Most severe cases of CHI are associated with defects in the components of adenosine triphosphate−sensitive K+ channels—encoded by ABCC8 and KNCJ11. Loss-of-function mutations have a causal link to uncontrolled insulin release, but CHI-causing mutations are also known to enhance islet cell proliferation in patients with diffuse disease and disruptions in islet cell identity, including nucleomegaly (16, 21, 22, , ). Here, ABCC8 is linked to congenital isolated hyperinsulinism.