J. Endocrinol. Invest.
24: 681-691, 2001
REVIEW ARTICLE
Congenital adrenal hyperplasia: Transition from
childhood to adulthood
P.W. Speiser
Division of Pediatric Endocrinology, North Shore-Long Island Jewish Health System; Professor,
New York University School of Medicine, New York, USA
ABSTRACT. Congenital adrenal hyperplasia
(CAH) is a group of disorders caused by inborn
errors of steroid metabolism. The most common
form owing to 21-hydroxylase deficiency (CAH-
21OHD) is present in about 1:10,000- 1:15,000
live births worldwide. In its classic salt-wasting
form (~66-75% of cases) patients may suffer po-
tentially lethal adrenal insufficiency. Non-salt-
wasting forms of CAH-21OHD are recognized by
genital ambiguity in affected females, and by
PATHOLOGY
Congenital adrenal hyperplasia (CAH) owing to 21-
hydroxylase deficiency (CAH-21OHD) is character-
ized by an adrenal cortex that cannot synthesize ad-
equate amounts of cortisol. Inefficient cortisol syn-
thesis leads to excessive secretion by the hypotha-
lamus and pituitary of CRH and ACTH, respective-
ly. This chronic adrenal stimulation induces hyper-
plasia. Similar pathophysiology applies in CAH due
to deficiency of several other enzymes crucial for
cortisol synthesis, i.e. 3β-hydroxysteroid dehydro-
genase, 11β-hydroxylase, and 17α-hydroxylase.
A by-product of a futile adrenal cortisol pathway is
the synthesis of excessive sex hormone precursors
that do not require 21-hydroxylation. These hor-
mones include progestins and androstenedione,
the latter converted outside the adrenal gland to
active androgens, such as testosterone and dihy-
drotestosterone, and to a lesser extent to estro-
gens.
Key-words: 21-hydroxylase deficiency, CAH-21 OHD.
Correspondence: Prof. Phyllis W. Speiser, Division of Pediatric Endocri-
nology, North Shore University Hospital, 300 Community Drive,
Manhasset, NY 11030, USA.
E-mail: speiser@nshs.edu
Accepted April 4, 2001.
681
signs of androgen excess in later childhood in
males. Non-classic CAH-21OHD may be detected
in up to 1-3% of certain populations, and is often
mistaken for idiopathic precocious pubarche in
children or polycystic ovary syndrome in young
women. This chapter will address issues relating
to transition of CAH care from the pediatric to
the adult endocrinologist.
(J. Endocrinol. Invest. 24: 681-691, 2001)
©2001, Editrice Kurtis
Most patients with classic CAH-21OHD also have
inadequate aldosterone and therefore cannot main-
tain sodium balance. If this condition is not recog-
nized and diagnosed promptly, potentially life-
threatening hyponatremic dehydration and shock
occur. About 25% of patients have sufficient al-
dosterone levels and no salt-wasting, yet still show
pre-natal virilization and/or markedly increased
production of hormonal precursors of 21-hydroxy-
lase [e.g. 17-hydroxyprogesterone (17-OHP)] These
individuals are referred to as “simple virilizers”.
Besides these functional abnormalities in adreno-
cortical steroid production, the structural organiza-
tion of both the adrenal cortex and medulla is dis-
rupted in CAH patients. The latter problem is ac-
companied by significantly lower than normal levels
of circulating catecholamines (1). Inability to mount
an appropriate catechol response to stress could
contribute to unstable cardiovascular status in pa-
tients prone to adrenal salt-wasting crises.
CLINICAL PRESENTATION: CLASSIC CAH DUE
TO 21-HYDROXYLASE DEFICIENCY
Physical stigmata in newborns
Newborn males with 21-hydroxylase deficiency usu-
ally show no overt signs of adrenal androgen ex-
cess; internal genitourinary structures and gonadal
function are also normal. Newborn females with
P.W. Speiser

classic virilizing CAH, however, manifest variable
degrees of genital ambiguity caused by high sys-
temic levels of adrenal androgens beginning at
about 7th week of gestation. Females with the
milder non-classic form of the disorder are distin-
guished by little or no virilization at birth (Table 1).
Biochemical profile
Classic 21-hydroxylase deficiency is diagnosed
based on a markedly elevated serum level of
17-OHP, the main substrate for the enzyme. Basal
17-OHP values usually exceed 10,000 ng/dl in
severely affected infants, whereas normal newborn
levels are below 100 ng/dl. Laboratory studies also
often show hyponatremia, hyperkalemia, and hy-
perreninemia. Hormonal diagnosis can be refined
by performing ACTH (cosyntropin) stimulation, thus
permitting differentiation of the various forms of
CAH by comparing precursor/product ratios after
stimulation. The efficacy of therapy is monitored by
periodic measurements of 17-OHP along with an-
drostenedione and, in females and pre-pubertal
males, testosterone.
Simple virilizing patients tend to have somewhat
lower 17-OHP levels, although the range overlaps
that seen in salt-wasting patients (2). Patients with
the non-classic form of CAH have modestly elevat-
ed hormone levels, especially in the newborn peri-
od. It is important to realize that random measure-
ments of basal serum 17-OHP are often normal in
non-classic patients (unless performed in the early
morning before or at 08:00 h), and the diagnosis is
most reliably made by the response to ACTH stim-
ulation.
Post-natal signs of abnormal sex hormone production
Ongoing adrenal sex hormone production in the
inadequately treated patient causes several prob-
lems. Boys show inappropriately rapid somatic
growth accompanied by marked advancement of
epiphyseal maturation after about 18 months (3).
Pubic hair and apocrine body odor develop, and

Table 1 - Features of different clinical forms of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency*. Modified from (55).
