Congenital adrenal hyperplasia (CAH) is caused by deficiencies in enzymes involved in cortisol production, leading to increased corticotropin levels and adrenal hyperplasia. The most common type (90% of cases) is due to 21-hydroxylase deficiency, causing cortisol and aldosterone deficiency or excess androgen levels. In females this causes virilization of external genitalia. Treatment involves glucocorticoid and mineralocorticoid replacement and surgery to correct ambiguous genitalia in females. Less common types involve 11β-hydroxylase and 17α-hydroxylase deficiencies, also resulting in hypertension and androgen excess.

1. CONGENITAL ADRENAL
HYPERPLASIA
MOHAMMAD NOUR ALSAEED
GROUP : 3
YEAR : 5th

2. • Congenital adrenal hyperplasia (CAH) is a family of
autosomal recessive disorders of cortisol biosynthesis.
• Cortisol deficiency increases secretion of corticotropin
(ACTH), which in turn leads to adrenocortical
hyperplasia and overproduction of intermediate
metabolites.
• Depending on the enzymatic step that is deficient, there
may be signs, symptoms, and laboratory findings of
mineralocorticoid deficiency or excess,
incomplete virilization or premature puberty in affected
males.
and virilization or sexual infantilism in affected females.

3. Congenital Adrenal Hyperplasia due to 21-
Hydroxylase Deficiency
• More than 90% of CAH cases are caused by 21-hydroxylase
deficiency.
P450 enzyme (CYP21, P450c21) hydroxylates progesterone and
17-hydroxyprogesterone (17-OHP) to yield 11-deoxycorticosterone
(DOC) and 11-deoxycortisol, respectively.
• These conversions are required for synthesis of aldosterone and
cortisol, respectively. Both hormones are deficient in the most
severe, “salt wasting” form of the disease.
• Slightly less severely affected patients are able to synthesize
adequate amounts of aldosterone but have elevated levels of
androgens of adrenal origin; this is termed simple virilizing disease.
• These two forms are collectively termed classic 21-hydroxylase
deficiency. Patients with nonclassic disease have relatively mildly
elevated levels of androgens and may have signs of androgen
excess postnatally.

4. • Classic 21-hydroxylase deficiency occurs in
about 1 in 15,000–20,000 births in most
populations.
• Approximately 75% of affected infants have the
salt-losing form, whereas 25% have the simple
virilizing form of the disorder.
• Nonclassic disease has a prevalence of about
1/1,000 in the general population but occurs
more frequently in specific ethnic groups such
as Ashkenazi Jews.

5. Clinical Manifestations
• ALDOSTERONE AND CORTISOL DEFICIENCY.
progressive weight loss,
anorexia,
vomiting,
dehydration,
weakness,
hypotension,
hypoglycemia,
hyponatremia and
hyperkalemia.
These problems typically first develop in affected infants at
approximately 2 wk of age. Without treatment, shock, cardiac
arrhythmias, and death may occur within days or weeks.

6. • PRENATAL ANDROGEN EXCESS.
• The most important problem caused by
accumulation of steroid precursors is that 17-
hydroxyprogesterone is shunted into the
pathway for androgen biosynthesis, leading to
high levels of androstenedione that are
converted outside the adrenal gland to
testosterone.
• This problem begins in affected fetuses by 8–10
wk of gestation and leads to abnormal genital
development in females

7. • The external genitalia of males and females normally appear
identical early in gestation. In normal females, the genital
tubercle becomes the clitoris; the urethral folds develop into
the labia minora, and the labioscrotal swellings become the
labia majora.
• In males, development of the external genitalia is normally
controlled by testosterone secreted by the fetal testes. The
genital tubercle enlarges to become the glans of the penis; the
urethral folds fuse to form the shaft of the penis and penile
urethra, and the labioscrotal swellings fuse to form the
scrotum.
• Testosterone also controls the development of the wolffian
ducts into male internal genital structures such as the
prostate, spermatic ducts, and epididymis, but higher levels of
testosterone are required than for development of the male
external genitalia.
• In contrast, testosterone has no effect on development of
female internal reproductive structures (cervix, uterus, and
fallopian tubes) from müllerian ducts. In male fetuses, these
structures involute under the influence of anti-müllerian
hormone (müllerian inhibitory factor) secreted by the testes.

8. • Thus, affected females, who are exposed in utero to high levels of
androgens of adrenal origin, have masculinized external genitalia.
• This is manifested by enlargement of the clitoris and by partial or
complete labial fusion. The vagina usually has a common opening
with the urethra (urogenital sinus).
• The clitoris may be so enlarged that it resembles a penis and,
because the urethra opens below this organ, some affected females
may be mistakenly presumed to be males with hypospadias and
cryptorchidism.
• The severity of virilization is greatest in females with the salt-losing
form of 21-hydroxylase deficiency. The internal genital organs are
normal, because affected females have normal ovaries and not
testes and thus do not secrete anti- müllerian hormone.

