Causes, incidence, and risk factors

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Causes, incidence, and risk factors   Congenital
adrenal hyperplasia can affect both boys and
girls. People with congenital adrenal
hyperplasia lack of an enzyme needed by the
adrenal gland to make the hormones cortisol and
aldosterone. Without these hormones, the body
produces more androgen, a type of male sex
hormones. This causes early (or inappropriate)
appearance of male characteristics. Newborn girls
with this disorder have a swollen clitoris with
the urethral opening at the base (ambiguous
genitalia, often appearing more male than
female). The internal structures of the female
reproductive tract (ovaries, uterus, and
fallopian tubes) are normal. As the female grows
older, some features start to appear male, such
as deepening of the voice, facial hair, and
failure to menstruate at puberty. No
obvious problems are seen in newborn males,
but changes can be seen long before puberty
normally occurs. The child becomes increasingly
muscular, the penis enlarges, pubic hair appears,
and the voice deepens. Boys may appear to enter
puberty as early as 2-3 years of age. At puberty,
the testes are small. Some forms of congenital
adrenal hyperplasia are more severe and cause
adrenal crisis in the newborn due to salt
wasting. In this salt-losing form of congenital
adrenal hyperplasia, newborns develop severe
symptoms shortly after birth, including vomiting,
dehydration, electrolyte changes, and cardiac
arrhythmias. Untreated, this condition can lead
to death within 1 to 6 weeks after birth. About 1
in 10,000 to 18,000 children are born with
congenital adrenal hyperplasia.
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Symptoms   In girls Ambiguous genitalia Early
appearance of pubic and armpit hair Excessive
hair growth Deep voice Abnormal menstrual
periods Failure to menstruate In boys Early
development of masculine characteristics
Well-developed musculature Enlarged penis
Small testes Early appearance of pubic and
armpit hair Both boys and girls will be tall as
children but significantly shorter than normal as
adults
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Complications   Adrenal crisis, including
hyponatremia and shock (especially in newborns)
Abnormal female external genitalia (internal
organs are normal) Early development of male
sexual characteristics Short adult stature
despite early, rapid childhood growth Tumors of
the testes in adult men High blood pressure Low
blood sugar Side effects of corticosteroids used
as treatment Prevention   Genetic counseling is
indicated for parents with a family history of
congenital adrenal hyperplasia (of any type) or a
family with a child who has the
condition. Prenatal diagnosis is available for
some forms of congenital adrenal hyperplasia.
Diagnosis is made in the first trimester by
chorionic villus sampling and in the second
trimester by measuring hormones such as
17-hydroxyprogesterone in the amniotic fluid. A
newborn screening test is available for the most
common form of congenital adrenal hyperplasia and
can be done on heelstick blood (as part of the
routine screenings done on newborns). This test
is not yet widely available.
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Incidence and Clinical Presentation CAH due to
21-hydroxylase deficiency is seen in roughly 1 of
every 15,000 live births worldwide it is a
relatively common disorder in humans. Clinically,
it is seen in three primary manifestations
Simple virilizing form Excessive prenatal
production of androgens in affected females
results in masculinization of the reproductive
tract to a point that the sex of the newborn is
not clear ("ambiguous genitalia") or appears
male-like. Affected males are usually normal at
birth. In both sexes, linear growth in childhood
is accelerated, but the epiphyses fuse early,
leading to short stature. The simple virilizing
form of CAH is seen in approximately 25 of those
with 21-hydroxylase deficiency. Salt-wasting
form Roughly 75 patients are unable to
synthesize adequate amounts of aldosterone, which
is essential for sodium homeostasis. Such
individuals lose large amounts of sodium in
urine, which leads to potentially fatal
electrolyte and water imbalance. Individuals with
severe deficiency usually present with "adrenal
crisis" between 1 and 4 weeks of age signs are
often non-specific, but can include poor
appetite, vomiting and failure to grow.
Replacement therapy is mandatory in such
patients. Non-classical form This form of the
disease is mild and usually manifest as some type
of androgen excess later in life. Aldosterone
deficiency is not usually observed
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Genetics The 21-hydroxylase enzyme is encoded by
the CYP21 gene. More than 50 different mutations
of CYP21 have been identified, of which about 15
account for a large majority of 21-hydroxylase
cases. Most mutations appear to be the result of
a recombination between CYP21 and a pseudogene
(CYP21P). One consequence of this multitude of
mutations is that there is considerable
variability in the clinical presentation of
disease, ranging from severe salt-wasting or
virilizing disease to milder syndromes. This
disorder is seen as a simple autosomal recessive
trait. Diagnosis and Prenatal Screening Most
commonly, 21-hydroxylase deficiency is first
suspected in a newborn infant with "ambiguous
genitalia". Finding elevated blood levels of
17-hydroxyprogesterone, in conjuction with
ultrasound examination of the abdomen and genital
tract usually leads to a rapid diagnosis.
Disorders that must be differentiated in such
cases include true hermaphorditism,
pseudohermaphroditism and certain types of sex
chromosome abnormalities, none of which should
have high concentrations of 17-hydroxyprogesterone
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Classical and nonclassical 21-OHD CAH are
diagnosed by serum elevations of the hormone
17-hydroxyprogesterone before and after a
60-minute adrenocorticotropin (ACTH) stimulation
test (Figure 3). Confirmation by molecular
genetic analysis of the CYP21 gene is advised.