Phenotype Classic Classic Non-classic
salt-wasting simple-virilizing
Males Females Males Females Males Females
Age at diagnosis Newborn-6 m Newborn-1 m 1.5-4 yr Newborn-2 yr Child-adult Child-adult
Genitalia Normal Ambiguous Normal Ambiguous Normal +/- ↑ clitoris
Aldosterone ↓ Normal Normal
Renin ↑ May be ↑ Normal
Cortisol ↓ ↓ Normal
17-OHP >20,000 ng/dl >10,000 -20,000 ng/dl 1500 - 10,000 ng/dl
(ACTH-stimulated)
Testosterone ↑ in pre- ↑ ↑ in pre- ↑ Variably ↑ in Variably ↑
puberty only puberty only pre-puberty
only
Treatment Glucocorticoid+ Glucocorticoid Glucocorticoid,
mineralocorticoid (+mineralocorticoid) if symptomatic
(+sodium)
Disease incidence** 1/10,000-15,000 1/50,000-60,000 1/1000
Typical mutations Deletion I172N V281L
Large conversion nt 656g P30L
Nt 656g («intron 2 g»)°
G11068nt
I236N/V237E/M239K
Q318X
R356W°
% enzymatic activity 0 1-2°° 20-50
*Although distinct categories are assigned here to the 3 major phenotypic forms of CAH, the true disease spectrum is better represented as a contin-
uum with indistinct borders. **Incidence in general white population from (4), (70). °Occasionally associated with low-level enzyme activity and simple
virilizing disease. °°Compound heterozygotes bearing this mutation often show variable phenotypes.

682

penile size increases without testicular enlargement.
Girls show similar signs of sex steroid excess as well
as progressive clitoral enlargement. In adolescence,
poorly controlled girls with classic CAH have hirsu-
tism, oligomenorrhea or amenorrhea, and acne.
Non-classic CAH is a mild, more common allelic vari-
ant of severe, classic CAH-21OHD (4, 5), and has a
variable presentation (6). Most often children mani-
fest precocious pubarche, whereas adolescents and
young adults have hirsutism, oligomenorrhea, or ac-
ne (7). Cross-sectional data suggest that, for some af-
fected individuals, these symptoms become pro-
gressively worse, if treatment is not instituted (7).
Longitudinal evaluation of children identified in new-
born screening programs should elucidate the fre-
quency and severity of hyperandrogenic symptoms
among individuals affected with mild degrees of 21-
hydroxylase deficiency, since these children are not all
symptomatic at the time of diagnosis and are not uni-
versally treated.
Although children with CAH grow too rapidly, adult
height is often one to two standard deviations be-
low the mean for target height (8). Balancing medi-
cal treatment is often complicated in CAH. Untreated
or inadequately treated patients grow rapidly and
may not reach their height potential; on the other
hand, those treated with excessive doses of gluco-
corticoids and/or mineralocorticoids suffer growth
retardation. Sensitivity to exogenously administered
steroids may be determined in part by inter-individ-
ual variations in drug metabolism and polymor-
phisms in receptors affecting in vivo action (9). Since
over-zealous treatment with glucocorticoids is a ma-
jor correlate of poor growth, it is important to treat
CAH patients with the lowest dose of glucocorticoid
effective in maintaining adrenocortical hormones in
a reasonable range. Optimal levels of these marker
hormones will change with age and sex, and strict
control guidelines are often relaxed at puberty. Al-
though the topic of growth inhibition by excessive
glucocorticoids has been studied in infants and
young children, there has been no careful prospec-
tive study of whether less stringent control at puberty
is effective in promoting maximal growth. Data are
also as yet unavailable concerning adult height
among CAH patients treated with low-dose con-
ventional therapy in addition to an aromatase-in-
hibitor and an androgen-receptor blocker, but pre-
liminary results are intriguing (10). GH and GnRH
analogs have been proposed as valuable adjunctive
treatments to enhance height in CAH patients, but
again, data are minimal and long-term outcomes
have not been reported. Non-classic CAH height
standard deviation scores are not significantly dif-
ferent from family heights (11, 12).
683
CAH: Transition
Psychosexual and cognitive development
Girls with CAH, especially salt-wasters, express
more typical male play in childhood, are more phys-
ically aggressive, and show less interest in infants
and maternal nurturing compared with controls (13).
Yet despite this early atypical female behavior, most
CAH patients raised as girls express female-typical
gender identity and heterosexual orientation (14).
Quality of life is not significantly impaired among
treated adult female CAH patients (15). Rarely, CAH
women have elected to undergo sex change, con-
travening their sex of rearing (16). Gender-atypical
behavior and gender dysphoria have not been re-
ported in CAH males. Psychological support from
professionals experienced in treating gender-relat-
ed problems should be provided on an as-needed
basis to patients and families. This is particularly im-
portant at the time of diagnosis in severely affect-
ed females, and in adolescence, especially if geni-
tal surgery is performed.
Learning disorders have been identified in some
studies as unusually prevalent among salt-wasting
CAH patients, presumably attributed to the detri-
mental effects upon the brain of severe fluid and
electrolyte disturbances. Nonetheless, overall in-
telligence quotient is probably similar among CAH
patients and properly matched controls (17). Overt
psychiatric disturbances are apparently not unusu-
ally common among CAH patients.
Reproductive function in CAH females
There are potentially far-reaching implications for psy-
chosexual and reproductive function. First, hypotha-
lamic-pituitary-gonadal function may be perturbed in
the setting of adrenal sex hormone excess. Women
with well-controlled classic CAH, but not those with
non-classic CAH, have exaggerated LH responses to
GnRH and increased production of ovarian andro-
gens. These data are potentially consistent with im-
printing by pre-natal exposure to androgens or pro-
gestins (18), although not specific for CAH.
Reproductive problems for women with CAH usu-
ally become apparent in adolescence. The average
age at which menarche occurs in inadequately
treated girls is late compared with healthy peers
(19). Such patients often have a clinical picture sim-
ilar to polycystic ovary syndrome with sonographic
evidence of multiple cysts, anovulation, irregular
bleeding and hyperandrogenic symptoms. More-
over, a significant reduction in insulin sensitivity, al-
though not frank diabetes, is found among non-
obese young women with non-classic CAH as com-
pared with controls of similar age and weight (20).
Insulin resistance is also associated with functional
ovarian hyperandrogenism independent of obesity
P.W. Speiser
(21), and with precocious pubarche unrelated to
CAH (22), although the precise pathophysiology in
these disease states is uncertain .
Possible explanations for the reproductive dys-
function in CAH include aromatization of excess
adrenal androgen to estrogen (23), or excess ad-
renal progesterone (19) inhibiting normal hypotha-
lamic-pituitary cyclicity. Alternatively, elevated sex
steroids could program the hypothalamus early in
development (18). Androgen excess could cause
direct gonadal damage. Finally, adrenal rests can
displace normal gonadal tissue.
