Congenital Adrenal

Hyperplasia
Dr. Abdelaziz Elamin. MD, PhD,
FRCPCH
Professor of Child Health
Sultan Qaboos University, Muscat,
Oman

What is CAH?
It is a familial disorder of adrenal steroid

biosynthesis with autosomal recessive mode of

inheritance.
The defect is expressed as adrenal enzyme
deficiency.
5 major Enzymes deficiency are clinically
important

21-Hydroxylase
11-b-Hydroxylase
17-a-Hydroxylase
3-b-Hsteroid hydrogenese
20,22 Desmolase deficiency

CAH
The enzyme deficiency causes

reduction in end-products,
accumulation of hormone precursors &
increased ACTH production.
The clinical picture reflects the effects

of inadequate production of cortisol &

aldosterone and the increased
production of androgens & steroid
metabolites.

21-Hydroxylase
Deficiency

Most common type, accounts for >80%

of cases.
Incidence is 1:5000 to 1:15000 live birth.
Gene is located on the short arm of

chromosome 6 near the C4 locus in close

association with HLA genes.
Heterozygous carriers can be detected

by ACTH stimulation test.

21-Hydroxylase deficiency/2
It is characterized by reduced

production of cortisol and aldosterone

and increased production of
progesterone;
17OH-progesterone, and sex steroids.
The urinary steroid metabolites

(17-ketosteroids and
pregnanetriol) are elevated above
normal levels.

21-Hydroxylase
deficiency/3
Decreased secretion of aldosterone results in

salt loss with hyponatremia and hyperkalemia;

plasma renin activity is therefore elevated.
In partial enzyme deficiencies, the aldosterone
deficiency is not expressed, and patients
remain normonatremic and normokalemic.
The excess androgens causes virilization of
girls & ambiguous genitalia & dark scrotum in
boys.

21-Hydroxylase Deficiency/4
2 forms, classic early virilization type

with or without salt-losing crisis and

non-classic type with late-onset
virilization.
Male babies with non salt-losing non-

classic type remains asymptomatic till

late childhood when they may show
signs of sexual precocity.

21-Hydroxylase
Deficiency/5
Because members of the same family

may have classic, non-classic &

asymptomatic forms, the disorder
may be due to allelic variations of
the same enzyme.
Mass neonatal screening using filter

paper blood sample for 17-OHProgesterone is used in the USA.

11--Hydroxylase
Deficiency

Accounts for 5-10% of cases of CAH.

Gene is located on the long arm of chromosome

8.
It is characterized by low plasma renin activity &
elevation of serum 11-Deoxycortisol and 11deoxycorticosterone.
Because of the strong mineralocorticoid activity
of deoxycorticosterone, the condition is
characterized by salt retention, hypertension &
hypokalemic alkalosis.
The elevated plasma androgens may cause
virilization of the female fetus.

17--Hydroxylase
deficiency
Genetic defect is on chromosome 10.
Presents with similar features of

those of 11-Hydroxylase deficiency

except that Androgens are low, so
no virilization in girls & genitalia is
ambiguous in boys.

3--hydroxysteroid
dehydrogenase deficiency
This is a very rare disorder that

results in accumulation of DHEA,

which is converted to testosterone
in peripheral tissues.
It can cause virilization of female

fetus and leads to ambiguous

genitalia in the newborn.

Pathophysiology
Anatomically, the adrenal gland can

be divided into 3 zones:

Zona

glomerulosa, which produces

predominately mineralocorticoid
Zona fasciculata, which produces
predominately glucocorticoid
Zona reticularis, which produces
predominately androgens

Enzyme pathway

Result of a 21-Hydroxylase Deficiency

ESSENTAILS OF
DIAGNOSIS
Increased linear growth with

advanced bone age and eventual

short stature
Pseudohermaphorditism in girls due
to androgen virilizing effect
Isosexual precocity in boys with
small infantile testes.

ESSENTAILS OF
DIAGNOSIS/2
Adrenal crisis with salt-loss &

metabolic acidosis or Hypertension

& hypokalemic alkalosis.
Low cortisol with high androgens,
ACTH and steroid precursors e.g. 17OH-Progest. or 11-Deoxycortisol.

