21-Hydroxylase Deficiency Transiently Mimicking Combined 21- and 11β-Hydroxylase Deficiency

Abstract

21-Hydroxylase deficiency (21OHD) is the commonest form of congenital adrenal hyperplasia, while 11betaOHD represents 5% of cases. Although both result from mutations in distinct genes, cases of 'apparent' combined 21OHD and 11betaOHD (AC21,11OHD) have been occasionally reported. A 6 year-old girl, born with ambiguous genitalia and salt-loss, had serum elevations (ng/dl) of androstenedione (>1,000), 17-hydroxyprogesterone (17OHP; 38,483), 21-deoxycortisol (21DF; 23,338), and 11-deoxycortisol (S; 4,928), suggesting AC21,11OHD. CYP21A and CYP11B1 genotyping identified mutations only in the former. On follow-up, serum S became normal but 17OHP and 21DF were still elevated. ACTH stimulation disclosed elevated levels of 17OHP and 21DF, but unresponsive S and undetectable deoxycorticosterone. The hormonal pattern initially suggested AC21,11OHD, but subsequent normalization of S showed transient 11-hydroxylase inhibition. This may have occurred by enzyme or co-enzyme immaturity or functional discrepancy, but also by selective inhibition of 11betaOH by excess intra-adrenal concentration of androgens, acting as pseudo-substrates for this enzyme.

Adrenal Hypoplasia Congenita Presenting as Congenital Adrenal Hyperplasia

“…Considering the cortisol synthesis pathway, it is not surprising to see elevations of 17-hydroxyprogesterone in 11 β -hydroxylase deficiency. More enigmatic have been the reports of elevations of 11-deoxycortisol and DOC in molecularly confirmed 21- hydroxylase deficiency [20]. In the latter scenario, cortisol precursors are accumulating distal to the enzymatic block.…”

“…In the latter scenario, cortisol precursors are accumulating distal to the enzymatic block. A “dysmaturity” of the 11 β -hydroxylase enzymatic function has been implicated in the elevations in 11-DOC in the presence of 21-hydroxylase deficiency [20]. Other authors have attributed these findings to selective inhibition of 11 β -hydroxylase by adrenal androgens acting as competitive inhibitors or pseudosubstrates for this enzyme [20, 22].…”

“…A “dysmaturity” of the 11 β -hydroxylase enzymatic function has been implicated in the elevations in 11-DOC in the presence of 21-hydroxylase deficiency [20]. Other authors have attributed these findings to selective inhibition of 11 β -hydroxylase by adrenal androgens acting as competitive inhibitors or pseudosubstrates for this enzyme [20, 22]. We speculate that similar mechanisms may be at play, leading to transient elevations in 11-deoxycortisol levels in both DAX1 mutations and in 21-hydroxylase deficiency.…”

Dual Heterozygous Mutations in CYP21A2 and CYP11B1 in a Case of Nonclassic Congenital Adrenal Hyperplasia

“… 4 In rare cases, it is possible for an individual to have 2 separate mutations in both 21-hydroxylase and 11β-hydroxylase. 5 , 6 , 7 , 8 , 9 , 10 There is a paucity of reports of such dual mutations in the literature, and the clinical manifestations of such a case are not thoroughly described. Here we report a case wherein a pair of heterozygous mutations in both CYP2A12 and CYP11B1 was detected in a new diagnosis of NCCAH.…”