Atypical HUS (also called D-HUS because it lacks a diarrhea prodrome), in contrast, may occur for numerous reasons. In some patients, it appears to reflect dysregulated activation of the complement system, which leads to endothelial damage and platelet aggregation. Affected individuals have been found to possess mutations in genes encoding inhibitors of the alternative, C3b-mediated complement pathway. These inhibitors include factor H, factor C, factor I, factor B, and membrane cofactor protein (MCP). If severe enough, these mutations cause spontaneous and recurrent activation of the complement system starting in childhood. The reason for the particular susceptibility of the renal circulation is not clear; however, it has been postulated that the presence of endothelial fenestrations in the glomerulus increases exposure of the circulating factors to subendothelial proteins, which may serve as a focus for complement activation. Patients with such mutations often have a family history of similar events and are therefore said to have a “familial” form of atypical HUS.