Congenital adrenal hyperplasia is due to 21-hydroxylase deficiency in > 90% of cases. This is a very common genetic disorder for which biochemical screening is now performed. The classical form occurs in 1:15,000–16,000 live births, while the nonclassical form occurs in 1:1000. Congenital adrenal hyperplasia is the most common cause of primary adrenal insufficiency in childhood. Undertreatment of the condition leads to acute risk of adrenal crisis and to long-term risk of short adult stature and infertility, whereas overtreatment is associated with short stature, obesity and other effects of hypercortisolism, including, but not limited to, osteoporosis.

1. Diagnosis and Management of Congenital Adrenal Hyperplasia in
the Child and Adolescent

2. Apollo Medicine 2011 December
Review Article
Volume 8, Number 4; pp. 261–265
© 2011, Indraprastha Medical Corporation Ltd
Diagnosis and management of congenital adrenal hyperplasia in
the child and adolescent
IPS Kochar*, Radhika Jindal**
*Senior Consultant, Paediatric and Adolescent Endocrinologist, Department of Paediatric and Adolescent Endocrinology,
**DNB Trainee, Department of Endocrinologist, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.
ABSTRACT
Congenital adrenal hyperplasia is due to 21-hydroxylase deficiency in >90% of cases. This is a very common
genetic disorder for which biochemical screening is now performed. The classical form occurs in 1:15,000–16,000
live births, while the nonclassical form occurs in 1:1000. Congenital adrenal hyperplasia is the most common cause
of primary adrenal insufficiency in childhood. Undertreatment of the condition leads to acute risk of adrenal crisis
and to long-term risk of short adult stature and infertility, whereas overtreatment is associated with short stature,
obesity and other effects of hypercortisolism, including, but not limited to, osteoporosis.
Keywords: Congenital adrenal hyperplasia (CAH), cortisol, nonclassical adrenal hyperplasia (NCAH)
Correspondence: Dr. IPS Kochar, E-mail: inderpal_kochar@yahoo.com
doi: 10.1016/S0976-0016(11)60002-1
INTRODUCTION
The clinical phenotype of congenital adrenal hyperplasia
(CAH) depends on the nature and severity of the enzyme
deficiency. The most common form is 21-hydroxylase
deficiency (CYP21). About 50% of patients with classic
CAH due to CYP21A mutations or deletions have salt wast-
ing (SW) due to inadequate aldosterone synthesis; the sex
of a neonate with CAH is often initially unclear because of
genital ambiguity.
Fetus Pathophysiology
Cortisol deficiency triggers a compensatory rise in cortico-
tropin (adrenocorticotropic hormone, ACTH) (first pro-
duced at 7 week) through negative feedback from reduced
cortisol (8–12 weeks). This results in the build-up of inter-
mediates (including 17-hydroxyprogesterone [17-OHP]),
leading to overproduction of androgens and virilization of
the external genitalia in females. The affected males have
normally formed external genitalia, as excess fetal androgen
production pales compared with normal testicular androgen
production.
Steroidogenic Pathway for Cortisol,
Aldosterone, and Sex Steroid Synthesis
Glucocorticoid physiology during pregnancy:
• Despite the lipophilic nature of glucocorticoids and, there-
fore, their ability to cross-placenta quite readily, the cir-
culating levels of cortisol are normally markedly higher
in mother than in fetus. This is because the placental
11-hydroxyepiandrosterone-2 (11-HSD-2) forms a func-
tional barrier restricting the free transfer of cortisol between
the maternal and fetal compartments by converting cortisol
into its much less active 11-keto form, cortisone. In con-
trast, synthetic corticosteroids, such as dexamethasone,
are poor substrates for 11B-HSD-2 and, therefore, readily
cross placenta and can be used for fetal therapy in CAH.
Prenatal diagnosis (after prior affected child) after confir-
mation of pregnancy is required, and maternal treatment
with dexamethasone (20μg/Kg in two or three divided
doses) is effective if started by 9 weeks after mother’s last
menstrual period. Confirmation or elimination of diag-
nosis by chorionic villus sampling at 9–11 weeks or by
amniocentesis at 15–18 weeks is required.
• Only 1 of 8 fetuses (affected females) will need to con-
tinue the treatment to the end of pregnancy.

