Combined 21- and llß-Hydroxylase Deficiency in Familial Congenital Adrenal Hyperplasia*

Abstract

Studies in three families (A, B, and C) revealed five patients with congenital adrenal hyperplasia (CAH) due to partial and combined 21- and 11 beta-hydroxylase deficiency. One patient (A-11 1), a 23-yr-old severely virilized chromosomal female, was reared as a male, and two females (B-11 2 and C-1) complained only of hirsutism, acne, and menstrual abnormalities. Patients A-11 2 and B-11 8 (17 1/2 and 10 yr old) were asymptomatic and detected by finding an HLA genotype identical to that of their respectively affected brother and sister. Three patients (A-11 1, A-11 2, and C-1) had moderate hypertension. In spite of the wide range of clinical manifestations, all individuals had elevated androgen levels, while cortisol secretion was severely impaired only in A-11 2. 21-Hydroxylase deficiency was diagnosed on the basis of markedly increased plasma and urinary levels of 17-hydroxyprogesterone (17-OHP) and 21-deoxycortisol and their respective urinary metabolites pregnanetriol and pregnanetriolone. PRA was elevated in three patients, while urinary aldosterone was normal or increased. 11 beta-Hydroxylase deficiency was diagnosed on the basis of increased 11-deoxycortisol and deoxycorticosterone in plasma and tetrahydro-11-deoxycortisol and deoxycorticosterone in urine, particularly after ACTH administration. In contrast to classical 11 beta-hydroxylase deficiency CAH, urinary 18-hydroxycorticosterone and 18-hydroxy-11-deoxycorticosterone were normal or elevated. The nature and mechanism of a combined enzymatic defect are unknown. The coincidental presence in a single individual of the mutant genes for both 21- and 11 beta-hydroxylase deficiency CAH is very unlikely to occur. Two alternative hypotheses may explain our findings. One is the existence of a genetically inherited abnormal (or aberrant) 11 beta-hydroxylase, whose affinity for its normal substrate is changed for an abnormal one (17-OHP). As a result, 11 beta-hydroxylation of 11-deoxycortisol is deficient while 17-OHP 11 beta-hydroxylation is markedly enhanced. Thus, both 11-deoxycortisol and 21-deoxycortisol as well as their urinary metabolites accumulate. The ability for 18-hydroxylation, however, remains normal. In this case, 21-hydroxylase is not deficient, yet 21-deoxycortisol cannot be further hydroxylated to cortisol, since this steroid is not a suitable substrate for the enzyme. Such a disorder may represent a new allelic variant of 11 beta-hydroxylase deficiency CAH, which, similar to 21-hydroxylase deficiency, is completely linked to the HLA complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Apparent activities of 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase are impaired in adrenal incidentalomas

“…A combined alteration of 21-hydroxylase and 11b-hydroxylase was observed in 7 cases. Apart from anecdotal records with evidence for an actual deficiency of these two enzymes (42), such findings have already been observed for patients with hyperandrogenism (23,24,43). The increased peak 21-DF levels displayed by 7 patients with high post-stimulation S/F ratios is difficult to reconcile with adrenal steroidogenesis.…”

Impact of Molecular Genetics on Congenital Adrenal Hyperplasia Management

“…Rare cases of apparent combined 21-and 11-hydroxylase deficiencies have been reported in the literature [Hurwitz et al, 1985;Penny and Vecsei, 1989;TonettoFernandes et al, 2006], but none have demonstrated concomitant mutations in CYP21A2 and CYP11B1 genes. In our experience, a female patient with the clinical (precocious pubarche, advanced bone age and no genital virilisation) and hormonal characteristics of NC 21-OHD showed an unusual double heterozygosis.…”

Adrenal Hypoplasia Congenita Presenting as Congenital Adrenal Hyperplasia

“…A recurring paradox in the congenital adrenal hyperplasia (CAH) literature is the numerous case reports describing “apparent combined” 21-hydroxylase and 11 β -hydroxylase deficiencies [18–22]. These reports have been enigmatic, given the distant chromosomal locations of the genes encoding the two enzymes.…”