PLCL2 Mutation Dysregulates GSK3β/β-Catenin Signaling in Extranodal Rosai–Dorfman Disease

Extranodal Rosai–Dorfman disease (RDD) is a rare histiocytic disorder that typically presents with histiocyte proliferation in tissues outside of the lymph nodes, such as the central nervous system (CNS), posing significant diagnostic challenges. The pathogenesis of extranodal RDD remains unclear, though it is believed that genetic and immune factors play a role. In this study, we collected clinical, imaging, and histopathological data from three cases of extranodal RDD and analyzed formalin-fixed, paraffin-embedded tissue samples by using whole exome sequencing (WES) to identify mutations. Imaging findings showed extranodal RDD involvement in the CNS, chest wall, and right cheek, with histopathology confirming classical features of the disease. WES identified the rs368284573 mutation in the Phospholipase C Like 2 (PLCL2) gene across all cases. Experimental analysis of this mutation revealed a reduction in p-GSK-3β levels, which in turn inhibited GSK3β activity, leading to increased β-catenin accumulation, a key factor promoting cell proliferation. Knocking down the mutant PLCL2 gene restored p-GSK-3β levels, reduced β-catenin expression, and inhibited cell proliferation. These findings suggest that the PLCL2 mutation contributes to dysregulation of GSK3β/β-catenin signaling in extranodal RDD, providing new insights into the pathogenesis and potential therapeutic targets for this rare disorder.