Apparent cortisone reductase deficiency: a unique form of hypercortisolism

We describe two female siblings who had production of cortisol (F; as determined from excretion of urinary metabolites) high enough to give rise to Cushing's disease, but who had no clinical indications of the condition. The teenage patients were hirsute as a result of adrenal hyperandrogenism. A notable feature of the condition was the elevated excretion of corticosteroid metabolites with 11-carbonyl groups and very low excretion of 11 beta-hydroxylated steroids. We termed this disorder apparent cortisone (E) reductase disorder. The steroid metabolite phenotype appeared to be the opposite of that seen in the apparent mineralocorticoid excess syndrome, in which the excretion of 11-keto compounds is attenuated. As an example, the tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone ratio was about 0.04 compared to normal values of about 1.0 and apparent mineralocorticoid excess syndrome values of 5.0-50.0. Paradoxically, among the F metabolites that had not undergone A-ring reduction, 11 beta-hydroxylated steroids dominated over 11-carbonyl compounds. The F/E ratio was about 1.8 compared to an average normal value of 0.54. Neither the father nor the mother of the patient had abnormal F metabolite/E metabolite ratios, although the father did excrete highly elevated free E and F, possibly an unrelated condition. A conclusion was not reached regarding the basis of the disorder. We considered that the most likely causes were 1) defective hepatic 11 beta-hydroxysteroid dehydrogenase-1, 2) failure to develop the adult form of F metabolism, or 3) excessive activity of A ring reduction enzymes acting on E.