Purpose of review: Monogenic disorders play significant roles in the pathogenesis of childhood-onset primary adrenal insufficiency (PAI). The most common form of PAI is congenital adrenal hyperplasia (CAH), which includes the enzymatic defects of the steroidogenic pathway. This review focuses on less common forms of monogenic PAI (i.e. non-CAH monogenic PAI) with particular attention on their cause, clinical phenotypes and genetic epidemiology.
Recent findings: Non-CAH monogenic PAI can be classified into three major categories: first, adrenocorticotropic hormone resistance, second, impaired adrenal redox homeostasis and third, defective organogenesis of the adrenal glands. The clinical phenotypes of the mutation-carrying patients vary depending on the responsible gene, and they are partially explained by the tissue RNA expression patterns. Genetic epidemiology studies conducted in Turkey and Japan showed that about 80% of PAI of unknown cause was monogenic.
Summary: Genetic basis of non-CAH monogenic PAI had been less clearly understood than CAH; however, significant advances have been made with use of new research techniques such as next-generation sequencing. Understanding of these rare forms of PAI may contribute to clarifying the physiology and pathology of the adrenal glands.