3. 262 Apollo Medicine 2011 December; Vol. 8, No. 4 Kochar and Jindal
© 2011, Indraprastha Medical Corporation Ltd
No adverse effects to fetus reported (although there are
some theoretical concerns). Mothers are at risk for edema,
stretch marks, and weight gain, but no diabetes or hypertension.
Treatment should only be undertaken after full discussion.
NEWBORN
Diagnosis
• Ambiguous genitalia: What caused the ambiguity?
• Immediate prognosis: What can go wrong? What do I tell
the family?
• Sex assignment: What is the appropriate sex of rearing
and what name should be used?
• Long-term prognosis: What does the future hold?
Definitions
• Hyperplasia: Increased growth and/or function of cells,
tissues or entire glands.
• Classical adrenal hyperplasia: CAH (synonymous with con-
genital adrenal hyperplasia, CAH, and more severe form).
• Simple virilizing (SV): 25%.
• Salt wasting (SW): 75%.
• Nonclassical adrenal hyperplasia: NCAH (synonymous
with late-onset and acquired adrenal hyperplasia and less
severe form), possibly the most common human autosomal-
recessive genetic disorder.
Newborn Screening Indications
The condition should be an important health problem.
Severe SW form affects 75% of patients. If females with
CAH are all identified at birth by genital ambiguity, then
the estimated prevalence of males with salt loss is 1:40,000
and could avoid incorrect gender assignment in females.
The condition is not otherwise recognizable at birth
(in males) and could cause early death: Urinary sodium loss
and reciprocal rise in serum potassium level develop gradu-
ally and clinical adrenal insufficiency usually becomes
manifest between 10 and 20 days of age. Nonsalt-losing
males present at several years of age with precocious
Cholesterol
StAR/20,22 demolase
Pregnenolone 17-OHP Dehydroepiandrosterone Androstenediol
3-β hydroxysteroid dehydrogenase
Progesterone
Deoxycorticosterone
CYP21A/21 hydroxylase
CYP11B2/Aldosterone synthetase
CYP17/17-a hydroxylase/
17,20 desmolase
CYP11B1/11-β hydroxylase
Corticosterone
Aldosterone
11-deoxycortisol Estrone Estradiol
Cortisol
17-ketosteroid reductase
17-OHP Androstenedione Testosterone
Aromatase
Figure 1 Steroid biosynthetic pathway.

4. Diagnosis and management of CAH in the child and adolescent Review Article 263
© 2011, Indraprastha Medical Corporation Ltd
puberty. A reliable screening test/protocol is available:
17-OHP. An effective therapy that prevents serious out-
comes must be available: Glucocorticoid and mineralocor-
ticoid replacement. The cost of case-finding (including the
diagnosis and treatment of patients) should be economically
balanced in relation to the possible expenditure on medical
care as a whole: Although the comparison of screened to
nonscreened populations failed to show higher rate of diag-
nosis of SW in screened cohort, screening in male infants is
associated with significantly earlier diagnosis, reduced
morbidity and shorter lengths of hospitalization.
Newborn Screening Methods
Filter paper 17-OHP measured in Auto Delfia Assay. First-tier
17-OHP measurement fraught with frequent false-positives
is an unnecessary worry by families 0.5% (1:200 unaffected
newborns require follow-up for every true case of CAH.
Few cases of NCAH are detected because of the relatively
low baseline levels of 17-OHP and, conversely, it is not known
what proportion of cases of NCAH diagnosed by new born
screening (NBS) eventually become symptomatic and hence
need treatment.
Limitations of 17-OHP level in diagnosing CAH: False-
positives, sick term newborn (17-OHP may reach 3300ng/dL),
prematurity/birth weight (secondary to delayed expression
of l l-hydroxylase), early sampling age, poor kidney func-
tion, stress, cross-reactivity of antibodies against 17-OHP
used in radioimmunoassays with other steroids, most nota-
bly 17-OH pregnenolone, secondary to reduced activity of
3-HSD that is seen in newborns. Limitations also include
false-negatives secondary to the maternal treatment with
betamethasone or dexamethasone.
CHILDHOOD
Variable Presentations of Adrenal
Hyperplasia
• Females birth: Male-looking genitals (the fusion of labio-
scrotal folds and the enlargement of clitoris) without
(SV) or with salt loss (CAH).
