Abstract
Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal.
Highlights
DYNAMICS OF HUMAN ADRENOCORTICAL MORPHOLOGY AND HORMONE SECRETION DURING DEVELOPMENT AND POSTNATAL LIFE The adrenal gland is a continuously evolving endocrine organ from the developmental to the elder age
Adrenal gland development begins at 3–4 weeks of gestation by a condensation of the coelomic epithelium lining the abdominal cavity, followed at 4–6 weeks of gestation by proliferation and migration of coelomic epithelial cells, and subsequent differentiation of fetal adrenal cortical cells into two distinct zones at 8–10 weeks of gestation, while neural crestderived cells start to infiltrate the gland at 7–8 weeks of gestation to give origin to adrenomedullary cells [1]
Fetal adrenal cells, which are large and rich in lipids, express the steroidogenic enzyme CYP17, which enables them to produce high levels of DHEA and its sulfoconjugate DHEAS, which play a key role for the maintenance of pregnancy, being metabolized into estrogens by the placenta [1, 2]
Summary
Molecular pathogenesis of pediatric adrenocortical tumors increase again by around 8 years of age. In the absence of p53, genetic alterations may accumulate in the adrenal driving proliferation [such as NR5A1 overexpression, [31, 32]; see below section on Whole Genome Studies in Children and Adult ACT Reveal Important Drivers for Tumorigenesis and LOH of 11p15 leading to IGF2 overexpression [18,19,20]] of specific cellular clones. This increased proliferative capacity may favor the emergence of further genetic alterations leading to clonal expansion and tumorigenesis [reviewed in Ref. An about 0.5 Mb identical by descent haplotype in 17p13 encompassing the TP53 gene carrying the R337H mutation is Frontiers in Endocrinology | Cellular Endocrinology
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