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The mechanism of adrenocortical tumors (ACT) in children is not known. Available evidence suggests that ACT originates from the fetal adrenal cells, which compose the largest portion of the adrenal cortex at birth. The genes H19, insulin-like growth factor II (IGF-II), and p57kip2 located on chromosome 11p are critical for fetal growth and development, and their expression is dysregulated in patients with ACT (Libe, Fratticci et al. 2007). Constitutional genetic factors are associated with pediatric ACT (Ribeiro, Pinto et al. 2010). Li and Fraumeni observed a high frequency of ACT (4 cases, or 10%) among 44 malignancies in children from families in which diverse cancers segregated in an autosomal-dominant pattern (Li and Fraumeni 1969). 

In 1990, researchers discovered that individuals with cancer from Li-Fraumeni families carried germline mutations in the TP53 gene (Malkin, Li et al. 1990). It is now well recognized that most of the constitutional genetic abnormalities in young children with ACT are mutations in TP53. These observations support the recommendation that children and adolescents with ACT should be screened for germline TP53 mutations. Other constitutional disorders that have been associated with an increase in pediatric ACT occurrence include Beckwith-Wiedemann syndrome (BWS), Cushing syndrome, familial adenomatous polyposis, multiple endocrine neoplasia (MEN1), and hemihypertrophy, but they contribute to less than 5% of all cases (Ribeiro, Pinto et al. 2010).