Cutaneous Pigmentary Changes During Setmelanotide Therapy: Dermoscopic and Confocal Findings in Two Patients

Setmelanotide is a melanocortin‐4 receptor agonist approved for the treatment of rare forms of genetic obesity. Through off‐target activation of the melanocortin‐1 receptor, it may induce cutaneous pigmentation changes; however, data regarding its effects on melanocytic nevi remain limited. We report two young patients with different skin phototypes who developed distinct pigmentary patterns during setmelanotide therapy. The first case involved a Caucasian girl (Fitzpatrick phototype III) who experienced rapid‐onset pigmentary and architectural changes in multiple melanocytic nevi, clinically and dermoscopically mimicking melanoma. Reflectance confocal microscopy was performed, and two nevi were excised, with histopathology excluding malignancy; the lesions progressively regressed after treatment discontinuation. The second case involved a patient with Fitzpatrick skin phototype V who developed diffuse skin, nail, and mucosal hyperpigmentation, resulting in generalised darkening of the entire skin surface consistent with Fitzpatrick phototype VI, without any clinical or dermoscopic changes in pre‐existing nevi. These cases highlight the heterogeneity of cutaneous pigmentary responses to setmelanotide and underscore the importance of close dermatologic monitoring, including dermoscopy and reflectance confocal microscopy (RCM), to accurately interpret therapy‐induced changes. Setmelanotide, a melanocortin‐4 receptor agonist approved for rare genetic obesity, may induce pigmentation through off‐target melanocortin‐1 receptor activation. We describe two patients who developed distinct pigmentary changes during therapy: melanoma‐like darkening and architectural changes of multiple melanocytic nevi in one patient, and diffuse skin, nail, and mucosal hyperpigmentation in the second. These cases underscore the heterogeneity of setmelanotide‐induced pigmentation and the importance of dermatologic monitoring, including dermoscopy and reflectance confocal microscopy.