CONGENITAL ADRENAL HYPERPLASIA

(Adrenogenital syndrome; CAH )

DR.P.N 1
 Introduction
1. Autosomal recessive disorders
2. Deficiency of one of the enzymes required for cortisol
synthesis in the adrenal cortex.
3. Cortisol deficiency → secretion of corticotrophin (ACTH) →
adrenocortical hyperplasia → overproduction of intermediate
metabolites
4. In some, it also involves overproduction of adrenal androgens,
which, in affected females, results in an ambiguous /male
external genitalia at birth.
5. In most cases, adrenal hyperplasia also involves a deficiency in
aldosterone, which results in mild to severe loss of body
sodium.
DR.P.N 2
DR.P.N 3
 Types
1. 21-hydroxylase deficiency accounts for the
vast majority of cases (90%),
2. 11-hydroxylase deficiency (5%),
3. Cholesterol desmolase deficiency
4. 17-hydroxylase deficiency
5. 3-hydroxysteroid dehydrogenase deficiency

DR.P.N 4
 21- OH DEFICIENCY

1. More than 90% of CAH cases are caused by 21-

hydroxylase deficiency. This P450 enzyme hydroxylates
as follows:
a. progesterone →11-deoxycorticosterone→
aldosterone
b. 17-hydroxyprogesterone →11-deoxycortisol→
cortisol
2. More than 90% of mutations causing 21-hydroxylase
deficiencies are recombination between CYP21 and
CYP21P.
3. Incidence: Classic 21-hydroxylase deficiency occurs in
approximately 1 in 15,000 - 20,000 births
DR.P.N 5
4. Accumulation of 17-hydroxyprogesterone leads to
high levels of androstenedione that are converted
outside the adrenal gland to testosterone.
5. This problem begins in 8-10 wk of gestation and leads
to abnormal genital development in females
6. 21-hydroxylase deficiency can be divided into classic
deficiency with and without salt wasting (cortisol and
aldosterone deficiencies) and non-classic type.
7. Non-Classic- will often present later on in childhood
with signs and symptoms of androgen excess.
DR.P.N 6
 CLASSIC 21-HYDROXYLASE DEFICIENCY
1. Virilizing syndrome:
a. Affected females are virilized in utero and present at
birth with cliteromegaly, labial fusion, and normal
internal organs.
b. This is the most common cause of ambiguous genitalia in
females.
2. Salt losing
a. > 75% of 21-OH deficiency have salt losing because there
is inadequate production of aldosterone.
b. These neonates will fail to gain weight, vomit, have
hyponatremia and hyperkalemia, hypoglycemia and be
acidotic. They may appear septic.
DR.P.N 7
 Clinical features
Affected female infant
1. Enlargement of the clitoris and by partial or complete labial
fusion.
2. The vagina usually has a common opening with the urethra
(urogenital sinus).
3. Some affected females may be mistakenly presumed to be males
with hypospadias and cryptorchidism.
4. The severity of virilization is usually greatest in females with the
salt-losing form of 21-hydroxylase deficiencies.
5. The internal genital organs are normal, because affected females
have normal ovaries and not testes and thus do not secrete
antimüllerian hormone.
DR.P.N 8
 Behavior problems:
1. Prenatal exposure of the brain to high levels of androgens →
sexually dimorphic behaviors in affected females.
2. Girls may demonstrate aggressive play behavior, tend to be
interested in masculine toys such as cars and trucks, and often
show decreased interest in playing with dolls.
3. Women may have decreased interest in maternal roles.
4. There is an increased frequency of homosexuality in affected
females.
5. Nonetheless, most function heterosexually and do not have
gender identity confusion or dysphoria.
6. It is unusual for affected females to assign themselves a male
role except in some with the severest degree of virilization.
DR.P.N 9
 Untreated female children

1. The clitoris may become further enlarged in

affected females.
2. Although the internal genital structures are female,
breast development and menstruation may not
occur unless the excessive production of androgens
is suppressed by adequate treatment.

DR.P.N 10
 Male infant
1. Male infants appear normal at birth.
2. Thus, the diagnosis may not be made in boys until signs
of adrenal insufficiency develop.
3. Because patients with this condition can deteriorate
quickly, infant boys are more likely to die than infant
girls.
4. For this reason, many countries have instituted
newborn screening for this condition.

