Epithelioid rhabdomyosarcoma is a rare rhabdomyosarcoma variant for which no diagnostic recurrent driver genetic events have been identified. Here we report a rapidly progressive and widely metastatic rhabdomyosarcoma with epithelioid features that arose in the thigh of a male infant. Conventional cytogenetics revealed a t(8;13)(p11.2;q14) translocation. Fluorescence in situ hybridization studies showed rearrangement of FOXO1 and amplification of its 3” end, and rearrangement of NSD3 and amplification of its 5` end. Next generation sequencing identified a NSD3::FOXO1 fusion, which is a previously unreported gene fusion. We also review the historic report of a FOXO1::FGFR1 fusion in a solid variant of alveolar rhabdomyosarcoma and propose that NSD3::FOXO1 fusion may have been the more appropriate interpretation of the data presented in that report.
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