CONGENITAL ADRENAL HYPERPLASIA

Congenital adrenal hyperplasia which is also abbreviated as CAH is autosomal

recessive disorder which is basically due to combination of genetic disorders in which
adrenal glands a pair of walnut sized organs located above the kidney do not function
rightly because of lack of 21-hyroxylase enzyme in the adrenal cortex characterized by
cortisol deficiency, excessive amount of androgen which is accompanied with or without
deficiency of aldosterone.
This disorder is called as congenital adrenal hyperplasia because this disease is by
birth and adrenal glands becomes hyperplastic due to uncontrolled Adrenocorticotrophic
hormone (ACTH) stimulation as a result of low levels of cortisol in adrenal cortex.

Common Name:

Congenital adrenal hyperplasia

Medical or Scientific Names:

Adrenogenital syndrome

Adrenal virilism

Congenital adrenal hyperplasia (classic or non-classic)

CAH

21-hydroxylase deficiency

Causes Of CAH:
The cause of congenital adrenal hyperplasia is:
i.

ii.

Limits synthesis of one of the many enzymes the adrenal glands use to make
cortisol. The enzyme most commonly lacking in congenital adrenal hyperplasia is
21-hydroxylase. Congenital adrenal hyperplasia also known as 21-hydroxylase
deficiency.
Lack of the synthesis of aldosterone in the adrenal glands which can lead to low
blood pressure, lower sodium level and higher potassium level. Sodium and
potassium normally work together in order to maintain the appropriate balance of
fluids in your body, transmit nerve impulses, and contract and relax your
muscles.

iii.

Excess synthesis of the male sex hormones (androgens such as testosterone)

which can resultantly cause short height, early puberty in boys, abnormal genital
development in girls and severe acne( red pimples on the skin).

Enzymes involved in Congenital adrenal hyperplasia:

Following are the enzymes involved in CAH :

Steroid 21-hydroxylase: (CYP21; P450c21; E.C.1.14.99.10)

Steriod 21-hydroxylase also known as 21-mono-oxygenase is a microsomal
cytochrome P450 enzyme that modify progesterone to deoxycorticosterone
(DOC) . It also converts
17a-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, in the glomerulosa
and fasciculata zones of the adrenal cortex . This enzyme is the product of a
gene (CYP21) present on the short arm of chromosome 6 and the zones
fasciculata and glomerulosa are the important sites of CYP21 gene
expression. Usually, 95% of cases are reported because of this deficiency
which can affect the final heights of patients This deficiency is as a
consequence of two recessive gene defects:
a severe 21-hydroxylase gene defect present in the index case with classical
CAH (21-OHCAM)
a mild 21-hydroxylase gene defect (21-OHCRYPTIC). -

11 beta-hydroxylase deficiency:
3-Hydroxysteroid dehydrogenase (3-HSD) deficiency is a rare cause of CAH
caused by inactivating mutations in the HSD3B2 gene.
17-hydroxylase/17
20-lyase
cholesterol desmolas

ADRENAL GLANDS :
Adrenal glands are small glands which are also called as suprarenal glands which are
located on the top of kidney .They are about the size of thumb and is has two parts

Adrenal cortex:
The outer part of gland is adrenal cortex and produces steroid hormones like
aldosterone, cortisol and hormones that can be changed into testosterone.
Adrenal medulla: The inner part of the gland is called the medulla and it
produce epinephrine and norepinephrine hormones which are also known as
adrenaline and non-adrenaline respectively.

ADRENAL HARMONES FUNCTION:

Androgens: It is a steroid hormone such as testosterone that stimulates growth and
male sexual characteristics growth and male sexual characteristics. This is also known
as androgenic hormone.

Aldosterone Cortisol: Aldosterone cortisol is mineralocorticoid which regulate

proper amount of salt like sodium and water in the body resulting in proper maintenance
of blood pressure and blood PH. They perform their function by sending signals to
kidneys which in turn absorb sodium into the blood stream and release potassium in
urine.