9. • Prenatal exposure of the brain to high levels of
androgens may influence subsequent sexually dimorphic
behaviors in affected females. Girls tend to be interested
in masculine toys such as cars and trucks and often
show decreased interest in playing with dolls. Women
may have decreased interest in maternal roles. There is
an increased frequency of homosexuality in affected
females, but most function heterosexually. It is unusual
for affected females to assign themselves a male role.
• Male infants appear normal at birth. Thus, the diagnosis
may not be made in boys until signs of adrenal
insufficiency develop. Because patients with this
condition can deteriorate quickly, infant boys are much
more likely to die than girls. For this reason, many states
and countries have instituted newborn screening for this
condition.

10. • POSTNATAL ANDROGEN EXCESS.
• Signs of androgen excess include rapid somatic growth and
accelerated skeletal maturation. Thus, affected patients are tall
in childhood but premature closure of the epiphyses causes
growth to stop relatively early, and adult stature is stunted .
Muscular development may be excessive.
• Pubic andaxillary hair may appear; and acne and a deep voice
may develop. The penis, scrotum, and prostate may become
enlarged in affected boys; however, the testes are usually
prepubertal in size so that they appear relatively small in
contrast to the enlarged penis.
• Occasionally, ectopic adrenocortical cells in the testes of
patients become hyperplastic similar to the adrenal glands,
producing testicular adrenal rest tumors.
• The clitoris may become further enlarged in affected females.
Although the internal genital structures are female, breast
development and menstruation do not occur unless the
excessive production of androgens is suppressed by adequate
treatment.

11. • Similar but milder signs of androgen excess may
occur in nonclassic 21-hydroxylase deficiency. In
this attenuated form, cortisol and aldosterone
levels are normal and affected females have
normal genitalia at birth. Males and females may
present with precocious pubarche and early
development of pubic and axillary hair.
Hirsutism, acne, menstrual disorders, and
infertility may develop later in life. However,
many females and males are completely
asymptomatic.

12. Laboratory Findings
• Patients with salt-losing disease have typical laboratory findings
associated with cortisol and aldosterone deficiency, including
hyponatremia, hyperkalemia, acidosis, and often hypoglycemia.
• Blood levels of 17-hydroxyprogesterone are markedly elevated.
After infancy, once the circadian rhythm of cortisol is established,
17-hydroxyprogesterone levels vary in the same circadian pattern,
being highest in the morning and lowest at night.
• Blood levels of cortisol are usually low in patients with the salt-
losing type of disease. They are often normal in those with the
simple virilizing type but inappropriately low in relation to the ACTH
and 17-hydroxyprogesterone levels. In addition to 17-
hydroxyprogesterone, levels of androstenedione and testosterone
are elevated in affected females; testosterone is not elevated in
affected males because normal infant males have high testosterone
levels compared with those seen later in childhood. 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. Corticotropin (ACTH) levels are elevated but
have no diagnostic utility over 17-hydroxyprogesterone levels.
Plasma levels of renin are elevated, and serum aldosterone is
inappropriately low for the renin level. However, renin levels are
normally high in the first few days of life.

13. Prenatal Diagnosis and treatment
• Prenatal diagnosis of 21-hydroxylase is possible late in the first
trimester by analysis of DNA obtained by chorionic villus sampling
or during the second trimester by amniocentesis. This is usually
done because the parents already have an affected child.
• Besides genetic counseling, the main goal of prenatal diagnosis is
to facilitate appropriate prenatal treatment of affected females.
• Recommendations for pregnancies at risk consist of administration
of dexamethasone, a steroid that readily crosses the placenta, in an
amount of 20?µg/kg prepregnancy maternal weight daily in two or
three divided doses.
• This suppresses secretion of steroids by the fetal adrenal, including
secretion of adrenal androgens.
• If started by 6 wk of gestation, this ameliorates the virilization of the
external genitalia in affected females

14. • Chorionic villus biopsy is then performed to determine
the sex and genotype of the fetus; therapy is continued
only if the fetus is an affected female.
• Maternal side effects of prenatal
treatment have included edema,
excessive weight gain, hypertension,
glucose intolerance, cushingoid facial
features, and severe striae.

15. Newborn Screening
• These programs analyze 17-hydroxyprogesterone levels
in dried blood obtained by heel-stick and absorbed on
filter paper cards; the same cards are screened in
parallel for other congenital conditions such as
hypothyroidism and phenylketonuria.
• Potentially affected infants are typically recalled for
additional testing (e.g., electrolytes and repeat 17-
hydroxyprogesterone determination) at approximately 2
wk of age.
• Infants with salt-wasting disease often have abnormal
electrolytes by this age but are usually not severely ill.
• Thus, screening programs seem to be effective in
preventing many cases of adrenal crisis in affected
males.

16. Treatment
• GLUCOCORTICOID REPLACEMENT.
• Cortisol deficiency is treated with
glucocorticoids. Treatment also suppresses
excessive production of androgens by the
adrenal cortex and thus minimizes problems
such as excessive growth and skeletal
maturation and virilization.
• This requires larger glucocorticoid doses
typically 10–20mg/m2 /24hr of hydrocortisone
daily administered orally in three divided doses.
• Double or triple doses are indicated during
periods of stress, such as infection or surgery.

