Primary adrenal insufficiency (PAI) is potentially life threatening, but rare. In children, genetic defects prevail whereas adults suffer more often from acquired forms of PAI. The spectrum of genetic defects has increased in recent years with the use of next-generation sequencing methods and now has reached far beyond genetic defects in all known
enzymes of adrenal steroidogenesis. Cofactor disorders such as P450
oxidoreductase (
POR) deficiency manifesting as a complex form of
congenital adrenal hyperplasia with a broad clinical phenotype have come to the fore. In patients with isolated familial
glucocorticoid deficiency (FGD), in which no mutations in the genes for the
ACTH receptor (MC2R) or its accessory
protein MRAP have been found, non-classic
steroidogenic acute regulatory protein (StAR) and
CYP11A1 mutations have been described; and more recently novel mutations in genes such as
nicotinamide nucleotide transhydrogenase (NNT) and
thioredoxin reductase 2 (TRXR2) involved in the maintenance of the mitochondrial redox potential and generation of
NADPH important for steroidogenesis and ROS detoxication have been discovered. In addition, whole exome sequencing approach also solved the genetics of some syndromic forms of PAI including
IMAGe syndrome (CDKN1C), Irish traveler syndrome (MCM4), MIRAGE syndrome (SAMD9); and most recently a syndrome combining FGD with
steroid-resistant nephrotic syndrome and
ichthyosis caused by mutations in the gene for
sphingosine-1-phosphate lyase 1 (SGPL1). This review intends do give an update on novel genetic forms of PAI and their suggested mechanism of disease. It also advocates for advanced genetic work-up of PAI (especially in children) to reach a specific diagnosis for better counseling and treatment.