Endocrine features and hormone-related pathways in Wilms' tumor: From developmental biology to clinical implications

Wilms' tumor (WT) is the most common primary renal malignancy in children and it is a paradigmatic developmental kidney tumor arising from disrupted nephrogenesis. Classically framed as a developmental disorder of the nephron progenitor compartment, WT also exhibits clinically relevant endocrine features, most notably renin-mediated hypertension and, less commonly, selected paraneoplastic syndromes including Cushing syndrome, erythrocytosis, hypercalcemia, and acquired von Willebrand disease. Biochemically, atypical elevations of α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-HCG) may complicate the differential diagnosis of pediatric renal and retroperitoneal masses. At the molecular level, hormone-linked pathways-including the insulin-like growth factor (IGF) axis, vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β)/Smad signaling, the renin-angiotensin system (RAS) and the WT1-centered gonadal-adrenal axis-converge on core processes that drive WT growth, angiogenesis, epithelial-mesenchymal transition (EMT) and microenvironmental remodeling. These pathways intersect with a heterogeneous genetic and epigenetic landscape dominated by alterations in WT1, 11p15/WT2, SIX1/2, WDR4 and dysregulated non-coding RNAs. In this narrative review, we first outline the clinical and diagnostic landscape of WT, and then summarize endocrine and paraneoplastic manifestations. We next dissect the main hormone-related signaling pathways and their genetic underpinnings, and discuss how these insights may inform risk stratification, supportive management, and future therapy, ranging from blood pressure control with RAS blockade to limited anti-VEGF exploration and more speculative IGF-axis and TGF-β-targeted interventions. Clinically, the endocrine interface of WT is narrow but important: renin-mediated hypertension and selected diagnostic dilemmas are directly actionable, whereas rare paraneoplastic syndromes are mainly case-based observations and most endocrine-related therapeutic pathways remain investigational. This evidence-stratified perspective may help align developmental biology with practical clinical decision-making.