The majority of CAH women eventually undergo
menarche. In general, the regularity of menses de-
pends on the adequacy of treatment. A small pro-
portion of women do not undergo menarche and
are unable to suppress progesterone levels even
when 17-OHP is adequately suppressed (24). Adre-
nalectomy may be considered when medical ther-
apies are unsuccessful in achieving adrenal sup-
pression (25).
Breasts may be atrophic in females with CAH.
Evidence from animal studies suggests that testos-
terone exposure in utero may suppress growth of
the breast anlage, resulting in poor breast devel-
opment at adolescence (26).
Data regarding reproductive function in non-clas-
sic CAH comes mainly from a biased referral pop-
ulation who seek treatment for symptoms and signs
of hyperandrogenism and/or infertility. Based on
information derived from individuals detected
through family studies, it is clear that many cases
of mild 21-hydroxylase deficiency, both male and
female, go undiagnosed for lack of clinically im-
portant symptoms. At present, there is no test to
predict which individuals affected with non-classic
CAH will progress and suffer adverse consequences
of the hormonal imbalance.
Pregnancy outcome in women with CAH
A recent review has found that up to about 80% of
simple virilizers and 60% of salt-wasters can bear chil-
dren (27). French investigators found that about 50%
of women affected with non-classic CAH became
pregnant before the diagnosis of mild 21-hydroxy-
lase deficiency was made and without receiving any
specific treatment. Among the other 50%, those who
desired pregnancy conceived during hydrocortisone
treatment; only 1 in 20 women required additional
treatment with clomiphene citrate to conceive (28).
Despite elevated maternal testosterone of 400-600
ng/dl during pregnancy unaffected female offspring
of even classic CAH mothers have no genital viriliza-
tion (27). Active placental aromatase prevents ma-
ternal androgens from reaching the fetus in both nor-
684
mal pregnancy, and in those in which the mother
herself is affected with CAH. Maternal SHBG, ele-
vated in pregnancy, and androgen antagonism by
progesterone also contribute to restricting transpla-
cental passage of androgens.
Reproductive function in CAH males
Impaired gonadal function is less frequent among
men with classic CAH compared with affected
women. Most CAH males are able to father chil-
dren, or at least have adequate sperm counts (29).
Oligospermia, observed in both classic and non-
classic CAH, does not preclude fertility (30). Among
simple virilizing patients, testicular integrity may be
normal even in the absence of treatment with CAH.
Testicular adrenal rests (also referred to as “testic-
ular tumors of adrenogenital syndrome”), some-
times nearly obliterating normal testis parenchyma,
may occur in CAH males, especially if they are in-
adequately treated salt-wasters (23, 31, 32). In one
study of 30 patients, 27% of subjects had sono-
graphic evidence of testicular masses, prompting
a recommendation for careful testicular examina-
tions and a baseline testicular sonogram by ado-
lescence (33). Testicular masses have been detect-
ed in boys with classic CAH as young as 3 years old
(34). These tumors, although benign, have a rock-
hard consistency, leading to biopsies and some-
times even orchiectomy. The preferred mode of
treatment actually consists of effective long-term
adrenal suppression with dexamethasone, since
many of these tumors are ACTH-responsive. When
there is no response to dexamethasone, testis-spar-
ing surgery may be performed (35). Adrenalectomy
would not be expected to alleviate problems
caused by gonadal adrenal rests. Male infertility and
testicular adrenal rest tumors are apparently un-
common in individuals with non-classic CAH.
Other problems associated with CAH
Adrenocortical hyperplasia is seen in some infants
and children with CAH. The diagnostic utility of
adrenal sonography is enhanced in newborn infants
by examining not only size, but also shape, surface
contours and echogenicity of the adrenal glands (36).
The incidence of adrenal masses increases with
age, and is higher in CAH patients and heterozy-
gotes than in the general population (37). Steroid-
responsive hyperplastic adrenal nodules can be the
first presenting sign in previously undiagnosed pa-
tients late in life and can potentially be confused
with virilizing adrenal adenomas (38). Virilizing
adrenal carcinoma is quite rare in adult CAH pa-
tients (39), and most adrenal masses in children with
CAH are benign (40).

HORMONAL REPLACEMENT THERAPY
Glucocorticoids
All patients with classic 21-hydroxylase deficiency,
and symptomatic patients with nonclassic disease,
require glucocorticoid treatment. Glucocorticoids
suppress secretion of CRH and ACTH by the hy-
pothalamus and pituitary, and reduce the elevated
levels of adrenal sex steroids. In children, the pre-
ferred cortisol replacement is hydrocortisone, which
is rapidly converted in vivo to active cortisol, in a
dose of 10 to 20 mg/m2/day in two or three divid-
ed doses. These doses exceed physiologic levels
of cortisol secretion, which are 6-7 mg/m2/day in
children and adolescents (41). Supraphysiologic
doses seem to be required to adequately suppress
adrenal androgens in CAH patients.
The short half-life of hydrocortisone minimizes
growth suppression and other adverse side effects
of longer acting, more potent glucocorticoids such
as prednisone and dexamethasone. On the other
hand, a single daily dose of a short-acting gluco-
corticoid is ineffective in controlling adrenocortical
hormone secretion. Children who are compliant, but
nonetheless difficult to control with hydrocortisone
alone, may benefit from morning hydrocortisone
combined with a night-time dose of prednisone to
more effectively suppress the overnight rise in
ACTH. Older adolescents and adults may be treat-
ed with prednisone (e.g. 5-7.5 mg daily in 2 divided
doses) or dexamethasone (total 0.25-0.5 mg given
as one or two daily doses). Patients should be mon-
itored carefully for signs of iatrogenic Cushing’s syn-
drome such as rapid weight gain, hypertension, pig-
mented striae, and osteopenia. Men with testicular
adrenal rests may require higher dexamethasone
doses to suppress ACTH.
