Genetic studies have shown that defects in the ISG15 gene can result in Mendelian susceptibility to Mycobacterium disease (MSMD) due to decreased excretion of ISG15, leading to IFN-γ deficiency, and increased susceptibility to Mtb, BCG, and environmental Mycobacterium (EM) [32,33,34]. This evidence concerns the gene ISG15 and hyperinsulinemic hypoglycemia, familial, 4.