Clinical and molecular features of type 1 pseudohypoaldosteronism

Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion. PHA type 1 (PHA1) causes neonatal salt loss, failure to thrive, dehydration and circulatory shock. Two different forms of PHA1 can be distinguished on the clinical and genetic level, showing either a systemic or a renal form of mineralocorticoid resistance. This review provides an overview on transepithelial sodium reabsorption and on clinical features and the underlying molecular pathology of systemic and renal PHA1 caused by mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the mineralocorticoid receptor coding gene NR3C2. The in vitro investigation of several mutants has resulted in important progress in the understanding of the physiology of ENaC and the mineralocorticoid receptor. Some mutations are discussed in more detail to demonstrate some of these findings. A better clinical work-up of the patients suffering from PHA1 may delineate additional associations between the genotype and phenotype in the future.