Endocrine Abstracts

JOINT2439

Introduction: Pro-opiomelanocortin (POMC) deficiency is a rare cause of monogenic obesity characterized by early-onset hyperphagia and severe obesity. Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the only approved treatment for this condition. Known side effects include skin hyperpigmentation and the development of hyperpigmented nevi, due to MC1R off-target activation, raising concerns about potential skin cancer risk. Despite these known effects, no previous cases have documented the histological impact of Setmelanotide on the skin. We present the case of a pediatric patient treated with Setmelanotide who underwent surgical excision of a hyperpigmented nevus, with histological findings providing novel insights into the drug’s dermatological effects. Additionally, we report the patient’s weight-related outcomes during the first six months of treatment.

Methods: An 8-year-old patient with genetically confirmed POMC deficiency was treated with Setmelanotide starting from 0. 5 and up to 1 mg/d. During Setmelanotide treatment a multidisciplinary follow-up was conducted according to the Italian Medicines Agency (AIFA) monitoring register. Furthermore, weight, body mass index (BMI), and metabolic parameters were monitored over six months of therapy.

Results: During dermatological follow-up, skin hyperpigmentation and an atypical hyperpigmented nevus on the lower leg was observed (maximum diameter 0. 9 cm). The nevus was surgically excised and sent to histological analysis. Histological examination revealed a compound melanocytic nevus with junctional and dermal melanocytic proliferation, without evidence of malignant transformation. Immunohistochemistry showed MART1 and HMB45 positivity both in junctional and dermal components, weak focal p16 positivity, and preserved PRKAR1A expression. During Setmelanotide treatment the patient exhibited reduced appetite and improved hyperphagia, and BMI decreased from +4. 2 SD (32. 6 Kg/m²) to +3. 8 SD (31. 3 Kg/m²) in six months. Skin hyperpigmentation remained stable without further complications.

Discussion: This is the first reported case to document histological effects of Setmelanotide on the skin, broadening the understanding of its dermatological safety profile. Our findings support the safety and efficacy of Setmelanotide in managing patients affected by POMC deficiency and highlight the importance of regular dermatological monitoring in those receiving this treatment, particularly in the presence of hyperpigmented lesions, to exclude rare adverse events and ensure optimal management of the therapy. Further studies are warranted to assess long-term dermatological outcomes and the potential implications of off-target MC1R activation.