– Childhood: Early development of pubic hair with or
without signs of virilization, including rapid linear
growth (no salt loss, NCAH).
– Adolescence and adulthood: Increased hair growth
(60%), absence or loss of menstrual periods (54%),
acne (33%) (no salt loss, NCAH).
– Any age: No symptoms (NCAH).
• Males birth: Not easily diagnosed (CAH or NCAH), already
have high levels of testicular testosterone (?large phallus).
– Infancy: Signs of salt loss (75%) at 10–20 days of life
(CAH).
– Childhood: Early development of pubic hair without or
with signs of virilization, including rapid linear growth
and advanced bone age (no salt loss, CAH or NCAH).
– Adolescence: Not a common time of presentation
(NCAH).
– Any age: No symptoms (NCAH).
Behavioral Issues
Gonadal hormones, particularly androgens, direct certain
aspects of brain development and exert permanent influ-
ences on sex, a typical behavior in nonhuman mammals.
Androgens also influence human behavioral development
with most convincing evidence coming from the studies of
sex-typical play.
Girls with CAH exposed to unusually high levels of
prenatal androgens that show increased preferences for
toys and activities usually preferred by boys and for male
playmates, and decreased preferences for toys and activities
usually preferred by girls. These findings suggest that andro-
gens during the early development influence the childhood-
play behavior in humans at least in part by altering brain
development.
DiagnosticTests for Congenital Adrenal
Hyperplasia
Blood: 17-OHP (stat in infancy) before (sufficient if sig-
nificantly elevated) and after 250ILg of synthetic ACTH
1–24 (cortrosyn=cosyntropin). Testosterone, electrolytes,
renin and occasionally other cortisol precursors (e.g., spe-
cific compound S=l L-desoxycortisol)+karyotype/FISH for
sex chromosome determination+gene testing. Radiology:
Pelvic ultrasound, genitogram and, possibly, pelvic MRI
(females). Early-morning 17-OHP in symptomatic individ-
uals beyond newborn period.
Adrenocorticotropic Hormone-stimulated
17-hydroxyprogesterone (ng/dL) Levels
Salt wasting classical adrenal hyperplasia up to 100,000;
SVCAH 10,000–30,000; NCAH 1500–10,000.
Genetics of 21-hydroxylase Deficiency
21-hydroxylase gene is located at 6p21.3 within human
leukocyte antigens (HLA) histocompatibility complex. Two
highly homologous 21-hydroxylase genes exist, of which
CYP2IA2 codes for active 21-hydroxylase and CYP21AIP
is inactive pseudogene. More than 90% of mutations of
active CYP21A2 gene are generated by recombinations
between active and inactive genes (most are compound

5. 264 Apollo Medicine 2011 December; Vol. 8, No. 4 Kochar and Jindal
© 2011, Indraprastha Medical Corporation Ltd
heterozygotes involving two or more single point mutations,
intronic changes and complete deletions or conversions).
• ‘Routine’ genetic testing only when biochemical testing
is equivocal depending on the residual activity of the
mutation. There is good correlation between the geno-
type and the phenotype regarding salt loss CYP21A2
gene in adrenal hyperplasia.
elevated renin suggesting subclinical salt loss). Sodium
chloride (?ALL): 4mEq/Kg/day or 1–2g/day in divided
doses (1st year).
Adrenal Crisis in Congenital Adrenal Hyperplasia:
Treatment
Dehydration/hyponatremia: Intravenous (i.v.) fluids (saline).