Cortisol : It is glucocorticoid hormone that helps regulate the bodys use of proteins,
fats and carbohydrates It helps the body to cope with stressful situations Its function is
to maintain blood pressure levels and blood sugar level. It also deals with body
sleep/wake cycle and it is mostly released during the times of stress to handle the
stressful situation by getting an energy boost

TYPES OF CAH
CAH can be classified into two types which is based upon its severity.

a) CLASSICAL CAH:
The severe type of CAH is classical CAH which is also termed as salt wasting
because of loss of body salts from body is frequent and it is major problem which
leads to cortisol and aldosterone deficiency. Hyperandrogenism and
hypocortisolism is visible severely in this form of CAH. The presence of adrenal
rests within the testes of adult males in the salt-wasting form results in higher risk

for infertility. Female with classical forms of 21-hydroxylase and 11b-hyrdroxylase

deficiency are born with ambiguous external genitalia In the classical forms of
21-hydroxylase and 11b-hydroxylase deficiency, the androgens produced in
excess amounts cause female pseudohermaphroditism (FPH) a condition in
which have female internal genitalia and female karyotype XX but they have
various degree of external genitalia virilization.

b) NON CLASSICAL CAH

The other Type of milder CAH is called as Non- Classical CAH or late onset and
it occurs at late onset which show up in later life. Non classical CAH type can
starts in women of any age group. In this type patients have normal genitalia at
birth time in both male and females. Its symptoms are similar to polycystic ovary
syndrome

FREQUENCY:
The occurrence of mild type which is non- classical CAH is very low i-e 1 in
1700 in general population but the presence of severe type which is classical
CAH is very high i-e 1 in 10000 among Caucasians . It has been reported that
90% of CAH are due to 21-hydroxylase deficiency found in 1:1000 to 1:15000
while Non classical is identified in 1:100 of mostly populations usually present

as precocious pubarche (having public hair in the age of 8 or 9 years in children)

or polycystic ovarian syndrome in young women

DIAGNOSIS:
Various diagnosis test are available for determination of CAH which are as follows :
. Prenatal diagnosis of 21-hydroxylase deficiency had done in the second trimester of
pregnancy on the basis of raised 17-OHP levels in the amniotic fluid. Recent studies of
the C4-CYP21 gene locus and the CYP21 mutations make easier the procedures for an
initial and accurate prenatal diagnosis in the first trimester. In recent times, prenatal
diagnosis is usually performed on chorionic villous sampling (CVS). However, if CVS is
not accessible or refused by the parents, amniocentesis can still be performed, and be
very helpful.

AMNIOCNETESIS:
Diagnosis of CAH in fetus is through amniocentesis also known as amniotic fluid test
or AFT. In AFT amniotic fluid is removed from fetus in order to determine chromosomal
abnormalities, fetal infection and sex determination of baby. It is done in order to

prevent birth defects and it provides genetic results usually about at 14 weeks of
gestation period.

17 OH PROGESTERONE:
17 -OH progesterone or Progesterone -17-OH is a blood test for diagnosis of CAH . In
this test blood sample is required which is drawn from vein located on the inside of
elbow except for infants lancet is used for puncturing of skin. Some medicines would be
stopped by your doctor before test because some medicines affect blood test outcomes.

Normal results:
Normal and abnormal values usually vary with age and weight . Typically, normal
Results are as follows:

Babies above than 24 hours old have fewer than 400 to 600 nanograms per
deciliter (ng/dL)
Children before puberty have around 100 ng/dL
Adults - fewer than 200 ng/dL

Abnormal results:
In case of abnormal results infants have 17-OHP level ranges beginning from 2,000 to
40,000 ng/dL but in adults congenital adrenal hyperplasia have level more than
200ng/dL which is due to less severe form non-classical adrenal hyperplasia.

Considerations:
Your doctor may recommend an ACTH test if 17-OH progesterone level is between the
200 to 800 ng/dL.