17. • MINERALOCORTICOID REPLACEMENT.
• Patients with salt-wasting disease (i.e., aldosterone deficiency)
require mineralocorticoid replacement with fludrocortisone.
• Infants have very high mineralocorticoid requirements in the first few
months of life, usually 0.1–0.3mg daily in two divided doses but
occasionally up to 0.4mg daily, and often require sodium
supplementation in addition to the mineralocorticoid.
• Older infants and children are usually maintained with 0.05–0.1mg
daily of fludrocortisone.
• In some patients, simple virilizing disease may be easier to control
with a low dose of fludrocortisone in addition to hydrocortisone even
when these patients have normal aldosterone levels in the absence
of mineralocorticoid replacement.

18. • SURGICAL MANAGEMENT OF AMBIGUOUS
GENITALIA.
• Significantly virilized females usually undergo
surgery between 4–12 mo of age.
• If there is marked clitoromegaly, the clitoris is
reduced in size, with partial excision of the
corporal bodies and preservation of the
neurovascular bundle.
• Vaginoplasty and correction of the urogenital
sinus usually are performed at the time of clitoral
surgery; revision in adolescence is often
necessary.

19. Congenital Adrenal Hyperplasia due to 11ß-
Hydroxylase Deficiency
• Etiology.
• CYP11B1 mediates 11-hydroxylation of 11-
deoxycortisol to cortisol.
• 11-deoxycortisol is not converted to cortisol, levels of
corticotropin are high.
• In consequence, precursors—particularly 11-
deoxycortisol and deoxycorticosterone—accumulate and
are shunted into androgen biosynthesis in the same
manner as occurs in 21-hydroxylase deficiency.
• incidence has been estimated as 1/250,000 to
1/100,000

20. • Clinical Manifestations.
• Although cortisol is not synthesized efficiently, aldosterone synthetic
capacity is normal, and some corticosterone is synthesized from
progesterone by the intact aldosterone synthase enzyme.
• Thus, it is unusual for patients to manifest signs of adrenal insufficiency,
such as hypotension, hypoglycemia, hyponatremia, and hyperkalemia.
• Hypertension is probably a consequence of elevated levels of
deoxycorticosterone, which has mineralocorticoid activity, or metabolites
thereof.
• Infants may transiently develop signs of mineralocorticoid deficiency after
treatment with hydrocortisone is instituted.
• This is presumably due to sudden suppression of deoxycorticosterone
secretion in a patient with atrophy of the zona glomerulosa caused by
chronic suppression of renin activity.
• All signs and symptoms of androgen excess that are found in 21-
hydroxylase deficiency may also occur in 11-hydroxylase deficiency.

21. • Laboratory Findings.
• Plasma levels of 11-deoxycortisol and deoxycorticosterone are
elevated
• aldosterone levels are low
• Hypokalemic alkalosis
• Treatment.
• Patients are treated with hydrocortisone in doses similar to those
used for 21-hydroxylase deficiency.
• Hypertension often resolves with glucocorticoid
treatment but may require additional therapy if it is of
long standing. Calcium channel blockers may be
beneficial under these circumstances.

22. Congenital Adrenal Hyperplasia due to 17-
Hydroxylase Deficiency
• Etiology.
• A single polypeptide, CYP17, catalyzes two distinct
reactions: 17-hydroxylation of pregnenolone and
progesterone to 17-hydroxypregnenolone and 17-
hydroxyprogesterone, respectively, and the 17,20-lyase
reaction mediating conversion of 17-
hydroxypregnenolone to DHEA and, to a lesser extent,
17-hydroxyprogesterone to ?4-androstenedione. DHEA
and androstenedione are steroid precursors of
testosterone and estrogen

23. • Clinical Manifestations and Laboratory Findings.
• cause hypertension, hypokalemia, and suppression of
renin and aldosterone secretion, as occurs in 11-
hydroxylase deficiency.
• patients with 17-hydroxylase deficiency are unable to
synthesize sex hormones.
• Affected males are incompletely virilized and present as
phenotypic females (but gonads are usually palpable in
the inguinal region or the labia) or with sexual ambiguity
(male pseudohermaphroditism).
• Affected females usually present with failure of sexual
development at the expected time of puberty. 17-
Hydroxylase deficiency in females must be considered in
the differential diagnosis of primary hypogonadism

24. • Treatment.
• Patients with 17-hydroxylase deficiency require cortisol
replacement to suppress secretion of
deoxycorticosterone and thus control hypertension.
• Females require estrogen replacement at puberty.
• Genetic males may require either estrogen or androgen
supplementation depending on the sex of rearing.
• As with androgen insensitivity syndrome, genetic males
with severe 17-hydroxylase deficiency being reared as
females require gonadectomy at or before adolescence
because of the chance of malignant transformation of
abdominal testes.

25. Thank you