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

Abstract

Studies in three families (A, B, and C) revealedfive patients with congenital adrenal hyperplasia (CAH) due to partial and combined 21- and 11β3-hydroxylase deficiency. One patient (A-ll 1), a 23-yr-old severely virilized chromosomalfemale, was reared as a male, and two females (B-ll 2 and C-l) complained only of hirsutism, acne, and menstrual abnormalities. Patients A-ll 2 and B-ll 8 (17½ 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-ll 1, A-ll 2, and C-l) had moderate hypertension. In spite of the wide range of clinical manifestations, all ndividuals had elevated androgen levels, while cortisol secretion was severely impaired only in A-ll 2. 21-Hydroxylase deficiency was diagnosed on the basis of markedly increased plasma and urinary levels of 17-hydroxyprogesterone (17-½) and 21- deoxycortisol and their respective urinary metabolites pregnanetriol and pregnanetriolone. PRA was elevated in three patients, while urinary aldosterone was normal or increased. 11β-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 11β-hydroxylase deficiency CAH, urinary 18-hydroxycorticosterone and 18-hydroxy-ll-deoxycorticosterone were normal or elevated. The nature and mechanism of a combined enzym`atic defect are unknown. The coincidental presence in a single individual of the mutant genes for both 21- and 11β-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) 11β-hydroxylase, whose affinity for its normal substrate is changed for an abnormal one (17-OHP). As a result, 11β-hydroxylation of 11-deoxycortisol is deficient while 17-OHP 11β-hydroxylation is markedly enhanced. Thus, both ll-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 11β-hydroxylase deficiency CAH, which, similar to 21-hydroxylase deficiency, is completely linked to the HLA complex. A second explanation is partial deficiency of both enzymes, one of which is congenital (21-hydroxylase) and the other one acquired (llβ-hydroxylase), as a result of the inhibitory effect of increased androgens on 11β-hydroxylation.