new england journal
n engl j med
Congenital Adrenal Hyperplasia
Phyllis W. Speiser, M.D., and Perrin C. White, M.D.
From the Department of Pediatrics,
Shore–Long Island Jewish Health System,
New Hyde Park, N.Y. (P.W.S.); New York
University Medical Center, New York
(P.W.S.); and the Department of Pediatrics,
University of Texas Southwestern Medical
Center at Dallas, Dallas (P.C.W.). Address
reprint requests to Dr. Speiser at Schneider
Children’s Hospital, 269-01 76th Ave., New
Hyde Park, NY 11042, or at pspeiser@
N Engl J Med 2003;349:776-88.
Copyright © 2003 Massachusetts Medical Society.
ongenital adrenal hyperplasia is a group of autosomal re-
cessive disorders resulting from the deficiency of one of the five enzymes re-
quired for the synthesis of cortisol in the adrenal cortex. The most frequent is
steroid 21-hydroxylase deficiency, accounting for more than 90 percent of cases. Since
the last Medical Progress article on this topic was published in the
much has been learned about the genetics of the various clinical forms of 21-hydroxy-
lase deficiency, and correlations between the genotype and the phenotype have been ex-
tensively studied. Gene-specific prenatal diagnosis is now feasible, and prenatal treat-
ment has been more widely implemented. This discussion will be limited to the most
common form of congenital adrenal hyperplasia.
Steroid 21-hydroxylase (CYP21, also termed CYP21A2 and P450c21) is a cytochrome
P-450 enzyme located in the endoplasmic reticulum. It catalyzes the conversion of
17-hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol, and the conver-
sion of progesterone to deoxycorticosterone, a precursor of aldosterone (Fig. 1).
Owing to this loss of enzyme function, patients with 21-hydroxylase deficiency can-
not synthesize cortisol efficiently, and as a result, the adrenal cortex is stimulated by cor-
ticotropin and overproduces cortisol precursors. Some of these precursors are diverted
to the biosynthesis of sex hormones, which may cause signs of androgen excess, includ-
ing ambiguous genitalia in newborn girls and rapid postnatal growth in both sexes. Con-
comitant aldosterone deficiency may lead to salt wasting with consequent failure to
thrive, hypovolemia, and shock.
A spectrum of phenotypes is observed. A severe form with a concurrent defect in aldos-
terone biosynthesis (salt-wasting type) and a form with apparently normal aldosterone
biosynthesis (simple virilizing type) are together termed classic 21-hydroxylase defi-
ciency. There is also a mild, nonclassic form that may be asymptomatic or associated
with signs of postnatal androgen excess.
Classic 21-hydroxylase deficiency is detected in approximately 1 in 16,000 births in
The nonclassic form occurs in approximately 0.2 percent of the gen-
eral white population but is more frequent (1 to 2 percent) in certain populations, such
as Jews of Eastern European origin.