Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency is a rare genetic disorder that disrupts the processing of hormones involved in metabolism and appetite regulation. PCSK1 is an enzyme responsible for activating hormones like insulin and adrenocorticotropic hormone (ACTH) by cleaving their precursors. PCSK1 deficiency leads to improper processing of these hormones. This results in a phenotype of severe early-onset obesity and endocrine disorders such as hypogonadism and adrenal insufficiency. However, the most common first presenting symptom is severe neonatal diarrhea, which also appears to be caused by the defective processing of gut peptides responsible for digestion. The disorder is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the PCSK1 gene. Heterozygous carriers of loss-of-function variants are likely at risk to develop obesity, but do not have the severe endocrine problems or neonatal diarrhea. Treatment for biallelic PCSK1 deficiency is available in the form of MC4R agonist setmelanotide.