Multisteroid analysis in children with terminal aldosterone biosynthesis defects

Abstract

Aldosterone (Aldo), the most potent mineralocorticoid, is synthesized in the adrenal zona glomerulosa, requiring 11 beta-hydroxylation of 11-deoxycorticosterone (DOC) to form corticosterone (B), hydroxylation at position C18 to form 18-hydroxycorticosterone (18-OHB), and finally oxidation at position C18. There is a single cytochrome P450 enzyme (P450aldo) catalyzing all three reactions in the zona glomerulosa. The gene encoding for this enzyme is termed CYP11B2. There are two inborn errors of terminal aldosterone biosynthesis characterized by overproduction of B and deficient synthesis of Aldo. Corticosterone methyl oxidase deficiency type I (CMO-I) is characterized by decreased production of 18-OHB, whereas CMO-II is characterized by overproduction of 18-OHB and an elevated plasma ratio of 18-OHB to Aldo. Both disorders have an autosomal recessive inheritance and are rare causes of salt-wasting and failure to thrive in early infancy. In the last 10 yr, we diagnosed 16 infants with CMO deficiencies by simultaneous multisteroid analysis in a small plasma sample (RIA after extraction and automated high performance gel chromatography). All patients presented with severe failure to thrive in the first 3 months of life, associated with severe hyponatremia, hyperkalemia, and increased PRA. Basal Aldo levels were decreased (range, 0.055-0.11 nmol/L), whereas B was elevated (range, 19-154 nmol/L). Plasma 18-OHB, ranging from 0.063-0.44 nmol/L, was decreased or in the lower normal range in seven patients, whereas the other seven patients had elevated 18-OHB levels (range, 12.1-57.7 nmol/L). 18-OH-DOC (range, 0.81-7.8 nmol/L) and DOC (range, 0.7-9.53 nmol/L) levels were elevated in all patients. In seven patients, we found an elevated ratio of 18-OHB/Aldo (range, 286-900) and a low ratio of B/18-OHB (range, 1.1-5.8), whereas seven other patients had a low 18-OHB/Aldo ratio (range, 1.1-6.95) and a high B/18-OHB ratio (range, 41-1360). These findings confirmed the diagnosis of CMO-I in seven patients (low 18-OHB, 18-OHB/Aldo ratio < 10, and B/18-OHB ratio > 40) and the diagnosis of CMO-II in seven other patients (high 18-OHB, 18-OHB/Aldo ratio > 100, and B/18-OHB ratio < 10), whereas 18-OHB could not be determined in two patients. The B/18-OHB ratio appears particularly useful in CMO cases with undetectably low Aldo plasma levels and uncalculable 18-OHB/Aldo ratios. In conclusion, the simultaneous multisteroid determination method allows the precise differentiation of CMO-I and CMO-II in a small plasma sample during early infancy.