To date, 22 C1r/C1s deficiency cases have been reported.22–27 Hereditary deficiencies of C1r and C1s tend to occur concomitantly.28 Within the complement system, C1s is a highly specific protease that cleaves C4, C2 and C1-inhibitor (C1-INH).13,29 Binding of C1q to its ligands activates C1r with C1r then cleaving C1s specifically to cause its activation. Here, C1R is linked to hyperinsulinemic hypoglycemia, familial, 4.