Nomogram relating baseline to ACTH-stimulated
serum concentrations of 17-hydroxyprogesterone
(17-OHP). The scales are logarithmic. A
regression line for all data points is shown.
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Prenatal diagnosis Prenatal diagnosis and
treatment are available. Prenatal diagnosis is
done by analysis of fetal DNA obtained by
amniocentesis or chorionic villus sampling (CVS).
Prenatal treatment with the drug dexamethasone
prevents virilization of the genitalia of
classically affected females and must be started
prior to the 9th week of pregnancy, as outlined
in the algorithm below (Figure 4). Figure 4.
Algorithm for prenatal diagnosis and treatment of
CAH.
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Treatment All patients with CAH, regardless of
form, are treated with glucocorticoid replacment
therapy. This not only alleviates glucocorticoid
(i.e. cortisol) deficiency, but more importantly,
provides negative feedback to suppress ACTH
secretion and prevent continued adrenal
stimulation. As a result, excessive
17-hydroxyprogesterone is not available as a
substrate for excessive androgen production.
Patients with the salt-wasting form of
deficiency must also receive mineralocorticoid
therapy to normalize the abnormalities in sodium
balance associated with aldosterone deficiency.
Prenatal treatment of the mother with
glucocorticoids can prevent or reduce that the
virilizing effects of fetal 21-hydroxylase
deficiency. This procedure has been used in cases
where couples have previously had a child with
virilizing CAH. In such cases, it is known that
both parents are carriers, and since only female
children require prenatal treatment, the
probability that the current fetus is affected is
1 in 8. Treatment of the mother with
glucocorticoids must begin at 6 to 7 weeks of
gestation, at which time it is almost never known
whether the fetus is affected. Hence, in 7 of 8
cases, the fetus does not actually require
therapy. The long term effect and safety of this
procedure is poorly defined A number of surigical
procedures have been developed to correct the
genital abnormalities of girls with the
virilizing form of CAH. These procedures are
complicated by concerns about when the surgery
should be performed, gender identity of the
patient and other factors.
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Deficiency Incidence Comments
11 beta-hydroxylase 1 in 100,000 livebirths Females virilized salt-wasting is rare
17 alpha-hydroxylase rare Males virilized females fail to achieve puberty. Salt-wasting not observed.
3 beta-hydroxysteroid dehydrogenase rare Males virilized female virilization mild. Salt-wasting may be seen.
aldosterone synthase rare Cortisol concentrations normal and virilization not seen. Salt-wasting occurs.
StAR rare Males virilized females fail to achieve puberty. Salt-wasting occurs.
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Lipoid congenital adrenal hyperplasia Gene map locus 15q23-q24, 8p11.2 Adrenal hyperplasia I Lipoid hyperplasia, congenital, of adrenal cortex with male pseudohermaphroditism Clinical features complete absence of steroid hormone biosynthesis male pseudohermaphroditism salt loss hyperkalemic acidosis dehydration Inheritance autosomal recessive
                                         lt/lt tdgt                                                             lt/lt tdgt                                                     lt/lt tdgt
Congenital Lipoid Adrenal Hyperplasia Caused by a Novel Splicing Mutation in the Gene for the Steroidogenic Acute Regulatory Protein Phenotypic Features Associated with Mutations in Steroidogenic Acute Regulatory Protein Phenotypic Features Associated with Mutations in Steroidogenic Acute Regulatory Protein
Journal of Clinical Endocrinology and Metabolism Journal of Clinical Endocrinology and Metabolism Journal of Clinical Endocrinology and Metabolism
 

          
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SCREENING Infant females with CAH often come to
medical attention because the disorder causes
affected females to exhibit recognizable genital
abnormalities and therefore receive prompt
treatment for adrenal failure and salt-wasting.
However, newborn males and females that, due to
the extent of their genital abnormalities are
miscast as males, show no other outward signs of
the disorder and are sent home.  Newborn
screening allows for these children to be
identified as possibly having CAH before they go
into adrenal crisis and present for urgent
medical attention at a time when they are beyond
resuscitation. A second diagnostic test then is
ordered and the diagnosis of CAH either confirmed
or denied. Current newborn testing is quite
effective in identifying infants with the severe
form of CAH, Classical Salt-Wasting CAH.  Some
babies with Simple Virilizing CAH also are
detected through this process.  It is rare that a
child with Non-classical or Late-onset CAH will
be picked-up through this type of testing.  To
learn more about Non-classical CAH diagnosis,
please visit our page on Genetic Testing. The
majority of infants detected through newborn
screening have Salt-wasting CAH. 
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SCREENING Infant females with CAH often come to
medical attention because the disorder causes
affected females to exhibit recognizable genital
abnormalities and therefore receive prompt
treatment for adrenal failure and salt-wasting.
