Somatic KRASG12V-Variant as a Driver for Localized Hypertrophic Neuropathy Mimicking Plexiform Neurofibroma

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Background/Purpose: Localized hypertrophic neuropathy (LHN) is a neoplastic disease characterized by hypertrophy of single peripheral nerves. Affecting spinal nerve roots, it can mimic plexiform neurofibroma (PN) growth. Since pathogenic somatic KRAS variants have been identified in biopsies from LHN patients, it is supposed that LHN is caused by dysregulation of the RAS-MAPK-signaling pathway and subsequent hyperproliferation of neural cells. Therefore, RAS-induced LHN might be a novel therapeutic target for the MEK inhibitor selumetinib in addition to the approved use for NF1-associated PN. Methods: A 15-year-old boy presented with a deep ulcer under the right foot due to persistent numbness for over 1 year. Clinical examination revealed gait disturbance and hypesthesia of both legs, but was not suggestive of a neurocutaneous disease. MRI showed massive localized tumor formation of the lumbar spinal roots reminiscent of PN growth in neurofibromatosis type 1 (NF1). Sequence analysis was unable to uncover a pathogenic NF1 variant in the germline DNA of the patient. Biopsy excluded a PN and demonstrated normal neural tissue dominated by mature ganglion cells. Furthermore, sequencing and SNP array of this nerve biopsy revealed no indication for NF1 inactivation. However, it revealed the somatic KRAS G12V variant. Results: This KRAS G12 V-variant, likely being the somatic driver of nerve hypertrophy, opened a new opportunity for a targeted therapy. However, specific KRAS inhibitors are only available for KRAS G12 C variants. We decided to use the MEK inhibitor selumetinib to downregulate KRAS-induced hyperactivity of the MAPK pathway and reduce nerve hypertrophy. To date, the patient is still on selumetinib treatment, which is tolerated with manageable adverse events. Conclusion: This patient adds to a growing number of cases that show oncogenic somatic KRAS-driver mutations might cause LHN, which can mimic PN growth in NF1. Selumetinib could provide a novel therapeutic option for LHN, as previously shown in other reports. Publication History Article published online: 26 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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