ESPE Abstracts

Objective: Somatic mutations in the USP8 gene were discovered as the most common genetic defects in corticotropinomas with a frequency of 30 to 60% in adult patients. With regard to pediatric patients, establishing prevalence of USP8 mutations is still challenging due to the rarity of CD incidence in childhood.

Aim: To determine the frequency of somatic genetic drivers of CD in a cohort of pediatric patients.

Patients and Methods: We studied 14 pediatric patients with CD who underwent surgical treatment between 2016 and 2020 and whose formalin fixed paraffin embedded corticotroph tumors and blood samples for DNA extraction were available. Germline and tumor whole-exome sequencing was performed in all of them.

Results: We identified three different somatic USP8 mutations in 3 out of 14 patients, resulting in a frequency of 21%. One variant was previously described as pathogenic, the other two novel variants were found to be likely pathogenic. We did not identify any other significant somatic or germline defects. The median of age of diagnosis in patients with USP8 mutations was 15.2 years and 13.5 years in patients without mutations. No significant differences in basal plasma ACTH or serum cortisol levels between groups were found (P=0.6 and P=0.88 respectively). In the group of patients with USP8 mutations, one patient had a macroadenoma, tumor size of the second patient was 9 mm, of the third patient – 5 mm. In the group of patients without USP8 mutations, only one patient had tumor size more than 8 mm. Not a statistical difference but tendency was found (р=0.038, significant р=0.02 after the Bonferroni correction). All patients with USP8 mutations achieved remission after first transsphenoidal surgery (TSS). In the group of patients without USP8 mutations, remission after first TSS was reported in 6 patients out of 11. The other five patients who did not achieve remission underwent second TSS. Four of these patients entered biochemical remission. The last patient underwent radiation treatment after the second TSS, which led to biochemical remission in one year. Follow-up time after achieved remission was from 1 to 6 years, recurrence of CD was not detected.

Conclusions: We report an estimate of the contribution of somatic genetic defects underlying CD and its genotype-phenotype correlation in a single pediatric cohort. Further research is required to unveil molecular abnormalities in CD which can be useful in designing strategies for clinical screening, prognosis of post-treatment outcome and lead to novel therapeutic targets.