Glucocorticoids during pregnancy
During pregnancy, CAH women should be treated
with hydrocortisone or prednisone (which do not
cross into the fetal circulation to any appreciable
degree) to maintain maternal serum testosterone
in the high normal range of about 200 ng/dl (42). If
pre-natal treatment is desired to suppress fetal
adrenal androgens of a potentially affected female
fetus, dexamethasone must be administered early
in the first trimester in a dose of 20 μg/kg pre-preg-
nancy weight/day, divided in 3 doses. Concerns
have been raised about potential adverse long-
term consequences to the fetus, especially to the
7 of 8 unaffected fetuses that are unnecessarily
treated with glucocorticoids to prevent virilization of
1 affected female. Data raising such concerns de-
rive mainly from animal models (43). Clinical trials
are ongoing, and although no major attributable
685
CAH: Transition
risk has been observed in these offspring during
nearly two decades (44), more long-term evalua-
tion is needed.
Dose titration
Treatment efficacy is assessed by monitoring 17-
OHP and androstenedione levels. Testosterone can
also be a useful parameter in females of any age,
and pre-pubertal males. Because of the adverse ef-
fects of over-treatment it is not desirable to com-
pletely suppress endogenous adrenal corticosteroid
secretion. A target 17-OHP range might be 300-
1000 ng/dl with commensurate age and gender-
appropriate androgen levels (45). Hormones should
be measured at a consistent time in relation to
medication dosing, preferably at 8:00 h at the phys-
iologic peak of ACTH secretion, or at the nadir of
hydrocortisone blood levels just before the after-
noon dose is given. Children should also have an
annual bone age X-ray and careful monitoring of
linear growth.
Stress dosing
As discussed above, patients with classic CAH cannot
mount a sufficient cortisol response to stress and re-
quire pharmacologic doses of hydrocortisone in such
situations as febrile illness and surgery under gener-
al anesthesia. Ideally, stress dosing with glucocorti-
coids should approximate endogenous adrenal se-
cretion in critically ill and perioperative patients (46),
but it is common practice to give larger doses.
Traditional dose guidelines include tripling the main-
tenance dose of oral hydrocortisone for up to sev-
eral days (administered in 3 divided doses) in minor
febrile illnesses. If a patient is unable to tolerate oral
medication, im hydrocortisone sodium succinate
(Solu-Cortef) may be given at home, but medical ad-
vice should be promptly sought about the need for
iv hydration. Patients and parents should receive in-
structions for these types of emergency contingen-
cies, and patients should carry or wear identification
with information about their medical condition.
For major surgery, administration of hydrocortisone
(empiric doses of 25, 50, or 100 mg/m2/day in in-
fants, children, and adults, respectively) divided in 4
iv doses is warranted for at least 24 h peri- and post-
operatively before tapering over several days to a
maintenance dose. Iv hydrocortisone is preferred
over equivalent glucocorticoid doses of methyl-
prednisolone (Solu-Medrol) or dexamethasone be-
cause, in high doses, hydrocortisone possesses sig-
nificant mineralocorticoid activity and is able to sub-
stitute for oral fludrocortisone. Stress doses should
be administered to women with CAH during labor
and delivery, and in the peripartum period.
P.W. Speiser
Patients with non-classic CAH do not require stress
doses of hydrocortisone for surgery, except if they
have been rendered temporarily hypoadrenal by
prior chronic administration of glucocorticoids. If
given adequate advance notice, one could discon-
tinue treatment and test the integrity of the hy-
pothalamic-pituitary-adrenal axis with a low-dose
ACTH stimulation test (47). There have been no re-
ports of fatal adrenal insufficiency among patients
with non-classic CAH. Thus, previously symptomatic
non-classic patients treated with glucocorticoids
may eventually discontinue drug therapy if they
have attained or are nearing completion of linear
growth, no longer suffer symptoms of hyperandro-
genism, or are not desirous of fertility.
Mineralocorticoids
Infants with the salt-wasting form of 21-hydroxylase
deficiency require mineralocorticoid (fludrocortisone,
usually 0.1-0.2 mg but occasionally up to 0.4 mg/day)
and sodium chloride supplements (1 to 2 g/day; each
g of sodium chloride contains 17 mEq of sodium) in
addition to glucocorticoid treatment. Older children
and adults typically consume a much higher sodium
diet, and therefore do not require daily supplements
of sodium chloride tablets. Frequently, fludrocorti-
sone dose requirements decrease with age, and can
be discontinued in some patients (48).
Although patients with the simple virilizing form of
the disease by definition secrete adequate amounts
of aldosterone, they are nevertheless often treated
with fludrocortisone. This can aid in adrenocortical
suppression, reducing the dose of glucocorticoid
required to maintain acceptable 17-OHP levels (49).
Plasma renin activity may be used to monitor min-
eralocorticoid and sodium replacement. Hyper-
tension, edema, tachycardia and suppressed plas-
ma renin activity are clinical signs of excessive treat-
ment with fludrocortisone. In this group of patients,
fludrocortisone may often be discontinued with ad-
vancing age.
SURGICAL TREATMENT
In the past, surgical correction of genital ambigui-
ty was considered an emergency to be repaired, at
least in part, before the infant was discharged from
the hospital, or in the first few months of life.
Current thinking and practice are evolving to allow
the families to play a greater decision-making role
in situations that do not require immediate atten-
tion (50). In some centers, a concerted surgical re-
pair may be performed in a single stage in early life
(51), while others will delay vaginal reconstruction
until nearer the time a girl is mature enough to be-
686
come sexually active. A multicenter task force re-
cently established in the USA will assess long-term
outcome of patients managed according to differ-
ent protocols. At present, for the individual, the de-
cision of whether, when, and what type of genital
surgery is desirable needs to be reviewed with the
family and/or patient, experienced surgeons, and
endocrinologist.
GENETIC COUNSELING
Epidemiology
CAH owing to 21-hydroxylase deficiency is among
the most common inborn errors of metabolism,
thus the carrier rate is high in most populations.
Estimated non-classic and classic heterozygote fre-
quencies are 10% and 1.5% in the general popula-
tion (4), respectively. Interestingly, CYP21 has the
highest rates of single nucleotide polymorphisms
among over 100 human genes tested (52), possi-
bly conferring some as-yet-unrecognized survival
advantage. More than 50 different mutant alleles
have been identified to date, however, ~95% of
CAH alleles are identified by a panel of 10 muta-
tions. Moreover, approximately 40-50% of muta-
tions are either deletions (53) or a single point mu-
tation altering splicing between the second and
third exons (54). For a detailed discussion of the
molecular genetics of the gene encoding 21-hy-
droxylase, CYP21, the reader is referred to a recent
review (55).
