IMPE Abstracts

Almost 40 years ago the first human CYP21A2 gene mutation was reported causing classic congenital adrenal hyperplasia. Meanwhile variants and associated disorders have been described for almost all genes involved in adrenal steroidogenesis leading to mineralocorticoid (MC), glucocorticoid and adrenal sex precursor deficiency in various combinations. In addition, variants in genes comprised in the hypothalamic-pituitary adrenal axis regulating steroidogenesis have been identified in individuals presenting with adrenal insufficiency (AI). By contrast to these variants that mostly cause isolated adrenal insufficiency (or additional differences of sex development at most), variants causing syndromic forms of AI have been found more recently through next generation sequencing approaches which revealed mutations in genes that affect cellular structures and thus the development and function of the adrenals among other organs. Furthermore, the mitochondrial oxidative phosphorylation (OXPHOS) system and its associated reactive oxygen species (ROS) balance seem to play a pivotal role for supporting adrenal steroid biosynthesis. Therefore, variants in genes involved in these systems as well as genetic disorders affecting mitochondrial function can also cause AI, although their clinical manifestation is often more complex, and AI may only manifest in later life. 

The lecture intents to give an overview on rare, newer genetic causes of hypoadrenalism with an emphasis on a novel form of syndromic isolated MC deficiency due to mutations in LGR4/GPR48 affecting the WNT/β-catenin signaling for adrenal zonation and function (doi: 10.1172/JCI164915).