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Abstract We report a 4‐year‐old girl developing therapy refractory paronychia induced by selumetinib, an oral selective inhibitor of mitogen‐activated protein kinase 1/2 prescribed for a large submandibular plexiform neurofibroma. Although this cutaneous reaction is well‐known and more prevalent in children than in adults, no histopathological characterisations of nail unit toxicity in children on selumetinib have been reported so far. We show histopathological studies on patient‐derived periungual inflamed skin to investigate the cutaneous impact of selumetinib therapy. Our findings are consistent with those of epidermal growth factor receptor inhibitors and support the role of a non‐specific immune activation rather than opportunistic infection in the underlying mechanism of the disease. Partial bilateral matricectomies with electrocautery were resolutive, and the child restarted selumetinib with no recurrence of paronychia during a follow‐up period of 3 months after nail surgery.