND METHODS: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centres all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017.

RESULTS: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis.

CONCLUSIONS: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation, have synchronous MTC, often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false negative rate, if no other MEN 2A component, specifically MTC, are found during work up or resection of PHPT.