Correlation of phenotype and genotype
In brief, patients with classic salt-wasting CAH-
21OHD carry two mutant alleles that preclude 21-
hydroxylase activity, e.g. CYP21 deletion. Simple
virilizing patients tend to carry one severe and one
moderate mutant allele, e.g. the point mutation
Ile172Asn in exon 4 (56) that permits ~2% of normal
enzyme activity (57). In contrast, non-classic CAH is
most often attributable to two mildly compromised
alleles, e.g. the point mutation Val281Leu in exon 7
(5) that permits up to 50% of normal enzyme activ-
ity (57). In ~90% or more of cases, phenotype
matches that expected based on in vitro studies in-
volving expression of mutant alleles (2, 58, 59).
Patients who are compound heterozygotes usually
present with a clinical picture consistent with the
function of the least deleterious allele; those carry-
ing severe and moderate mutations on their re-
spective CYP21 alleles exhibit the greatest degree
of phenotypic variability (60). In actuality, there is a
continuum of disease severity, rather than sharp
lines demarcating disease classification as salt-wast-
ing, simple virilizing and non-classic CAH.

Clinical applications
Knowing an established patient’s CYP21 geno-
type does not necessarily aid in making treatment
decisions. Genotyping is helpful, however, in per-
forming pre-natal diagnosis when there is a
known proband in the family (61). Diagnostic er-
rors in pre-natal diagnosis can be minimized by
genotyping both parents whenever possible and
by the concomitant use of linked microsatellite
markers (62). Two large-scale studies have also
shown the utility of CYP21 genotyping as an ad-
junct to hormonal measurements in newborn
screening programs (63, 64). Hormonal screening
of newborns is now increasingly widespread and
is effective in promoting prompt diagnosis and
treatment, and in reducing morbidity and mor-
tality from CAH (65).
A common practical problem arises when a wom-
an has been told she has “CAH” and is treated
with glucocorticoids, but the hormonal data are
either unavailable or in doubt. It is preferable not
to continue long-term treatment, initiate pre-na-
tal treatment, or perform invasive diagnostic test-
ing unnecessarily. Since hormonal diagnosis is un-
reliable during or immediately following gluco-
corticoid treatment, genotyping is a viable alter-
native in such situations.
Women with non-classic CAH may wish to know
whether they carry a classic allele; genetic test-
ing may be undertaken for this purpose. If the
genotype is unknown, the empiric risk to a non-
classic CAH parent and a partner of unknown sta-
tus is about 1:1000 to 1:2000 for having a girl af-
fected with classic CAH. This is based on a 20-
40% chance of a non-classic patient carrying a
classic allele, a 2% heterozygote frequency in the
general population, and a 50% chance of trans-
mitting the affected allele, with 50% female off-
spring. Since this overall risk is relatively low com-
pared with the 1:8 risk to a couple who have al-
ready produced a child with classic CAH, pre-na-
tal treatment and invasive prenatal diagnosis
seem unwarranted. Offspring of such couples
should rather be tested for CAH in early infancy or
childhood as indicated.
Heterozygotes
Family members often wish to know their risk of trans-
mitting CAH. For this autosomal recessive disease,
obligate heterozygote parents have a 50% risk of
transmitting the affected haplotype to offspring, and
this risk is the same in each successive pregnancy.
Thus, there is a 25% disease risk for each sibling of a
CAH proband born by the same parents. In about
1% of patients, there is a de novo mutation in one
687
CAH: Transition
CYP21 allele (60), i.e. the mutation is not found in the
DNA analyzed from a parent’s peripheral blood sam-
ple, but presumably was a germline mutation involv-
ing a single sperm or ovum. In a study of healthy vol-
unteers, approximately 1:105 to 1:106 sperm have
identifiable CYP21 mutations not found in blood (66).
In such cases, it is statistically unlikely that a second
child would be affected with CAH.
Carriers of a single mutant allele have mildly el-
evated 17-OHP levels after ACTH stimulation.
The range of most heterozygotes’ 17-OHP re-
sponse at 60 min following cosyntropin stimula-
tion is approximately 200-1000 ng/dl, overlap-
ping the general population to some extent (2).
In one study, only 50% of obligate heterozygotes
had 17-OHP measurements after ACTH stimula-
tion which differed significantly from those of
genotypically normal individuals (67). Heterozy-
gotes can be more reliably identified hormonal-
ly by examining the ratio of 17-OHP to cortisol
(68), but genotyping is the gold standard for pur-
poses of genetic counseling, especially when the
proband’s mutation is known. Heterozygotes for
CAH alleles do not suffer from any significant
symptoms or hormone imbalance, and are con-
sequently not candidates for hormonal replace-
ment therapy (69).
CONCLUSIONS
Classic CAH is a congenital disease with far-reach-
ing ramifications in childhood, adolescence and
adult life. Recent research has clarified clinical,
biochemical and genetic problems in diagnosis
and treatment, but several areas remain to be
studied. Non-classic CAH is of variable severity,
and should be treated in cases with overt clinical
evidence of androgen excess. Whereas treatment
duration is lifelong in classic disease, this is not
necessarily so for the non-classic disorder. Cli-
nicians must be aware of the long-term outlook
for CAH patients and tailor treatment according
to gender, age, biochemical profile and pheno-
type. Genotyping is useful in select instances to
provide genetic counseling and clarify ambigu-
ous cases.
REFERENCES
1. Merke D.P., Chrousos G.P., Eisenhofer G., Weise M.,
Keil M.F., Rogol A.D., Van Wyk J.J., Bornstein S.R.
Adrenomedullary dysplasia and hypofunction in
patients with classic 21-hydroxylase deficiency.
N. Engl. J. Med. 2000, 343: 1362-1368.
P.W. Speiser
2. Wilson R.C., Mercado A.B., Cheng K.C., New M.I.
Steroid 21-hydroxylase deficiency: genotype may
not predict phenotype.
J. Clin. Endocrinol. Metab. 1995, 80: 2322-2329.
3. Thilen A., Woods K.A., Perry L.A., Savage M.O.,
Wedell A., Ritzen E.M.
Early growth is not increased in untreated moder-
ately severe 21-hydroxylase deficiency
Acta Paediatr. 1995, 84: 894-898.
4. Speiser P.W., Dupont B., Rubinstein P., Piazza A.,
Kastelan A., New M.I.