However, newborn males and females that, due to
the extent of their genital abnormalities are
miscast as males, show no other outward signs of
the disorder and are sent home.  Newborn
screening allows for these children to be
identified as possibly having CAH before they go
into adrenal crisis and present for urgent
medical attention at a time when they are beyond
resuscitation. A second diagnostic test then is
ordered and the diagnosis of CAH either confirmed
or denied. Current newborn testing is quite
effective in identifying infants with the severe
form of CAH, Classical Salt-Wasting CAH.  Some
babies with Simple Virilizing CAH also are
detected through this process.  It is rare that a
child with Non-classical or Late-onset CAH will
be picked-up through this type of testing.  To
learn more about Non-classical CAH diagnosis,
please visit our page on Genetic Testing. The
majority of infants detected through newborn
screening have Salt-wasting CAH. 
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Genetic Testing for CAH The polymerase chain
reaction (PCR) is a common method used for
genetic testing that can tell one gene apart from
another. PCR can be thought of as a "genetic
Xerox machine." By using PCR, the laboratory can
make up to a million copies of a specific gene or
piece of a gene from a DNA sample for
studies.Some laboratories use a technique
called a Southern blot. In this method, extracted
DNA is cut at specific sites near or within the
gene and pseudogene. A specially made piece of
DNA, referred to as a probe, is used to detect
the specific DNA pattern of the gene and
pseudogene. A Southern blot will usually find
large gene deletions and rearrangements. After a
lab performs a Southern blot, it will also need
to perform PCR and some other method, like
sequencing, in order to find those smaller
changes.PCR can also be used to distinguish the
pseudogene and functional gene, and in most cases
can determine the number of functional genes and
pseudogenes a person has in their DNA without
using the Southern blot technique. Unique
landmarks outside the gene and pseudogene are
used to separately copy and identify the gene,
the pseudogene, as well as any rearranged copies
of the gene and pseudogene that might be present.
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In families where the diagnosis of CAH due to
21-hydroxylase deficiency has been proven but a
mutation cannot be identified, another test
called linkage can be used to determine if a
relative has the mutation or if a pregnancy is
affected. Linkage cannot be performed without
testing multiple family members. At least both
parents must be tested, as well as a previously
born affected child. Unique genetic landmarks
either within the gene or pseudogene, or close
to, or "linked" to the CYP21A2 gene are used to
identify and follow copies of the mutated gene
causing CAH from generation to generation without
actually knowing the exact mutation involved.
Sequencing small areas of the pseudogene and
functional gene can provide good genetic
information for linkage analysis. Linkage can be
used to predict whether or not a subsequent child
will be affected with a high degree of accuracy.
Because linkage does not test for the actual
mutation, however, there is a small risk that the
linked genetic landmark will become unlinked and
thus an incorrect result will be obtained.
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Who Might Consider Genetic Testing?Genetic
testing can be used to confirm the diagnosis of
CAH and identify the mutations present in a
person who is suspected of having classic or
non-classic CAH. For example, genetic testing can
help confirm the diagnosis in infants that have a
positive newborn screen for CAH. Adults with
suspected CAH due to infertility problems or
women who have symptoms of androgen excess might
also have their diagnosis confirmed through
genetic testing.Parents of a child with CAH may
want to know the genetic alterations present in
their affected child. This information can be
used, early in pregnancy, to determine whether a
subsequent child has CAH by testing the baby
through amniocentesis or chorionic villus
sampling. The information could help direct
prenatal treatment with dexamethasone or help
families and doctors anticipate and prepare for
the birth of an affected child. Genetic
information can also be used for preimplantation
genetic diagnosis in future pregnancies in order
to significantly reduce the chance of a having
another child affected with CAH
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Genetic testing can also be used to screen an
unaffected person who has no family history of
CAH to determine if they carry CAH. This can be
especially useful for the partners of individuals
who are either affected by CAH, or are known
carriers of CAH, for the purpose of family
planning and pregnancy management. If both
members of a couple are known carriers, they can
consider the option of starting dexamethasone
treatment early in the pregnancy which would
reduce the degree of masculinization of the
female genitalia in an affected female
infant.For couples that have no known personal
or family history of CAH, but are currently
pregnant with a female fetus that has ambiguous
genitalia detected by prenatal ultrasound,
genetic testing for CAH may be appropriate after
other causes have been ruled out. The advance
knowledge can help the family and physicians
prepare for the medical, social and emotional
issues related to the diagnosis and birth of an
affected child.
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Prenatal Testing for CAHPrenatal testing can be
performed by two methods. Chorionic villus
sampling (CVS) is a procedure that obtains fetal
cells by sampling cells from the developing
placenta. The procedure is usually done with
ultrasound guidance to see the physical
structures of the patient and fetus. CVS is
typically offered at 10-12 weeks from the last
known menstrual period. As with any prenatal
procedure, CVS carries with it a small risk of
miscarriage. The advantage of CVS is that the
procedure takes place in the first trimester and
genetic test results can be obtained early in the
pregnancy. The cells obtained are taken to a
laboratory and grown so that the DNA can
ultimately be obtained and tested.