Hyperkalemia: Usually responds to hydrocortisone replace-
ment, but may require specific emergency measures. Hypo-
glycemia: Intravenous glucose. Cortisol and aldosterone
replacement: High-dose (∼5–10×) i.v. hydrocortisone in four
divided doses or as a continuous infusion (these high doses
also provide significant aldosterone effect. In adrenally insuf-
ficient individuals experiencing a physiological stressor,
deficient medullary catecholamine production and respon-
siveness without which patients with CAH have additional risk
factor for collapse during stress and responsiveness. Proper
in utero glucocorticoid secretion by adrenal cortex is necessary
for adrenomedullary organogenesis and epinephrine synthe-
sis. Cortisol is a co-factor for phenylethanolamine N-methyl
transferase (PNMT) enzyme activity necessary for the med-
ullary conversion of norepinephrine to epinephrine (rate-
limiting step in catecholamine synthesis). Nonclassical adrenal
hyperplasia: Whom to treat with glucocorticoids? Children:
Bone age significantly advanced, growth rate accelerated
for age, rapidly progressing signs of puberty. Girls/women:
Hirsutism or severe acne, oligomenorrhea, polycystic ovarian
syndrome (may require specific therapy). Infertility (men
or women), stress coverage (??), when to stop treatment
(??), onset of puberty, growth complete, no symptoms, no
fertility problems. Female surgical issues: Decision should
be made by parents and requires an experienced surgeon
who heads a designated surgical team that performs at least
3 or 4 cases per year. Goals of surgery: Genital appearance
compatible with gender, unobstructed urinary emptying
without incontinence or infections, good adult sexual and
reproductive function. If high proximal junction between
vagina and urethra: Best time is 3–6 months of age (techni-
cally easier than at later times) and because female patients
are able to undergo more natural psychological and sexual
development when they have normal appearing vagina.
More severely virilized females have high vagina entering
into the masculine-appearing urethra at area of a false veru-
montanum proximal to the external urethral sphincter for
which techniques such as total urogenital sinus mobilization
is employed. If junction is low between the vagina and ure-
thra, i.e., near perineum, surgery may not be necessary.
Anatomical studies required to make best decision.
Clitoroplasty may not be necessary. If clitoroplasty is per-
formed, must preserve neurovascular bundle, glans and
preputial skin related to the glans. If surgery is done early,
should be a one-stage repair using the newest techniques of
Type Genotype Enzyme activity
SWCAH deletions or None None
nonsense mutations
SVCAH missense Ilel72Asn (Iq72N) 1–2%
mutations
NCAH missense Val281Leu (V281L), 20–60%
mutations Pro30Leu (P30L)
SWCAH: salt wasting classical adrenal hyperplasia; SVCAH: simple virilizing
classical adrenal hyperplasia; NCAH: nonclassical adrenal hyperplasia.
Monitoring in Congenital Adrenal Hyperplasia
Patients (q6 mo)
Height and weight changes; clinical, e.g., regular menstrua-
tion, lack of virilization. Blood tests: AM through 17-OHP,
testosterone and rostenedione, renin+ACTH. Bone age.
Urine tests generally not used. Effects of control: Day-to-day
treatment of CAH (Table 1).
Oral Hydrocortisone (ALL)
At 10–20mg/m2
/day in divided doses (usually 1/4 in AM,
1/4 in afternoon and 1/2 at bedtime) with more at night to
suppress normal overnight rise in ACTH. Higher doses
required at diagnosis. In homogeneous suspensions to be
avoided (tablets only). Higher doses required at puberty
secondary to increased physiological clearance. Stress-
dosing: Oral doses must be increased 2- to 3-fold during
intercurrent illness and/or a parenteral form administered in
CAH (although not necessarily in NCAH). Longer-acting
synthetic forms, e.g., dexamethasone, can be used in the
late adolescence and adulthood. Medical identification
indicating adrenal insufficiency (?ALL), oral mineralocor-
ticoid (?ALL): Fludrocortisone usually at 0.1mg/day (even
for those without obvious salt loss, but perhaps with mildly
Table 1 Effects of control on monitoring parameters.
Parameter Undercontrolled Overcontrolled
Height velocity Too fast Too slow
Weight velocity Normal Too fast
17-OHP, testosterone, High Low
renin
Bone age Too fast Too slow
Adult height Short Variable
OHP: hydroxyprogesterone.

6. Diagnosis and management of CAH in the child and adolescent Review Article 265
© 2011, Indraprastha Medical Corporation Ltd
(flap) vaginoplasty (vaginal exteriorization), clitoral and
labial surgery. Revision vaginoplasty often required at ado-
lescence, surgery between 12 months of age and adoles-
cence not recommended in the absence of complications
causing medical problems, vaginal dilation before adoles-
cence contraindicated, minimize genital examinations and
photographs to only those absolutely necessary. Pros and
cons of adrenalectomy as treatment for CAH (for patients
who fail medical therapy). Pros: To help recalcitrant infer-
tility, to control unsuppressible hyperandrogenism and
worsening glucocorticoid-induced obesity, relatively safe
procedure via laparoscopic surgery. Cons: Increases the
risk of life-threatening Addisonian crises with complete
loss of both adrenal cortex and medulla, problematic hyper-
pigmentation, stimulation of testicular (and ovarian) rest
tissue and may induce pituitary hyperplasia! Tumor.