High frequency of nonclassical steroid 21-hydrox-
ylase deficiency.
Am. J. Hum. Genet. 1985, 37: 650-667.
5. Speiser P.W., New M.I., White P.C.
Molecular genetic analysis of nonclassic steroid 21-
hydroxylase deficiency associated with HLA-B14,
DR1.
N. Engl. J. Med. 1988, 319: 19-23.
6. Kohn B., Levine L.S., Pollack M.S., Pang S.,
Lorenzen F., Levy D., Lerner A.J., Rondanini G.F.,
Dupont B., New M.I.
Late-onset steroid 21-hydroxylase deficiency:
a variant of classical congenital adrenal hyper-
plasia.
J. Clin. Endocrinol. Metab. 1982, 55: 817-827.
7. Moran C., Azziz R., Carmina E., Dewailly D., Fruzzetti
F., Ibanez L., Knochenhauer E.S., Marcondes J.A.,
Mendonca B.B., Pignatelli D., Pugeat M., Rohmer
V., Speiser P.W., Witchel S.F.
21-Hydroxylase-deficient nonclassic adrenal hy-
perplasia is a progressive disorder: A multicenter
study.
Am. J. Obstet. Gynecol. 2000, 183: 1468-1474.
8. Eugster E.A., Dimeglio L.A., Wright J.C., Freidenberg
G.R., Seshadri R., Pescovitz O.H.
Height outcome in congenital adrenal hyperpla-
sia caused by 21-hydroxylase deficiency: A meta-
analysis.
J. Pediatr. 2001, 138: 26-32.
9. Huizenga N.A., Koper J.W., De Lange P., Pols H.A.,
Stolk R.P., Burger H., Grobbee D.E., Brinkmann
A.O., De Jong F.H., Lamberts S.W.
A polymorphism in the glucocorticoid receptor
gene may be associated with and increased sensi-
tivity to glucocorticoids in vivo.
J. Clin. Endocrinol. Metab. 1998, 83: 144-151.
10. Merke D.P., Keil M.F., Jones J.V., Fields J., Hill S.,
Cutler G.B. Jr.
Flutamide, testolactone, and reduced hydrocorti-
sone dose maintain normal growth velocity and
bone maturation despite elevated androgen levels
in children with congenital adrenal hyperplasia.
J. Clin. Endocrinol. Metab. 2000, 85: 1114-1120.
11. New M.I., Gertner J.M., Speiser P.W., del Balzo P.
Growth and final height in classical and nonclassi-
cal 21-hydroxylase deficiency.
Acta Paediatr. Jpn. 1988, 30 (Suppl.): 79-88.
688
12. Cameron F.J., Tebbutt N., Montalto J., Yong A.B.,
Zacharin M., Best J.D., Warne G.L.
Endocrinology and auxology of sibships with non-
classical congenital adrenal hyperplasia.
Arch. Dis. Child. 1996, 74: 406-411.
13. Berenbaum S.A., Duck S.C., Bryk K.
Behavioral effects of prenatal versus postnatal an-
drogen excess in children with 21-hydroxylase-defi-
cient congenital adrenal hyperplasia.
J. Clin. Endocrinol. Metab. 2000, 85: 727-733.
14. Dittmann R.W., Kappes M.E., Kappes M.H.
Sexual behavior in adolescent and adult females
with congenital adrenal hyperplasia.
Psychoneuroendocrinology 1992, 17: 153-170.
15. Kuhnle U., Bullinger M., Schwarz H.P.
The quality of life in adult female patients with
congenital adrenal hyperplasia: a comprehensive
study of the impact of genital malformations and
chronic disease on female patients life.
Eur. J. Pediatr. 1995, 154: 708-716.
16. Meyer-Bahlburg H.F., Gruen R.S., New M.I., Bell
J.J., Morishima A., Shimshi M., Bueno Y., Vargas
I., Baker S.W.
Gender change from female to male in classical con-
genital adrenal hyperplasia.
Horm. Behav. 1996, 30: 319-332.
17. Berenbaum S.A.
Cognitive function in congenital adrenal hyper-
plasia.
Endocrinol. Metab. Clin. North Am. 2001, 30: 173-
192.
18. Barnes R.B., Rosenfield R.L., Ehrmann D.A., Cara
J.F., Cuttler L., Levitsky L.L., Rosenthal I.M.
Ovarian hyperandrogynism as a result of congeni-
tal adrenal virilizing disorders: evidence for perina-
tal masculinization of neuroendocrine function in
women.
J. Clin. Endocrinol. Metab. 1994, 79: 1328-1333.
19. Helleday J., Siwers B., Ritzen E.M., Carlstrom K.
Subnormal androgen and elevated progesterone
levels in women treated for congenital virilizing 21-
hydroxylase deficiency.
J. Clin. Endocrinol. Metab. 1993, 76: 933-936.
20. Speiser P.W., Serrat J., New M.I., Gertner J.M.
Insulin insensitivity in adrenal hyperplasia due to
nonclassical steroid 21-hydroxylase deficiency.
J. Clin. Endocrinol. Metab. 1992, 75: 1421-1424.
21. Mather K.J., Kwan F., Corenblum B.
Hyperinsulinemia in polycystic ovary syndrome corre-
lates with increased cardiovascular risk independent
of obesity.
Fertil. Steril. 2000, 73: 150-156.
22. Ibanez L., Potau N., Chacon P., Pascual C.,
Carrascosa A.
Hyperinsulinaemia, dyslipaemia and cardiovascular
risk in girls with a history of premature pubarche.
Diabetologia 1998, 41: 1057-1063.

23. Bonaccorsi A.C., Adler I., Figueiredo J.G.
Male infertility due to congenital adrenal hyperpla-
sia: testicular biopsy findings, hormonal evaluation,
and therapeutic results in three patients.
Fertil. Steril. 1987, 47: 664-670.
24. Holmes-Walker D.J., Conway G.S., Honour J.W.,
Rumsby G., Jacobs H.S.
Menstrual disturbance and hypersecretion of pro-
gesterone in women with congenital adrenal hy-
perplasia due to 21-hydroxylase deficiency.
Clin. Endocrinol. (Oxf.) 1995, 43: 291-296.
25. Van Wyk J.J., Gunther D.F., Ritzen E.M., Wedell A.,
Cutler G.B. Jr., Migeon C.J., New M.I.