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Prenatal Testing for CAHThe cells obtained are
taken to a laboratory and grown so that the DNA
can ultimately be obtained and tested.Amniocente
sis is another technique that can be used to
obtain a sample of fetal cells for genetic
testing. This method is typically performed at
15-20 weeks from the last menstrual period. This
procedure requires that a thin needle is passed
through the abdomen, under ultrasound guidance,
into the fluid filled sac that surrounds the
fetus. A few tablespoons of the fluid are taken
from the sac. This fluid contains cells from the
baby that are then grown in a laboratory. As is
the case with CVS, amniocentesis is not a
risk-free procedure. With amniocentesis, there is
a small risk of about 1 in 200 that the procedure
will cause a miscarriage. The risks and benefits
must be taken into consideration when considering
prenatal testing. Your doctor and genetic
counselor are good resources for additional
information regarding these procedures.
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Treatment Research has shown Congenital Adrenal
Hyperplasia to be a spectrum disease. That is, a
condition that manifests itself in varying
degrees the severe form being Classical
Salt-wasting CAH and the mild form being
Non-classical CAH with Simple-Virilizing CAH
somewhere in between. In all cases, however, CAH
is caused by an adrenal insufficiency resulting
in impaired production of hormones. All
individuals affected by Classical CAH require
glucocorticoid (hydrocortisone, prednisone,
dexamethasone) replacement therapy. Those with a
salt-wasting component to their insufficiency
also require mineralocorticoids (fludrocortisone
and sodium). The following pages outline
medication dose guidelines for all individuals
with CAH as agreed upon by the leading pediatric
endocrinologists in the United States and Europe
in 2002. As always, this information is
provided for your reference to help you better
understand decisions made regarding medication
dosing and in no way should be taken to be the
provision or practice of medical, nursing or
professional healthcare advice or services. This
information should not be considered complete or
exhaustive and should not be used in place of the
visit, call, consultation or advice of your
physician or other healthcare provider.
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Dosing of Medications - from the Joint LWPES/ESPE
2002 CAH Consensus Statement (pages 4050-51,
footnotes omitted) Optimal Glucocorticoids
Dosing. During infancy, initial reduction of
markedly elevated adrenal sex hormones may
require up to 25 mg hydrocortisone (HC)/m 2 .d,
but typical dosing is 10-15 mg/m 2.d divided
three times daily. HC oral suspension is not
recommended divided or crushed tablets of HC
should be used in growing children. ...HC is
considered the first drug of choice. Excessive
doses, especially during infancy, may causes
persistent growth suppression, obesity and other
Cushingoid features. Insufficient data exist to
recommend higher morning or evening dosages.
Whereas HC is preferred during infancy and
childhood, long-acting glucocorticoids may be an
option at or near completion of linear growth.
Prednisone and prednisolone need to be given
twice daily.The dose (2-4 mg/m 2.d) should be
approximately one-fifth the dose of HC. The
dosage of Dexamethasone is 0.25-0.375 mg/m 2.d,
given once daily. Monitoring of these more potent
glucocorticoids should include BP, in addition to
weight, and other clinical and laboratory
variables. These steroids have minimal
mineralocorticoid effect, compared with HC. In
children with advanced bone age, such as boys
with non-salt losing CAH, initiation of therapy
may precipitate central precocious puberty,
requiring treatment with a GnRH agonist.
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Mineralocorticoid use. All classic CAH patients
should be treated with fludrocortisone at
diagnosis in the newborn period. Dosage
requirements in early infancy range from
0.05-0.30 mg/d, whereas typical maintenance doses
are 0.05-0.2 mg/d, depending on the sodium
intake.Sodium chloride supplements are often
needed in infancy at 1-3gm/d(17-51mEq/d),
distributed in several feedings. body surface
area calculator for medications
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Although it may seem that monitoring and testing
in CAH is confusing, there are several approaches
that can be used to adequately assess hormone
production. It is also very important to
emphasize that monitoring changes in physical
growth and maturation is as important, if not
more important, as the laboratory testing in CAH.
Growth Bone Density Monitoring growth and
maturation in CAH.Growth and weight The rate of
growth provides very important clues about
treatment in CAH. In general, with proper
treatment the child with CAH should grow along
the same percentile for height, which reflects
the height of the parents. Between two years of
age and puberty, the average child grows about
2-1/2 inches per year and gains 2-3 pounds for
every inch of height gain. During infancy and
puberty, rates of growth are even faster than
during childhood. In general, a child will
usually grow along the same percentile on growth
charts from infancy though adolescence. Thus,
height and weight need to be both monitored and
plotted on standard growth charts to assess
growth in CAH.
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Looking at growth charts and following changes in
height and weight, one can detect signs of over-
and undertreatment. If glucocorticoid
(hydrocortisone, prednisone, dexamethasone) doses
are too high, growth will slow and weight will
increase. It takes about 3-6 months to appreciate
changes in growth rates (changes in height).
Changes in weight, though, can be seen much
sooner. Increases in weight, above and beyond
that which are normally expected (more than 3 lbs
per inch of growth more than 7 lbs per year),
can be a sign of overtreatment. Thus, it is very
useful for families to monitor weight at home.
For example, if the weight increases by more than
one pound over 2-4 weeks after a dose change, it
may be a sign that the dose is too high. Whereas
slowing of growth can represent signs of
overtreatment, increased growth can reflect
undertreatment. With undertreatment, there is
increased androgen production, which can
stimulate growth. Undertreated children may
therefore climb to higher height percentiles on
growth charts.
