Medium/large/giant congenital melanocytic nevi (CMN) are somatic rasopathies. Their management when complications have not developed is controversial and when they do appear, their course is fatal. Not all CMNs have a similar evolution, being possible disproportionate proliferation, development of melanoma, regression or stability. No clinical, analytical, histological or genetic predictors have been defined to personalize the approach or the advice to patients. A proliferation marker would be very useful to establish which lesions are in the active phase and should be treated and which others are stable and can be followed. We hypothesize, based on pathophysiologic plausibility, studies in other neoplasms and a preliminary study, that S-100, RAGE and SOX10 proteins could be elevated in serum and their levels could correlate with clinicopathologic and/or genetic features. We propose a study to determine the significance and usefulness of these three biomarkers, as well as a possible pharmacological modulation with new target therapies. Analysis of serum biomarkers has been completed during the last year. The results are under review in a dermatology journal. In a group of 10 patients with CMN we have performed tissue explant cultures and tested different treatments. During the last year, multiplex image analysis has been completed to study if the cellularity and/or proliferation of nevomelanocytes varies with any of the treatments tested. The results are being analyzed.