This variant, formerly titled ISOLATED MINERALOCORTICOID DEFICIENCY, has been reclassified based on the findings of Verrijn Stuart et al. (2007).
In an 11-year-old prepubertal Dutch boy with a mild form of congenital adrenal hypoplasia (AHC; see 300200) involving prominent hypoaldosteronism without clear evidence of glucocorticoid insufficiency, Verrijn Stuart et al. (2007) identified a G-to-C transversion in the NR0B1 gene, resulting in a trp105-to-cys (W105C) substitution in the N terminus of DAX1. In vitro studies of DAX1 expression and function in transfected cells demonstrated mild loss of both repression and activation functions; structure-function analysis suggested that mutations in the N terminus are compensated by the presence of repeat LXXLL motifs that mediate DAX1 interactions with other proteins. An initial ACTH stimulation test in the proband revealed subnormal cortisol results; however, a second test showed normal cortisol values, and he did not experience adrenal crisis while on mineralocorticoid treatment only. The mutation, which was not found in 100 Dutch controls, was present in the proband's mother and was also detected in 3 asymptomatic male relatives. Verrijn Stuart et al. (2007) suggested that phenotypic heterogeneity might result from the effects of other genes that modify or compensate for NR0B1 function, or that environmental events or exposure to medications might unmask underlying adrenal dysfunction.