The use of adrenalectomy as a treatment for con-
genital adrenal hyperplasia.
J. Clin. Endocrinol. Metab. 1996, 81: 3180-3190.
26. Imperato-McGinley J., Binienda Z., Gedney J.,
Vaughan E. Jr.
Nipple differentiation in fetal male rats treated with
an inhibitor of the enzyme 5 alpha-reductase: defi-
nition of a selective role for dihydrotestosterone.
Endocrinology 1986, 118: 132-137.
27. Lo J.C., Schwitzgebel V.M., Tyrrell J.B., Fitzgerald
P.A., Kaplan S.L., Conte F.A., Grumbach M.M.
Normal female infants born of mothers with classic
congenital adrenal hyperplasia due to 21-hydroxy-
lase deficiency.
J. Clin. Endocrinol. Metab. 1999, 84: 930-936.
28. Feldman S., Billaud L., Thalabard J.C., Raux-Demay
M.C., Mowszowicz I., Kuttenn F., Mauvais-Jarvis P.
Fertility in women with late-onset adrenal hyperpla-
sia due to 21-hydroxylase deficiency.
J. Clin. Endocrinol. Metab. 1992, 74: 635-639.
29. Urban M.D., Lee P.A., Migeon C.J.
Adult height and fertility in men with congenital vir-
ilizing adrenal hyperplasia.
N. Engl. J. Med. 1978, 299: 1392-1396.
30. Prader A., Zachmann M., Illig R.
Fertility in adult males with congenital adrenal
hyperplasia due to 21-hydroxylase deficiency.
Acta Endocrinol. 1973, 177 (Suppl.): 57.
31. Willi U., Atares M., Prader A., Zachmann M.
Testicular adrenal-like tissue (TALT) in congenital
adrenal hyperplasia: detection by ultrasonography.
Pediatr. Radiol. 1991, 21: 284-287.
32. Avila N.A., Shawker T.S., Jones J.V., Cutler G.B. Jr.,
Merke D.P.
Testicular adrenal rest tissue in congenital adrenal
hyperplasia: serial sonographic and clinical find-
ings.
AJR. Am. J. Roentgenol. 1999, 172: 1235-1238.
33. Vanzulli A., DelMaschio A., Paesano P., Braggion F.,
Livieri C., Angeli E., Tomasi G., Gatti C., Severi F.,
Chiumello G.
Testicular masses in association with adrenogenital
syndrome: US findings.
Radiology 1992, 183: 425-429.
689
CAH: Transition
34. Srikanth M.S., West B.R., Ishitani M., Isaacs H. Jr.,
Applebaum H., Costin G.
Benign testicular tumors in children with congenital
adrenal hyperplasia.
J. Pediatr. Surg. 1992, 27: 639-641.
35. Walker B.R., Skoog S.J., Winslow B.H., Canning
D.A., Tank E.S.
Testis sparing surgery for steroid unresponsive tes-
ticular tumors of the adrenogenital syndrome.
J. Urol. 1997, 157: 1460-1463.
36. Al-Alwan I., Navarro O., Daneman D., Daneman A.
Clinical utility of adrenal ultrasonography in the di-
agnosis of congenital adrenal hyperplasia.
J. Pediatr. 1999, 135: 71-75.
37. Jaresch S., Kornely E., Kley H.K., Schlaghecke R.
Adrenal incidentaloma and patients with homozy-
gous or heterozygous congenital adrenal hyper-
plasia.
J. Clin. Endocrinol. Metab. 1992, 74: 685-689.
38. Ravichandran R., Lafferty F., McGinniss M.J., Taylor H.C.
Congenital adrenal hyperplasia presenting as mas-
sive adrenal incidentalomas in the sixth decade of
life: report of two patients with 21-hydroxylase de-
ficiency.
J. Clin. Endocrinol. Metab. 1996, 81: 1776-1779.
39. Bauman A., Bauman C.G.
Virilizing adrenocortical carcinoma. Development in
a patient with salt- losing congenital adrenal hyper-
plasia.
JAMA 1982, 248: 3140-3141.
40. Lightner E.S., Levine L.S.
The adrenal incidentaloma. A pediatric perspective.
Am. J. Dis. Child. 1993, 147: 1274-1276.
41. Kerrigan J.R., Veldhuis J.D., Leyo S.A., Iranmanesh
A., Rogol A.D.
Estimation of daily cortisol production and clearance
rates in normal pubertal males by deconvolution
analysis.
J. Clin. Endocrinol. Metab. 1993, 76: 1505-1510.
42. Lo J.C., Grumbach M.
Pregnancy outcomes in women with congenital vir-
ilizing adrenal hyperplasia.
Endocrinol. Metab. Clin. North Am. 2001, 30207-229
43. Seckl J.R., Miller W.L.
How safe is long-term prenatal glucocorticoid treat-
ment?
JAMA 1997, 277: 1077-1079.
44. New M.I.
Prenatal treatment of congenital adrenal hyperpla-
sia: The United States experience.
Endocrinol. Metab. Clin. North Am. 2001, 30: 1-13.
45. Bode H.H., Rivkees S.A., Cowley D.M., Pardy K.,
Johnson S.
Home monitoring of 17 hydroxyprogesterone lev-
els in congenital adrenal hyperplasia with filter paper
blood samples.
J. Pediatr. 1999, 134: 185-189.
P.W. Speiser
46. Lamberts S.W., Bruining H.A., de Jong F.H.
Corticosteroid therapy in severe illness.
N. Engl. J. Med. 1997, 337: 1285-1292.
47. Zarkovic M., Ciric J., Stojanovic M., Penezic Z.,
Trbojevic B., Drezgic M., Nesovic M.
Optimizing the diagnostic criteria for standard (250
μg) and low dose (1 μg) adrenocorticotropin tests
in the assessment of adrenal function.
J. Clin. Endocrinol. Metab. 1999, 84: 3170-3173.
48. Speiser P.W., Agdere L., Ueshiba H., White P.C.,
New M.I.
Aldosterone synthesis in salt-wasting congenital
adrenal hyperplasia with complete absence of
adrenal 21-hydroxylase.
N. Engl. J. Med. 1991, 324: 145-149.
49. Rosler A., Levine L.S., Schneider B., Novogroder M.,
New M.I.