Adolescent and Adult: Puberty
Onset in both sexes usually occurs at an expected age if
treated satisfactorily from early life. However, the true pre-
cocious puberty may occur in well-treated children. True
precocious puberty may occur after the initiation of gluco-
corticoid therapy secondary to a sudden decrease in sex
steroids, which causes hypothalamic activation. In most
untreated or poorly treated adolescent girls and in some
adolescent boys, spontaneous true pubertal development
does not occur until proper treatment is initiated. This is
thought to result from excess adrenal male hormones
(which are converted to female hormones) suppressing
hypothalamic/pituitary hormones (gonadotropins) that reg-
ulate puberty. Many patients with treated AH have regular
menses after menarche. Menarche may not occur if treat-
ment is withheld or can be delayed with overtreatment.
However, menstrual irregularity and secondary amenorrhea
are not uncommon in teenage girls with CAH and are
thought to result from poorly controlled disease and can be
corrected by suppressing excess adrenal male hormones
with long-acting and potent glucocorticoids.
Long-term Issues
Height and weight: Some degree of adult short stature is
common (height average −1 to −2 SD below normal popu-
lation=2nd to 16th percentiles). Growth delay may occur
with CAH or NCAH. Effects on the height are related to
medication noncompliance, chronic high doses of gluco-
corticoids, and late diagnosis and advanced bone age at
time. With increasing age, there is a tendency toward obes-
ity, which may be due to the dosing of glucocorticoids that
does not mimic the normal daily pattern of cortisol secretion,
because of the suppression of growth hormone that results in
increased body fat, or both, and may be worse when long-
acting glucocorticoids, e.g., dexamethasone, are used.
Metabolic: Adult obesity, reduced insulin sensitivity,
increased intimal medial thickness and reduced bone min-
eral density.
Reproductive function in females: Symptoms of poly-
cystic ovarian syndrome (PCOS), including the lack of
ovulation and absent or irregular periods, may develop dur-
ing adolescence, 80% of women with SV and 60% of those
with severe salt-losing are fertile. The rate of successful
pregnancies has increased with improvements in surgical,
medical and psychological therapies. Deliveries are usually
by cesarean section. Potential causes of infertility, overpro-
duction of progesterone (decreased rate of ovulation through
suppression of pituitary LH/FSH, ‘mini-pill’), hyperandro-
genism affecting uterine lining, hypoandrogenism affecting
libido, increased insulin 2 to obesity (PCOS), psychological
factors affecting the rate of sexual activity or the ability to
reach orgasm, anatomical differences, e.g., narrow vagina
preventing normal insemination.
Reproductive Function in Males
Compared with affected women, men with CAH have fewer
problems with reproductive function. Most men have normal
sperm counts and are able to father children.A common prob-
lem is the development of benign testicular tumors (‘rests’
of adrenal tissue). These ‘rests’ of adrenal tissue can nearly
replace all the normal tissues, and decreased sperm produc-
tion has been reported in boys as young as 3 years of age.
Boys with CAH require careful testicular examinations
and sonographical screening beginning in adolescence;
occur most often in under-treated SWs, are ACTH-sensitive
and will usually shrink in response to pituitary suppression
with dexamethasone (usually precluding the need for biopsy
and/or surgery).
REFERENCES
1. Speiser PW, Azziz R, Baskin LS, et al. Endocrine society.
Congenital adrenal hyperplasia due to steroid 21-hydroxylase
deficiency: an Endocrine Society clinical practice guideline.
J Clin Endocrinol Metab 2010;95:4133–60.
2. Auchus, Feldman Witchel S, Leight KR, et al. Guidelines for the
development of comprehensive care centers for congenital adre-
nal hyperplasia: guidance from the CARES Foundation Initi-
ative. Int J Pediatr Endocrinol 2010; doi: 10.1155/2010/275213.
3. Kwon C, Farrell PM. The magnitude and challenge of false-
positive newborn screening test results. Arch Pediatr Adolesc
Med 2000;154:714–8.
4. Pasterski V, Hindmarsh P, Geffner M, et al. Increased aggres-
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