DR.P.N 11
 Untreated male children
1. Child may have rapid somatic growth and accelerated skeletal
maturation.
2. Thus, affected patients are tall in childhood but premature
closure of the epiphyses causes growth to stop relatively early,
and adult stature is stunted.
3. Muscular development may be excessive.
4. Pubic and axillary hair may appear, and acne and a deep voice
may develop.
5. The penis, scrotum, and prostate may become enlarged the
testes appear relatively small in contrast to the enlarged penis.
6. Ectopic adrenocortical cells in the testes may producing testicular
adrenal rest tumors.
DR.P.N 12
Three virilized females with untreated congenital adrenal hyperplasia. All
were erroneously assigned male sex at birth, and each
had a normal female sex-chromosome complement.

DR.P.N 13
A 6-yr-old girl with congenital virilizing adrenal hyperplasia. The
height age was 8.5 yr, and the bone age was 13 yr.

DR.P.N 14
Her 5 yr old brother was not considered to be abnormal by the
parents. The height age was 8 yr, and the bone age was 12.5 yr.

DR.P.N 15
 Non-classic forms
1. Similar but usually milder signs of androgen excess may
occur in non classic 21-hydroxylase deficiency.
2. In this attenuated form, cortisol and aldosterone levels
are normal and affected females have normal genitals at
birth.
3. Males and females may present with precocious
pubarche and early development of pubic and axillary
hair.
4. Hirsutism, acne, menstrual disorders, and infertility may
develop later in life, but many females and males are
completely asymptomatic.
DR.P.N 16
 Adrenomedullary Dysfunction
1. Development of the adrenal medulla requires exposure to
the extremely high cortisol levels normally present within
the adrenal gland.
2. Thus patients with classic CAH have abnormal
adrenomedullary function.
3. They may have blunted epinephrine responses, decreased
blood glucose, and lower heart rates with exercise.
4. But ability to exercise is unimpaired and the clinical
significance of these findings is uncertain.
DR.P.N 17
 LABORATORY FINDINGS
1. Salt-losing disease: hyponatremia, hyperkalemia, metabolic
acidosis, and, often, hypoglycemia; abnormalities can take 10-
14 days or longer to develop after birth.
2. Blood levels of 17-hydroxyprogesterone are markedly
elevated. However, levels of this hormone are high during the
1st 2-3 days of life even in unaffected infants and especially if
they are sick or premature.
3. Blood levels of cortisol are low in patients with the salt-losing
type of disease. They are often normal in patients with simple
virilizing disease but inappropriately low in relation to the
ACTH and 17-hydroxyprogesterone levels.

DR.P.N 18
4. In addition to 17-hydroxyprogesterone, levels of androstenedione
and testosterone are elevated in affected females;
5. Testosterone is not elevated in affected males, because normal
infant males have high testosterone levels compared with those
seen later in childhood.
6. Levels of urinary 17-ketosteroids and pregnanetriol are elevated
but are now rarely used clinically because blood samples are easier
to obtain than 24 hr urine collections.
7. ACTH levels are elevated but have no diagnostic utility over 17-
hydroxyprogesterone levels.
8. Plasma levels of renin are elevated, and serum aldosterone is
inappropriately low for the renin level.
DR.P.N 19
9. Diagnosis of 21-hydroxylase deficiency is most reliably established
by measuring 17-hydroxyprogesterone before and 30 or 60 min
after an intravenous bolus of 0.125-0.25 mg of cosyntropin (ACTH
1-24). Nomograms exist that readily distinguish normals and
patients with nonclassic and classic 21-hydroxylase deficiency.

10. Genotyping is clinically available and may help confirm the

diagnosis, but it is expensive.

11. Prenatal diagnosis of 21-hydroxylase is possible late in the 1st

trimester by analysis of DNA obtained by chorionic villus sampling
or during the 2nd trimester by amniocentesis.