The interrelationship of sodium balance, plasma
renin activity and ACTH in congenital adrenal hy-
perplasia.
J. Clin. Endocrinol. Metab. 1977, 45: 500-512.
50. Reiner W.G.
Assignment of sex in neonates with ambiguous gen-
italia.
Curr. Opin. Pediatr. 1999, 11: 363-365.
51. Schnitzer J.J., Donahoe P.K.
Surgical treatment of congenital adrenal hyper-
plasia.
Endocrinol. Metab. Clin. North Am. 2001, 30: 137-
154
52. Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie
K., Patil N., Shaw N., Lane C.R., Lim E.P.,
Kalyanaraman N., Nemesh J., Ziaugra L., Friedland
L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
Lander E.S.
Characterization of single-nucleotide polymorphisms
in coding regions of human genes.
Nat. Genet. 1999, 22: 231-238.
53. White P.C., Vitek A., Dupont B., New M.I.
Characterization of frequent deletions causing ste-
roid 21-hydroxylase deficiency.
Proc. Natl. Acad. Sci. USA 1988, 85: 4436-4440.
54. Higashi Y., Tanae A., Inoue H., Hiromasa T., Fujii-
Kuriyama Y.
Aberrant splicing and missense mutations cause
steroid 21-hydroxylase [P-450(C21)] deficiency in hu-
mans: possible gene conversion products.
Proc. Natl. Acad. Sci. USA 1988, 85: 7486-7490.
55. White P.C., Speiser P.W.
Congenital adrenal hyperplasia due to 21-hydroxy-
lase deficiency.
Endocr. Rev. 2000, 21: 245-291.
56. Amor M., Parker K.L., Globerman H., New M.I.,
White P.C.
Mutation in the CYP21B gene (Ile-172——Asn) caus-
es steroid 21-hydroxylase deficiency.
Proc. Natl. Acad. Sci. USA 1988, 85: 1600-1604.
690
57. Tusie-Luna M.T., Traktman P., White P.C.
Determination of functional effects of mutations in
the steroid 21- hydroxylase gene (CYP21) using re-
combinant vaccinia virus.
J. Biol. Chem. 1990, 265: 20916-20922.
58. Wedell A., Thilen A., Ritzen E.M., Stengler B.,
Luthman H.
Mutational spectrum of the steroid 21-hydroxylase
gene in Sweden: implications for genetic diagnosis
and association with disease manifestation.
J. Clin. Endocrinol. Metab. 1994, 78: 1145-1152.
59. Jaaskelainen J., Levo A., Voutilainen R., Partanen J.
Population-wide evaluation of disease manifestation
in relation to molecular genotype in steroid 21-
hydroxylase (CYP21) deficiency: good correlation in
a well-defined population.
J. Clin. Endocrinol. Metab. 1997, 82: 3293-3297.
60. Speiser P.W., Dupont J., Zhu D., Serrat J.,
Buegeleisen M., Tusie-Luna M.T., Lesser M., New
M.I., White P.C.
Disease expression and molecular genotype in con-
genital adrenal hyperplasia due to 21-hydroxylase
deficiency.
J. Clin. Invest. 1992, 90: 584-595.
61. Carlson A.D., Obeid J.S., Kanellopoulou N., Wilson
R.C., New M.I.
Congenital adrenal hyperplasia: update on prena-
tal diagnosis and treatment.
J. Steroid Biochem. Mol. Biol. 1999, 69: 19-29.
62. Day D.J., Speiser P.W., Schulze E., Bettendorf M.,
Fitness J., Barany F., White P.C.
Identification of non-amplifying CYP21 genes when
using PCR-based diagnosis of 21-hydroxylase defi-
ciency in congenital adrenal hyperplasia (CAH) af-
fected pedigrees.
Hum. Mol. Genet. 1996, 5: 2039-2048.
63. Fitness J., Dixit N., Webster D., Torresani T.,
Pergolizzi R., Speiser P.W., Day D.J.
Genotyping of CYP21, linked chromosome 6p mark-
ers, and a sex-specific gene in neonatal screening
for congenital adrenal hyperplasia.
J. Clin. Endocrinol. Metab. 1999, 84: 960-966.
64. Nordenstrom A., Thilen A., Hagenfeldt L., Larsson
A., Wedell A.
Genotyping is a valuable diagnostic complement to
neonatal screening for congenital adrenal hyper-
plasia due to steroid 21-hydroxylase deficiency.
J. Clin. Endocrinol. Metab. 1999, 84: 1505-1509.
65. Therrell B.L. Jr., Berenbaum S.A., Manter-Kapanke
V., Simmank J., Korman K., Prentice L., Gonzalez J.,
Gunn S.
Results of screening 1.9 million Texas newborns for
21-hydroxylase-deficient congenital adrenal hyper-
plasia.
Pediatrics 1998, 101: 583-590.
66. Tusie Luna M.T., White P.C.
Gene conversions and unequal crossovers between

CYP21 (steroid 21-hydroxylase gene) and CYP21P
involve different mechanisms.
Proc. Natl. Acad. Sci. USA 1995, 92: 10796-10800.
67. Witchel S.F., Lee P.A.
Identification of heterozygotic carriers of 21-hydroxy-
lase deficiency: sensitivity of ACTH stimulation tests.
Am. J. Med. Genet. 1998, 76: 337-342.
68. Lejeune-Lenain C., Cantraine F., Dufrasnes M.,
Prevot F., Wolter R., Franckson J.R.
An improved method for the detection of heterozy-
gosity of congenital virilizing adrenal hyperplasia.
Clin. Endocrinol. (Oxf.) 1980, 12: 525-535.
691
CAH: Transition
69. Knochenhauer E.S., Cortet-Rudelli C., Cunnigham
R.D., Conway-Myers B.A., Dewailly D., Azziz R.
Carriers of 21-hydroxylase deficiency are not at in-
creased risk for hyperandrogenism.
J. Clin. Endocrinol. Metab. 1997, 82: 479-485.
70. Pang S.Y., Wallace M.A., Hofman L., Thuline H.C.,
Dorche C., Lyon I.C., Dobbins R.H., Kling S., Fujieda
K., Suwa S.
Worldwide experience in newborn screening for
classical congenital adrenal hyperplasia due to 21-
hydroxylase deficiency.
Pediatrics 1988, 81: 866-874.