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The importance of regular follow-upTo assess
physical changes in CAH and be able to respond to
signs of over- or undertreatment in a timely
manner, many practitioners will see individuals
with CAH every 3-4 months. Because signs of
over-treatment (facial roundness) can be subtle,
it is preferable to see the same practitioner at
each visit. There are physical signs that
clinicians can see that suggest either over- or
undertreatment. With overtreatment, the face can
become round. With significant overtreatment,
striae (purple "stretch-marks") can occur.
Features of undertreatment include dark or
"dirty"-looking knuckles caused by excessive ACTH
secretion. Stomach pain and being excessively
tired are also symptoms of undertreatment. The
blood pressure can provide clues about
mineralocorticoid (Florinef, fludrocortisone)
treatment. If the blood pressure is elevated,
this may indicate that the mineralocorticoid dose
or salt supplementation is too high and should be
reduced. Yet, if the dose is normal or too low,
the blood pressure is normal. Signs of pubertal
development are also monitored. In girls, one of
the earliest signs of puberty is breast
development. In boys, enlargement of the size of
the testes is the earliest signs that puberty has
started. If puberty begins less than seven years
of age in girls and less than nine years of age
in boys, it is said to be early or "precocious".
Because the adrenal hormones can affect the
pituitary gland, precocious puberty is seen in
CAH and warrants attention.
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The Usefulness of Bone AgesOne of the best tools
for monitoring changes in physical maturation is
the "bone age". The growth centers, which can be
easily visualized with an x-ray of the hand,
provide a wonderful marker of long-term androgen
secretion. As children get older, the shape of
the growth centers change and have characteristic
appearances at each age. By comparing the size
and shapes of the growth centers in the child's
hand to those found in a book of standards, a
"bone age" can be determined. Because there is
variability from practitioner to practitioner in
bone age interpretation, it is useful to have
bone ages interpreted by the same individual.
Also, some pediatric endocrinologists may be more
experienced in interpreting bone ages than
general radiologists. When there is excessive
androgen secretion, the skeleton matures at a
more rapid pace than usual. This will result in
an advanced bone age. Thus, an undertreated child
at 6 years of age may have a bone age of 9 years
of age. Yet, if the bone age is within a year or
so of the actual age, this suggests that
treatment has been fine. The bone age also
reflects hormone secretion over the preceding
6-12 months. Changes in the bone age may lag
behind recent periods of excess androgen
secretion. Many practitioners therefore obtain
bone ages every 6 to 12 months.
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Laboratory Testing Monitoring of Hormone Levels
in CAHThe levels of adrenal hormones in the
blood vary over the 24-hour day. Cortisol and
androgen production is highest in the morning and
lowest in the afternoon and evening. Hormone
levels are also affected by medications.
Following a dose of glucocorticoids, androgen
levels will fall. Yet, as the medication wears
off, hormone levels may rise excessively. Care
must be taken to consider the time of day and the
timing of doses when interpreting hormone levels.
There are several different approaches that can
be used to assess adrenal hormone production.
Urine testing is a "gold standard" and can be
used to measure hormone production throughout the
day. Blood testing provides important information
about hormone production and is preferred by many
clinicians due to convenience. Testing of hormone
levels several times a day using filter paper
specimens has also been shown to be an effective
monitoring tool, but is not widely available.
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Laboratory Testing Blood TestingAssessing
control from a single blood test is very commonly
used due to its convenience. However, a single
test may not always reflect if there is adequate
control of adrenal gland activity. One also needs
to consider the time of day and the timing of
doses in interpreting blood levels. Some hormone
levels are also better than others in assessing
treatment. A number of hormones that reflect
adrenal gland activity can be measured in the
blood. These factors include ACTH, 17
hydroxyprogesterone (17 OHP), androstenedione,
and testosterone. Electrolytes and renin are used
to assess mineralocorticoid replacement. Of
these different hormones, androstenedione and
testosterone most closely match 24-hour 17 KS
production and reflect adrenal androgen
production. These hormones are especially useful
in prepubertal children and females. Because
testosterone levels rise in puberty in males,
testosterone levels are not as useful in
adolescent or adult males. In comparison with
androstenedione and testosterone, 17 OHP levels
can fluctuate widely and may be elevated even
when there is good control. The pituitary hormone
ACTH has been shown to provide a nice measure of
control and is elevated 75 of the time when
there is undertreatment.
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Laboratory Testing Blood TestingFor children
without CAH and who are not in puberty, average
levels of androstenedione are 25 ng/dl, average
levels of testosterone levels are 5 ng/dl, and
average 17OHP levels are 50 ng/dl. During
puberty, levels of these hormones rise. It is
possible to achieve normal levels of these
hormones in children with CAH. Yet, treating CAH
to "normalize" all hormone levels, especially 17
OHP levels, can result in growth suppression and
weight gain. Thus, many clinicians aim for
androstenedione and testosterone levels that are
normal or modestly (about 25) above normal.
Because 17 OHP levels can fluctuate widely and be
elevated when there is adequate treatment, some
clinicians will accept mid-day 17 OHP levels of
500-1000 ng/dl others will aim for lower levels.