DR.P.N 20
 NEWBORN SCREENING
1. Because 21-hydroxylase deficiency is often undiagnosed in affected
males until they have severe adrenal insufficiency, newborn screening is
mandatory.
2. These programs analyze 17-hydroxyprogesterone levels in dried blood
obtained by heelstick and absorbed on filter paper cards; the same cards
are screened in parallel for other congenital conditions, such as
hypothyroidism and phenylketonuria.
3. The nonclassic form of the disease is not reliably detected by newborn
screening.
4. The main difficulty is that the cutoff 17-hydroxyprogesterone levels for
recalls are set so low that there is a very high frequency of false-positive
results
DR.P.N 21
 TREATMENT
1. Glucocorticoid Replacement
a. Cortisol deficiency is treated with glucocorticoids. 15-20
mg/m2/24 hr of hydrocortisone daily administered orally
in 3 divided doses.
b. Double or triple doses are indicated during periods of
stress, such as infection or surgery.
c. Glucocorticoid treatment must be continued indefinitely
in all patients with classic 21-hydroxylase deficiency but
may not be necessary in patients with nonclassic disease
unless signs of androgen excess are present.
d. Therapy must be individualized.
DR.P.N 22
e. Children with simple virilizing disease true precocious
puberty may be treated with a gonadotropin hormone–
releasing hormone analog such as leuprolide .
f. Males with 21-hydroxylase deficiency who have had
inadequate corticosteroid therapy may develop testicular
adrenal rest tumors, which usually regress with increased
steroid dosage.
g. Testicular MRI, ultrasonography, and color flow Doppler
examination help define the character and extent of
disease

DR.P.N 23
 Monitoring:
1. Growth: crossing to higher height percentiles may suggest
under treatment, whereas loss of height percentiles often
indicates overtreatment with glucocorticoids.
Overtreatment is also suggested by excessive weight gain.
2. Pubertal development should be monitored by periodic
examination
3. Skeletal maturation is evaluated by serial radiographs of
the hand and wrist for bone age.
4. 17-hydroxyprogesterone and androstenedione, should be
measured early in the morning
5. Menarche may be delayed in girls with suboptimal control.
6. .

DR.P.N 24
 Mineralocorticoid Replacement
1. Patients with salt-wasting disease require mineralocorticoid
replacement with fludrocortisone.
1. Infants 0.1-0.3 mg daily in 2 divided doses with
2. sodium supplementation (sodium chloride, 8 mmol /kg) in
addition to the mineralocorticoid.
3. Older infants and children: 0.05-0.1 mg daily of
fludrocortisone
2. Therapy is evaluated by monitoring of vital signs; tachycardia and
hypertension & Serum electrolytes
3. Plasma renin activity is a useful way to determine adequacy of
therapy; it should be maintained in or near the normal range but
not suppressed.
DR.P.N 25
 Surgical Management of Ambiguous Genitals

1. Virilized females usually undergo surgery between 2-6

mo of age.
2. The clitoris is reduced in size, with partial excision of the
corporal bodies and preservation of the neurovascular
bundle;
3. Moderate clitoromegaly may become much less
noticeable even without surgery as the patient grows.
4. Vaginoplasty and correction of the urogenital sinus are
performed at the time of clitoral surgery; revision in
adolescence is often necessary.
DR.P.N 26
5. Female sexual dysfunction increases in severity in
those with the genital virilization
6. Adrenalectomy (with hormone replacement) may be
an alternative to standard medical hormone
replacement therapy, but patients may become more
susceptible to acute adrenal insufficiency.

DR.P.N 27
 Sex assignment
1. Confused gender identity is not common with CAH with
the salt-wasting form with virilization.
2. surgery should be delayed until the patient decides on
sex
3. Severely virilized genotypic (XX) females raised as males
have generally functioned well in the male gender as
adults.

DR.P.N 28
 Prenatal Treatment
1. Mothers with pregnancies at risk are given dexamethasone, a steroid that
readily crosses the placenta, in an amount of 20 μg/kg daily in 2 or 3
divided doses.
2. This suppresses secretion of steroids by the fetal adrenal, including
secretion of adrenal androgens.
3. If started by 6 wk of gestation, it ameliorates virilization of the external
genitalia to determine the sex and genotype of the fetus; therapy is
continued only if the fetus is female.
4. Chorionic villus biopsy is then performed to determine the sex and
genotype of the fetus; therapy is continued only if the fetus is female.
5. Maternal side effects of prenatal treatment have included edema,
excessive weight gain, hypertension, glucose intolerance, cushingoid facial
features, and severe striae.
DR.P.N 29