Implications of the Phenotype of POMC Deficiency for the Role of POMC‐Derived Peptides in Skin Physiology

After the isolation of the POMC-derived peptide, α -MSH, from pituitary extracts in 1955, and its synthesis in 1957, several in vivo studies clearly demonstrated the darkening effect of α -MSH on human skin. 1 Cloning the melanocortin receptor gene family, including the MC1 receptor, revealed a molecular basis for α -MSH function on pigmentation. 2 Moreover, the observation of receptor crosstalk within the MC-receptor–POMC-peptide network, which enables binding and activation of MC1R by ACTH in addition to α -MSH, explained the phenomena of skin and hair darkening that occur during pathological situations with ACTH excess, as in Addison disease 3 and ACTH-R deficiency. 4 More recently additional functions of POMC-derived peptides have been proposed as a result of the demonstration of skin expression by the POMC gene itself, as well as the other components of the entire hypothalamus–pituitary–adrenal axis; for example, CRH, CRH-R, and ACTH-R. 5,6 An impact on skin immune responses has been especially implicated. However, the final proof of the physiological significance of POMC function, besides skin pigmentation, awaits the establishment of an animal model for POMC deficiency. Therefore, we present our preliminary and short-term observations on two patients in whom we have demonstrated a genetic defect of the POMC gene. 7