We report a 9-month-old male who was diagnosed with an adrenocortical tumor and later found to harbor a novel TP53 c.559 G > C germline variant, resulting in p.Gly187Arg.
Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors.
An inherited germline mutation in the p53 gene (TP53R337H) is detected in virtually all children with ACT in this region and accounts for the excess cases observed.
Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.
The objective of the study was to analyze expression of IGF-II and its receptor (IGF-IR) in pediatric and adult adrenocortical tumors and the effects of a selective IGF-IR kinase inhibitor (NVP-AEW541) on adrenocortical tumor cells.
We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell line NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1 CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes.
In adrenocortical tumors, the malignant phenotype is associated with rearrangements (paternal isodisomy) at the 11p15 locus and IGF-II gene overexpression, strongly suggesting that the IGF system is a major determinant of adrenocortical tumor progression.
During investigation, an adrenocorticotropic hormone (ACTH) independent CS was identified and the possibility of an adrenocortical tumor was suggested.