Morning levels of 17 OHP, androstenedione, and
testosterone are much higher than mid-day levels,
especially when there is undertreatment. This
occurrence reflects the general observation that
adrenal glands become more active in the early
morning hours and at a time when the medication
from the day before is wearing off. It can
therefore be very useful to obtain morning
hormone levels. It has been recently shown that
when there is good control of adrenal gland
activity, 17 OHP levels are less than less than
600 ng/dl in the morning before medication is
given and less than 200 ng/dl during the day. In
undertreated individuals, 17 OHP levels average
10,000 ng/dl in the morning before the dose, and
5000 ng/dl during the day.
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Laboratory Testing Blood TestingTo measure if
the child is getting enough salt and/or
fludrocortisone, renin and electrolyte levels are
measured. An elevated renin levels indicates a
need for more salt and/or fludrocortisone. A
suppressed renin suggests that the dose of salt
and/or fludrocortisone is too high. Filter
Paper SpecimensWhereas a single blood test
during the day can provide important insights
into CAH control, they can sometimes be
misleading. If a sample is obtained in an
undertreated child a few hours after a dose of
hydrocortisone has been given, levels of 17OHP
can decrease. As the medication wears off, 17 OHP
levels can increase dramatically. One can
overcome potential pitfalls of obtaining once
daily samples by obtaining filter-paper specimens
over the course of the day. Children with
diabetes check their blood sugar by finger stick
3-4 times a day to be able to properly dose
insulin levels. Similarly, one can measure 17 OHP
levels on filter paper specimens taken at
different times of day. Thus, one can identify
times of day when levels are high and others when
levels are low and adjust doses accordingly.
Filter paper 17OHP levels can be measured by
state laboratories that perform newborn screening
for CAH using filter-paper specimens.
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Hormone Prepubertal Mid-Pubertal Pubertal and
adult Blood testing     ACTH (pg/ml) 30 (10-60)30
(10-60)30 (10-60) Androstenedione(ng/dl)25
(8-50)70 (50-100)115 (70-200) 17 OHP (ng/dl)40
(3-100) 80 (10-150)100 (25-250)T estosterone
(ng/dl)5 (3-10)    Males150 (100-300)600
(300-1000)  Female  25 (15-35)  30 (10-55)Urine
testing17 Ketosteroids (mg/24 hr) 1.5 (0.2- 3)
Males 5 (3-10) 15 (10-25)Female 3.5 (2.5-8) 10
(6-14)Pregnanetriol (mg/24 hr) 0.5 1.0 2.0 -In
CAH, levels of androstenedione, testosterone and
17 ketosteroids that are normal or modestly
(about 25) above normal are acceptable. Because
blood 17 OHP levels can vary widely in CAH,
higher 17 OHP levels are acceptable, but are
usually less than 1000 ng/dl with adequate
treatment.-To convert ng/dl units to pmol/L,
multiply androstenedione levels by 34, 17 OHP by
30, testosterone by 34.
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CARES strongly recommends that no surgery be done
until 1) the child is medically stable 2) the
parents are fully informed of the risks and
benefits and 3) an expert surgeon is
found. Ultimately, the decision about whether and
when to perform surgery is intensely personal. 
Whatever you choose, you must be comfortable and
confident in your decision and your choice of
surgeon.  Below are some frequently asked
questions that may help guide you through the
decision-making process.
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How different are our daughters genitals from
other female children?Your daughter may look
different, but she has all of the female
reproductive organs. She has a uterus, vagina and
ovaries. She will be able to bear children. The
degree of virilization (masculinization)
affecting your daughter will be can be graded on
a classification known as the Prader Scale.  Your
daughters pediatric urologist or pediatric
endocrinologist will be able to tell you what
Prader Level she is. Typical Prader 4
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What is the Prader Scale and what are the Prader
Scale levels?The Prader Scale is a scoring
system for grading the degrees of genital
masculinization.  The Prader Scale starts at 0,
which is an unvirilized female, and ends at 5
which is a completely virilized female (a female
who appears externally male at birth with the
labial/scrotal sac empty since there are no
testicles).  The picture below shows the Prader
Virilization Scores. (From Speiser and White
Congenital Adrenal Hyperplasia due to
21-Hydroxylase Deficiency Endocrine Reviews
21(3) 245-291 2000)
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When should surgery be performed?The decision of
when to have surgery can be one of the hardest. 
How can we be sure that we are doing the right
thing?  There is no right decision.   There is
only what is right for you and your daughter. 
Gather as much information as you can, and work
to make the best decision you can. The 2002 CAH
Consensus Statement states, based on recent
clinical experience, the recommended time for
surgery is at 2-6 months, although this is not
universal practice.  It is important to note that
surgery at this stage is technically easier than
at later stages. Technically easier, refers to
how easy it is for the surgeon and to the
benefits of faster healing in babies. Very young
children tend to heal faster following surgery,
and the surgery is easier because the area
disturbed is smaller. Also, following surgery,
babies not yet walking, crawling or standing are
less likely to pull stitches out with their
movement.  How do Adult Women with CAH Feel
about the Timing of Surgery? Some adult women
with CAH recommend that parents wait and allow
the child to make the decision as an adult.  Some
adult women with CAH recommend that parents wait
until the child is old enough to be consulted
about her desires for surgical reconstruction.
Others are grateful that their parents made the
decision for them early in life and that they did
not have to deal with growing up with genital
anomalies. 