ESSENTIALS OF
DIAGNOSIS/3
Diagnosis is confirmed by

measurement of ACTH, Cortisol,

Aldosterone,
17-OHprogesterone, Testosterone & urinary
17-ketosteroids.
Needs alertness for the possibility in
all babies with Diarrhea & Vomiting,
hypoglycemia or BP.

CLINICAL COURSE
The clinical phenotype depends upon

the nature and severity of the enzyme

deficiency.
Approximately 50% of patients with
classic congenital adrenal hyperplasia
due to 21-hydroxylase (CYP21)
deficiency have salt wasting due to
inadequate aldosterone synthesis.
Girls are usually recognized at birth
because of ambiguous genitalia .

CLINICAL COURSE/2
Non salt losing CAH present late in

childhood with precocious pubic hair

and/or clitoromegaly, often
accompanied by accelerated growth and
advanced bone age.

Those individuals with mild deficiencies

of the enzyme present in adolescence or

adulthood with varying virilizing
symptoms ranging from oligomenorrhea
to hirsutism and infertility.

GIRLS WITH CAH

Have ambiguous genitalia at birth:
complete fusion of the labioscrotal folds
and a phallic urethra. clitoromegaly and
partial fusion of the labioscrotal folds
In less severe forms, genitalia is normal at
birth. Precocious pubic hair &
clitoromegaly and excess facial or body
hair appear later in childhood, often
accompanied by tall stature.

BOYS WITH CAH

Are unrecognized at birth because their

genitalia are normal.

They are not diagnosed until later, often with a
salt wasting crisis resulting in dehydration,
hypotension, hyponatremia and hyperkalemia or
later in childhood with early pubic hair & phallic
enlargement accompanied by accelerated linear
growth and advancement of skeletal maturation.
High blood pressure & hypokalemia may occur in
those with 11--hydroxylase deficiency and 17-hydroxylase deficiency due to the accumulation
of the mineralocorticoid desoxycorticosterone

Laboratory Findings
Demonstration of inadequate production of

cortisol and/or aldosterone in the presence of

accumulation of excess concentrations of
precursor hormones is diagnostic.
In 21-hydroxylase deficiency, very high serum

17-hydroxyprogesterone is characteristic
together with very high urinary
pregnanetriol (metabolite of 17hydroxyprogesterone).

Laboratory Findings/2
11--hydroxylase deficiency is

characterized by high serum 11deoxycorticosterone and 11deoxycortisol concentrations with

elevation of its urinary metabolites
(tetrahydrocompound-S).
Both are accompanied by elevated 24hour urinary 17-ketosteroids, the urinary
metabolites of adrenal androgens.

Laboratory Findings/3
Salt wasting forms of adrenal hyperplasia

are accompanied by low serum

aldosterone, hyponatremia,
hyperkalemia and elevated plasma renin
activity indicating hypovolemia.

In contrast hypertensive forms of adrenal

hyperplasia (11--hydroxylase deficiency

and 17--hydroxylase deficiency) are
associated with suppressed plasma renin
activity and hypokalemia.

Other Tests
A karyotype

is essential in the evaluation of the

infant with ambiguous genitalia in
order to establish the chromosomal
sex.
Prenatal diagnosis of adrenal

hyperplasia is possible through

biochemical and genetic tests.

Imaging studies
A pelvic ultrasound: in the infant with

ambiguous genitalia to demonstrate the

presence or absence of a uterus or associated
renal anomalies
A urogenitogram is often helpful to define the
anatomy of the internal genitalia.
A CT scan of the adrenal gland to R/O
bilateral adrenal hemorrhage in the patient
with signs of acute adrenal failure
A bone age study is useful in the evaluation of
the child who develops precocious pubic hair,
clitoromegaly, or accelerated linear growth.

TREATMENT PRINCIPLES
Treatment is life-long
Treatment goals are:
to

maintain growth velocity & skeletal

maturation.
to normalize electrolytes & hormone
levels using the smallest dose of
glucocorticoids that will suppress the
ACTH to normal. Mineralocorticoid
replacement may be needed to sustain
normal electrolyte homeostasis.