CHORIONIC VILLUS SAMPLING (CVS):

Chorionic villus sampling (CVS)is a prenatal test used for detecting genetic makeup of
baby usually done in between 10 to 15 weeks of baby and in this test a chorionic villi is
obtained from placenta during prenatal treatment of pregnancies having risk of CAH
CVS is conducted for analysis of restriction length polymorphisms (RFLP).
SHORT ACTH STIMULATION TEST:
KARYOTYPING:

SYMPTOMS :
Symptoms of classic CAH: acidosis, and a general failure to thrive.
Signs and symptoms of classic congenital adrenal hyperplasia in patients include:

Ambiguous genitalia in girls

Enlarged penis in boys

Poor weight gain

Weight loss

Dehydration

Vomiting

Very early puberty

Rapid growth during childhood, but shorter than average final height

Irregular menstrual cycles in women

Infertility in women and men

Symptoms of Non-classic CAH:

Signs and symptoms in both males and females include:

Early development of armpit and pubic hair

Rapid growth during childhood
Early or severe acne
Infertility or decreased fertility

Adolescent girls and adult women also may have

Masculine characteristics such as facial hair and a deep voice

Infrequent or absent menstrual periods

TREATEMENTS:

Mineralocorticoids
Mineralocorticoids a class of steroid hormones is required in patients who have saltwasting or classical congenital adrenal hyperplasia. This treatment is done in order to
replace the aldosterone that produced by the adrenal cortex in excessive amounts.

Mineralocorticoid treatment In SW patients life-long mineralocorticoid treatment is

necessary, but additional salt supplements are needed to maintain plasma sodium
concentration and renin in the normal ranges during infancy (0.55 nmol/l/day). We
adjust the mineralocorticoid dose necessary to restore normal renin levels (active
renin, or plasma renin activity). The only oral mineralocorticoid available is 9afluocortisol. The dose is usually 3075 mg per day, rarely .150mg in our experience,
but some authors apparently use higher doses (up to 400mg/day)

Fludrocortisone acetate (Florinef)

Synthetic adrenocortical steroid mainly having mineralocorticoid properties and it acts
on renal tubule which long convoluted tubules in kidneys and stimulate sodium
retention in exchange for potassium or hydrogen ion and thus maintain intravascular
and extracellular volume. For patients who require parenteral mineralocorticoid therapy,
high-dose hydrocortisone is preferable. This is available in medical stores only as tablet
and usually it is crushed for intake by infants and children.

Glucocorticoids: Glucocorticoid treatment

comprised of hydrocortisone and 9afludrocortisol which is usually spilt into two or three daily doses. Mostly preferred
glucocorticoid replacement is hydrocortisone, usually take in a dose of 1015 mg/m2
/day, but adjusted to the smallest dose in order to normalize growth and physical
maturation, and simultaneously to balance hormonal values within acceptable limits.
Other long-acting, more effective glucocorticoids, are prednisone and dexamethasone
which have harmful effects upon growth, but are more widely used in adult CAH
patients because they are more convenient. Adolescent and adult may be treated with
prednisone (57.5 mg daily in two divided doses), or dexamethasone( 0.250.5 mg in
one or two daily doses)
Following are the purposes of glucocorticoid therapy in congenital adrenal hyperplasia:
(1) I to replace the body's requirement for glucocorticoids under normal conditions and
during stress
(2) to suppress ACTH secretion, thereby reducing the stimulus for the adrenal glands to
overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia.

Treatment of fetus:
If the parents of baby are both carriers of the genetic disease congenital adrenal
hyperplasia (CAH) gene, the treatment must be offered to fetus and usually its is done
with dexamethasone tablets. This assists to lessen the effect that the condition has on

the unborn baby's genitalia in case of a baby girl. If the tests show that the baby is a boy
or a girl who is not affected, then in this case there is no need of treatment and
treatment should be stopped immediately. Recent studies of the C4-CYP21 gene locus
and the CYP21 mutations make easier the procedures for an initial and accurate
prenatal diagnosis in the first trimester.

Treatment of new born baby who has CAH:

Affected babies with classic CAH are salt-losers. They require the treatment through a
drip to replace fluid, salt and glucose so in order to prevent severity of disease they are
treated with long-term glucocorticoid treatment.