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What are the differences among reduction
clitoroplasty, vaginoplasty and
labioplasty?Genital reconstruction in CAH
generally involves three separate procedures.
These are often done at the same time when early
surgery is chosen.  Clitoral reduction surgery
(clitoroplasty) involves reducing the size of the
clitoris by removing a portion of the erectile
tissue.  If done properly, the nerve bundles are
preserved and left intact.  The CAH Consensus
Statement states that, surgery to reduce the
clitoral size requires careful consideration. 
Total removal of the clitoris should never be
performed.  If clitoral reduction is elected, it
is crucial to preserve the neurovascular bundle,
the glans, and the preputial skin related to the
glans. Vaginoplasty involves rebuilding the
vaginal area to improve functioning of the vagina
and urethra.  This involves creating a vaginal
opening on the perineum separate from the
urethra. It is often done by moving the recessed
vagina out to the perineum or can include
complete separation of the vagina from urethra at
the site of confluence.
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Confluence in CAH where the urethra and vagina
meet. (courtesy RC Rink) Labioplasty is the
construction of the labia majora and/or minora
when absent or inadequate. Most children with CAH
are lacking labia minora so they are created. The
labia majora , while present often require
repositioning.
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The Consensus Statement on Management of
Intersex Disorders (Hughes, et als, 2006),
states The surgeon has a responsibility to
outline the surgical sequence and subsequent
consequences from infancy to adulthood. Only
surgeons with expertise in the care of children
and specific training in the surgery of DSD
should perform these procedures. Parents now
appear to be less inclined to choose surgery for
less severe clitoromegaly. Surgery should only be
considered in cases of severe virilization
(Prader III, IV and V) and be performed in
conjunction, when appropriate, with repair of the
common urogenital sinus. As orgasmic function and
erectile sensation may be disturbed by clitoral
surgery, the surgical procedure should be
anatomically based to preserve erectile function
and the innervation of the clitoris. Emphasis is
on functional outcome, rather than a strictly
cosmetic appearance. It is generally felt that
surgery that is performed for cosmetic reasons in
the first year of life relieves parental distress
and improves attachment between the child and the
parents. The systematic evidence for this belief
is lacking. Hence, clitoroplasty should not be
performed on mildly virilized girlsthose whose
virilization is below Prader 3.
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When is vaginoplasty appropriate?When the
vagina, because of internal fusion with the
urethra (common urogenital sinus), does not
extend all the way to the perineum (the front of
the body), urine may pool in the vagina or
backflow into the bladder where it can cause
infection and discomfort.  In addition, in some
girls, the common urogenital sinus may be
inadequate for the flow of menstrual blood. 
Therefore, vaginoplasty is often performed in
these girls to avoid backup of the menstrual
flow, discomfort and possible infections.
Possible Backflow Problems (courtesy RC Rink)
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How will my daughter look after the
surgery?First ask to see some pictures of the
surgeons work.  They will be happy to show you. 
Please remember that directly after the surgery
the area will appear swollen and bruised as would
any surgical site of the body.  The actual
results will not be seen for about six months
when the swelling and bruising subside. There may
be some exterior scarring, but an experienced
surgeon should deliver a good cosmetic result.
Functional results (loss of sexual sensation)
will not be known until the girl is much older.
What has been the outcome of previous
surgeries?There are many female adults living
with CAH and the consequences of genital
surgeries.  Unfortunately, there have been few
studies that look at long-term follow-up of CAH
reconstructive surgery.  Also, the techniques for
performing both clitoroplasty and vaginoplasty
have improved significantly over the years,
resulting in better functional and cosmetic
results. In the past, techniques used did cause
significant problems for women with CAH.
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COMPLICATII INCLUZII TESTICULARE DE TESUT ADRENAL
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Weight Management for Children with CAHby
Michelle May, MD Hot from the headlines
Obesity has reached epidemic proportions in our
society, fast approaching smoking as the leading
cause of preventable disease and death. Although
this is a frightening statement, obesity can be
prevented. Prevention of obesity and the
development of lifetime healthy eating habits
begins in childhood. Currently, 15 percent of
children and adolescents are overweight or obese,
putting them at risk for high cholesterol, high
blood pressure, and type 2 diabetes. They may
also face social stigmatization, have low
self-esteem, and face an increased chance of
adult obesity. Children with CAH are particularly
at risk for weight problems due to the bodys
reaction to glucocorticoid therapy. Some children
complain of increased appetite with medication
increases, and oversuppression can cause excess
weight gain. Even once the oversuppression is
eliminated, excess weight may still continue to
be a problem.
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Weight Management for Children with CAHby
Michelle May, MD Children with CAH are
particularly at risk for weight problems due to
the bodys reaction to glucocorticoid therapy.
Some children complain of increased appetite with
medication increases, and oversuppression can
cause excess weight gain. Even once the
oversuppression is eliminated, excess weight may
still continue to be a problem. So what can you
do? Consult your childs endocrinologist and
primary care physician to discuss whether your
child is significantly overweight. Then,
determine if there are medical issues
contributing to their weight problems (such as
oversuppression), or if their weight is causing
any medical problems. Then together, you can
determine the best approach for helping your
child reach a healthier weight. Many overweight
children do not actually need to lose weight, but
instead, can maintain their weight while they
"grow into it." Even for extremely overweight
children, weight loss should be gradual. Since
many overweight children are still growing, their
diet must be nutritious and their exercise
program should be safe and enjoyable.