MODES OF TREATMENT
Steroid replacement
Supportive therapy when needed
Treatment is life-long
Plastic surgery for ambiguous

genitalia at early age

Genetic counseling
Psychological support

Acute Medical
Management
Fluid therapy in babies with salt losing
crisis 0.9% sodium chloride 20 ml/kg as IV
bolus, followed by a continuous IV infusion
of 0.9% or 0.45% saline 3200 ml/m2/day.
If the patient is hypoglycemic, 2-4 ml of
10% dextrose will correct the
hypoglycemia.
Patients with 11--hydroxylase and 17alpha-hydroxylase deficiency, may be
hypokalemic and require potassium.

Long Term Therapy

Glucocorticoids Replacement

Hydrocortisone 10-15 mg/m2/day divided

in 3 oral doses. Dose should doubled
during crisis & stressful conditions. The
goals of therapy are:
To replace the body's requirement under
normal conditions and during stress.
To suppress ACTH secretion, which drives
the adrenal gland to overproduce adrenal
androgens in virilizing forms of congenital
adrenal hyperplasia.

Long Term Therapy/2

Mineralocorticoids Treatment

Fludrocortisone acetate 0.05-0.2 mg

once daily orally is indicated for
patients who have salt-wasting
forms of CAH to replace the
aldosterone that is insufficiently
produced by the adrenal cortex. It
will restore the sodium- potassium
balance.

New Trends of
treatment
A New approach therapy is the combined
use of 4 drugs:
glucocorticoid (to suppress ACTH and adrenal

androgen production),
mineralocorticoid (to reduce angiotensin II

concentrations),
aromatase inhibitor (to slow skeletal maturation),
flutamide (an androgen blocker to reduce

virilization)

Surgical Management
Infants with CAH may require surgical

evaluation and, if needed, corrective surgery.

Traditional approach is clitroplasty early in
life, followed by vaginoplasty after puberty.
Some female infants with adrenal hyperplasia

are only mildly virilized and may not require

corrective surgery if they receive adequate
medical therapy to prevent further
virilization.

Further Outpatient Care

Monitor patients adequacy of dosing of

glucocorticoid and/or mineralocorticoid.

Too little glucocorticoid results in symptoms of
adrenal insufficiency (e.g., anorexia, nausea,
vomiting, abdominal pain, asthenia) and will
result in progressive virilization and
advancement of skeletal maturation in virilizing
forms of CAH.
Too much glucocorticoid results in excess
weight gain, cushingoid features, hypertension,
hyperglycemia, cataracts, and growth failure.

Patient Education
Educate the caretakers and patients

about the nature of the disease.

Patients & parents must understand
the need for additional
glucocorticoids in times of illness and
stress in order to avoid an adrenal
crisis which may be life-threatening.

Neonatal Screening
Is done by measuring 17-hydroxyprogesterone

from heel blood samples collected on filter paper.

Mass neonatal screening program is adopted in
the USA.
This approach has permitted early identification
of newborns with CAH and prevented salt wasting
crisis in boys who are unrecognized at birth.
It also identifies the completely virilized girls with
ambiguous genitalia who may be mistaken for
boys with cryptorchidism

Prenatal diagnosis
Done by chorionic villus sampling at

8-12 wk & amniocentesis at 18-20

wk.
HLA typing in combination with

measurement of 17-OHprogesterone & androstenedion in

amniotic fluid is used for antenatal
diagnosis.

Prenatal Treatment
Prenatal treatment of 21-hydroxylase

deficiency prevents intrauterine virilization

of female fetuses.
According to the protocol proposed by
Carlson et al, the mother is treated with
dexamethasone (20 /kg/d in 3 divided
doses) as soon as the pregnancy is
recognized to suppress fetal ACTH
secretion & prevent the fetal adrenal gland
from overproducing adrenal androgens.

PROGNOSIS
Is good and complications like short

stature, sexual precocity & metabolic

effects are not seen with early
adequate therapy.
However, children with CAH are at

risk of developing mesodermal

tumours e.g. osteogenic sarcoma,
pulmonary liposarcoma, uterine
leiomyomata and brain tumours.

PROGNOSIS /2
Late diagnosis & inadequate therapy

may cause:
Death of newborns with salt-losing
types & if patients are not provided
with stress doses of glucocorticoid in
times of illness, trauma, or surgery.
Psychological problems in girls with
ambiguous genitalia.
Short stature and infertility.