SURGICAL TREATMENT:
Surgical treatment of CAH is mostly done when the child got one year old, in
the age of ten years it is the right time to surgically operate the child because she is big
enough to cope with surgical complications and as she is so young she would not get
embarrassment about the appearance of her gentalia. The nature of surgery required
depends on the degree of masculinization (abnormal development of male
characteristics in females). Usually the surgeon treated these patients by reducing the
size of clitoris ,(female sex organ) while carefully preserving the sensitive network of
nerves and blood vessels at the tip so that normal sexual relationships can be
experienced in the future. Also, the surgeon may try to open the entrance to the vagina.
The timespan of stay in hospital differ, but usually it is between 5 and 10 days .
At times it is not better to open the vagina completely at once and mostly some girls
need further operations in future but it is likely to do operation at the time of puberty or
before they want to begin a sexual relationship.
Once girls has gone through her puberty
Once puberty has started, therefore, it is suggested that these girls must visit their
former surgeon or gynecologist in order to reexamine whether any further operation is
required or not in future. Such girls are referred either back to the original surgeon, or to
a gynaecologist, in order to reassess whether any further surgery is going to be needed.
During this whole procedure parent support especially mother support is advisable and
patient must consult psychologist.

GENETICS OF CAH: The classical CAH occur due to the combination of

severe/severe mutations, whereas the combination of mild/severe mutations is
associated with non-classical CAH. Prediction of the clinical form of CAH in a couple
at risk: if a partner is known to have a severe mutation. The couple is at risk of
having a child with a classical form of CAH if the other partner has at least one
severe mutation (whether heterozygote (A), or affected with a non-classical CAH (B)
or a classical form of the disease (C). (b) In contrast, when one partner is known to
be heterozygote for a mild mutation, there will be no risk of the couple having a

child affected with a classical CAH whatever the genotype of the other partner:
heterozygote for severe (D) or mild mutation (E), CAH affected with a nonclassical
form (F or G), or even a classical form (H) of CAH

Congenital adrenal hyperplasia (CAH) is one of the most common inherited

metabolic disorders. It comprises a group of autosomal recessive disorders
caused by the deficiency of one of four steroidogenic enzymes involved in
cortisol biosynthesis or in the electron donor enzyme P450 oxidoreductase (POR)
that serves as electron donor to steroidogenic cytochrome P450 (CYP) type II
enzymes. The biochemical and clinical phenotype depends on the specific
enzymatic defect and the impairment of specific enzyme activity. Defects of
steroid 21-hydroxylase (CYP21A2) and 11-hydroxylase (CYP11B1) only affect
adrenal steroidogenesis, whereas 17-hydroxylase (CYP17A1) and 3hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency also impact on
gonadal steroid biosynthesis. Inactivating POR gene mutations are the cause of
CAH manifesting with apparent combined CYP17A1CYP21A2 deficiency. P450
oxidoreductase deficiency (ORD) has a complex phenotype including two unique
features not observed in any other CAH variant: skeletal malformations and
severe genital ambiguity in both sexes. 21-OHD is caused by mutations in
the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90%
of these mutations result from intergenic recombination between CYP21 and
the closely linked CYP21P pseudogene. The degree to which each mutation
compromises enzymatic activity is strongly correlated with the clinical
severity of the disorder. This close association between genotype and
phenotype makes it possible to predict clinical outcome in affected subjects.

Conclusions The management of children and adolescents with CAH remains

difficult. Paediatric endocrinologists , surgeons , gynaecologists, geneticists and

psychologists deals with patients of CAH. Firstly, prenatal diagnosis is done during
second trimester of pregnancy . In families which are at risk,prenatal
dexamethasone therapy is performed at a median gestational age of 6 weeks in a
median dose of 20 mg/kg/day. The only oral mineralocorticoid available is 9afluocortisol. Adolescent and adult may be treated with prednisone (57.5 mg daily in
two divided doses), or dexamethasone( 0.250.5 mg in one or two daily doses). Hence,
monitoring treatment over the first 2 years and during puberty is critical for the
height outcome of these patients (New et al., 1989). In boys, excessive prepubertal
androgen exposure due to uncontrolled CAH is associated with a reduction in adult
somatic height but it does not routinely result in micropenis (Levy and Husmann,
1996). Fertility Fertility is classically reported as low in CAH female patients. Several
factors have been suggested to contribute to this impaired fertility: adrenal
overproduction of androgens and progestins (17-OHP and progesterone), ovarian
hyperandrogenism, POCS, ovarian adrenal rest tumours, neuroendocrine factors,
genital surgery, and psychological factors such as delayed psychosexual
development, reduced sexual activity and low maternal feelings. Improving
endocrine, surgical and psychological management could contribute to improving
fertility chances in these patients.

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