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)