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Build Healthy AttitudesDemonstrate your
unconditional love for your child.
Childrenespecially overweight childrenneed
support, acceptance, and encouragement from their
parents. Build self-esteem by focusing on all of
your childs positive qualities, unique talents,
and individuality. By developing interests and
skills that increase their success and pleasure,
they will be less likely to turn to food for
fulfillment.Help your child develop good
communication skills, encourage them to express
their feelings, and teach them effective coping
skills to decrease the chance that food will
serve that purpose. Emphasize the importance of
good health, not ideal weight.Never tease or
criticize a child or adolescent about their
weight. Such comments are hurtful and can stick
with a person for a lifetime.Be a positive role
model. When your child observes you enjoying
healthful foods and physical activity, they are
more likely to do the same.
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Develop Healthy Eating Habits Children have the
ability to regulate their caloric intake to meet
their needs. Respect these internal cues of
hunger and satisfaction.Do not force children
to clean their plates or bribe them with dessert
for finishing their meal. Never use food as a
reward. Reward desired behavior with praise,
extra attention, and privileges.Do not comfort
your child with food.Do not impose stringent
food rules, since this may lead to rebellious
eating when the child is away from parental
control. Dont say or imply that some foods are
"good" while others are "bad." Instead, teach
children that some foods are healthier than
others. This will help them learn to balance
eating for health with eating for
pleasure.Involve children in shopping, meal
planning, and preparation. This is a great
opportunity to teach them about nutritionand
they will be more likely to try new foods if they
helped make them!
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Develop Healthy Eating Habits Since children
(and adults!) have a natural preference for sweet
and high fat foods, its reasonable to limit the
amount of sugary and fatty foods that are readily
available to encourage intake of more nutrient
dense foods. Provide a variety of delicious
healthy choices for snacks and mealtimes.
Suggestions include fresh or dried fruits,
vegetables with tasty low fat dips, pretzels,
reduced fat cheese or peanut butter and crackers,
yogurt, fruit smoothies, whole fruit ice pops,
granola bars, turkey roll-ups, or snack mixes
made of cereal, dried fruit, and nuts. A
healthy breakfast is a great way to start the day
and is important for achieving and maintaining a
healthy weight.Encourage children to drink
water and fat free or low fat milk instead of
sugary sodas, fruit drinks, and sports
drinks.Promote a high fiber diet by giving your
child whole wheat breads and pastas, brown rice,
and five servings of fruits and vegetables daily.
They will prefer these types of foods if that is
what they are used to.Perhaps most importantly,
sit down and eat together as a family. Mealtimes
should be a pleasant time to reconnect with one
another.
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Enjoy an Active Lifestyle Help your child build
a lifetime exercise habit by making consistent
physical activity a high priority in your
family. For children that have been relatively
inactive, an exercise program should be initiated
very gradually to avoid injury and
discouragement. Encourage active play like
biking, swimming, and playing ball. Participatio
n in individual and team sports can be a great
way to build coordination, athletic skills, and
self-confidence. Reduce the amount of time
your family spends in sedentary activities like
TV and video games. Instead, plan fun family
activities that provide everyone with exercise
and enjoyment. While management of weight
problems in childhood can be difficult, the
benefits can last a lifetime!
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Ehrhardt (1975) studied 17 female CAH patients
age 4.3 to 19.9 years,
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CAH appears to have a significant effect on
gender role behaviours. Patients exhibit
significantly more male-typical behaviours than
unaffected siblings.
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Money, Schwartz Lewis (1984) asked 30 women
born with CAH about their sexual orientation.
Their replies are shown in this diagram together
with an estimate of the base rate of female
homosexuality according to Kinsey 1953. See
Carlson for further details. 40 of CAH patients
were exclusively heterosexual 37 were bisexual
or homosexual Zucker et al (1996) review eight
studies that have explored sexual orientation in
women with CAH. Zucker et al (1996) found that
most women with CAH have a female gender
identity. However, significantly more women with
CAH live as men than would be expected by chance
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4. Metabolic Syndrome Manifestations in Classic
Congenital Adrenal Hyperplasia (Evangelia
Charmandari, George P. Chrousos)Classic
congenital adrenal hyperplasia (CAH) due to
21-hydroxylase deficiency is an autosomal
recessive disorder characterized by impaired
adrenocortical and adrenomedullary function, and
adrenal hyperandrogenism. Compared to normal
subjects, patients with classic CAH have
increased incidence of obesity and visceral
adiposity, hyperinsulinism and insulin
insensitivity, hypertension and hyperandrogenism.
The impaired adrenomedullary function,
intermittent hypercortisolism, and adrenal and/or
ovarian hyperandrogenism in the not adequately
controlled patients and females with polycystic
ovarian syndrome, may account for the above
abnormalities and may predispose these subjects
to the development of metabolic syndrome-related
atherosclerotic cardiovascular disease in
adulthood. The aim of the present study is to
investigate whether treatment with insulin
sensitizers improves the metabolic profile of
patients with classic CAH.
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BMD si CAH