ESPE Abstracts

Background: Familial PTC manifesting in childhood has been described only in single cases, mainly in the context of rare syndromes (APC-associated-syndrome, PTEN-hamartoma syndromes etc). PTC in Grave’s disease (GD) has been described in adults, but not in familial cases including young children.

Objective and hypotheses: We investigated the association of large metastatic papillary carcinoma (PTC) in a 10 years old female and her mother evolving rapidly in both after the manifestation of Grave’s disease (GD). Our aim was to investigate the genetic basis for the occurrence of non-syndromic familial GD and PTC in an ethnic background with a reported high prevalence of thyroid carcinoma in adults Grave’s disease.

Methods: Genetic analysis of the tumor was performed by targeted array analysis to investigate known mutations to be involved in familial and syndromic PTC. Sequencing of the TSH-receptor gene was performed in DNA obtained from PBC of all living family members (index case, mother, four older siblings without thyroid disorders).

Results: GD was confirmed biochemically in the clinically symptomatic patient. TSH-R Ab were elevated. A 2.1 x 1.3 cm nodule in the right lobe developed 3 months after manifestation of GD and turned out to be a PTC (FNAB and ablative thyroidectomy). GD and subsequent development of a metastatic PTC had been diagnosed in the mother a year preceding the diagnosis in her daughter. Panel sequencing of tumour tissue excluded somatic variants for RAF/11, DDR2 15-18, EGFR 18-21, ERBB2 5,6,15,20,23,29, FGFR1 3,7,13,17,FGFR3, HRAS 2-4,KIT 9-11,13,17,18, KRAS 2-4, MET 3,8,11,14,19, NRAS 2-, PDGFR 12,14,18, PIK3CA 3,5,10,16,21, RET 10,11,13-16, TP53 4-9, APC 1-16, DICER1 1-28, PRKARIA 1-11 and PTEN 1-9 and revealed the PTC-typical BRAF-Mutation (V600E) and 2 described TSH-R variants (c.154C>A?p.Pro52Thr and c.170+63G>C). Segregation of the phenotype with the TSH-R variants in the family could not be demonstrated by Sanger sequencing.

Conclusion: A far undescribed association of familial GD and PTC was not associated with germline variants in the TSH-R gene. NGS (whole exome sequencing of the tumor and PBC derived DNA) will be used to detect the underlying genetic mechanism.