Somatic mutations in 29 hot nodules in children

Hot nodules in children are rare. Most have been reported in case reports and the maximum number described thus far in one report was 4. We present clinical and molecular data for 29 benign hot thyroid nodules detected in Poznan, Poland, between 1996 and 2008. The age of manifestation/diagnosis of thyroid nodule/s with or without hyperthyroidism was 15.2 years (range 11 – 18 years).

Methods: DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue. Real-time quantitative PCR (RT-qPCR) and pyrosequencing were employed to detect TSHR RAS, and BRAF mutations, as well as PAX8/PPARG and RET/PTC 1 and 3 rearrangements.

Results: 17 of the 29 hot nodules (59%) harboured somatic TSHR mutations with 8 different amino acid changes. Two additional base exchanges did not lead to amino acid changes in the TSHR gene. The most commonly observed mutation in these samples was the M453T mutation (in 8 of the 29 samples; 28%). The T632I and the D633Y mutation were each detected twice. All other TSHR mutations were each only found in one sample. The D727E polymorphism was detected in 9 samples: 2 homozygous and 7 heterozygous, 5 without a concomitant constitutive TSHR mutation and 4 (2 homozygous) with a concomitant TSHR mutation. A single NRAS mutation was detected in a hot nodule with a M453T mutation. In the remaining 12 nodules (41%) no TSHR, RAS and BRAF mutation, PAX8/PPARG and RET/PTC 1 and 3 rearrangements were detected.

Conclusion: In contrast to previous studies in adults where the M453T mutation in the TSHR of hot nodules was only reported in 10% of the cases, this mutation is significantly more (p = 0.0004) prevalent (28% of all cases; 47% of cases with detected TSHR mutations) in children. The percentage of TSHR mutation positive hot nodules in children is within the range observed in adults. As in adults there is still a number of hot nodules in children with unknown molecular etiology.