Download Congenital Adrenal Hyperplasia

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;
17-OH-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 nonclassic 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-OH-Progesterone is
used in the USA.
11-b-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-a-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-b-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. 17-OHProgest. or 11-Deoxycortisol.
ESSENTIALS OF DIAGNOSIS/3
Diagnosis is confirmed by measurement
of ACTH, Cortisol, Aldosterone,
17-OH-progesterone, 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-b-hydroxylase deficiency and 17-ahydroxylase 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 17-hydroxyprogesterone).
Laboratory Findings/2
 11-b-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-b-hydroxylase deficiency
and 17-a-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-b-hydroxylase and 17alpha-hydroxylase deficiency, may be
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 sodiumpotassium 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 812 wk & amniocentesis at 18-20 wk.
HLA typing in combination with
measurement of 17-OH-progesterone &
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 m/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.