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.
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
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 17hydroxyprogesterone 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.
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 nonspecific, 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
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 17hydroxyprogesterone, 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
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 17hydroxyprogesterone (17-OHP). The scales are logarithmic. A regression line for all data
points is shown.
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.
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 17hydroxyprogesterone 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.
Deficiency
11 beta-hydroxylase
17 alpha-hydroxylase
3 beta-hydroxysteroid
dehydrogenase
aldosterone synthase
StAR
Incidence
Comments
~1 in 100,000 livebirths
Females virilized; saltwasting is rare
rare
Males virilized; females
fail to achieve puberty.
Salt-wasting not
observed.
rare
Males virilized; female
virilization mild. Saltwasting may be seen.
rare
Cortisol concentrations
normal and virilization not
seen. Salt-wasting
occurs.
rare
Males virilized; females
fail to achieve puberty.
Salt-wasting occurs.
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]
</<
</< td>
</< td>
td>
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
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 Nonclassical 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.
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 Nonclassical 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.
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.
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.
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
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.
Prenatal Testing for CAH
Prenatal 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.
Prenatal Testing for CAH
The cells obtained are taken to a laboratory and grown so that the DNA can
ultimately be obtained and tested.
Amniocentesis 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.
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.
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.
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
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.
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.
The importance of regular follow-up
To 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.
The Usefulness of Bone Ages
One 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.
Laboratory Testing
Monitoring of Hormone Levels in CAH
The 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.
Laboratory Testing
Blood Testing
Assessing 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.
Laboratory Testing
Blood Testing
For 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.
Laboratory Testing
Blood Testing
To 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 Specimens
Whereas 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.
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)
Males:150 (100-300)600 (300-1000)
Female: 25 (15-35) 30 (10-55)Urine testing
17 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.
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 decisionmaking process.
How different are our daughter’s 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 daughter’s pediatric
urologist or pediatric endocrinologist will be able to tell you what Prader Level
she is.
Typical Prader 4
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 21Hydroxylase Deficiency; Endocrine Reviews 21(3): 245-291; 2000)
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, “[b]ased 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.
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,
“[s]urgery 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.
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.
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 girls—those
whose virilization is below Prader 3.
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)
How will my daughter look after the surgery?
First ask to see some pictures of the surgeon’s 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 longterm 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.
COMPLICATII INCLUZII TESTICULARE DE
TESUT ADRENAL
Weight Management for Children with CAH
by 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
body’s 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.
Weight Management for Children with CAH
by Michelle May, MD
Children with CAH are particularly at risk for weight problems due to the
body’s 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 child’s 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.
Build Healthy Attitudes
Demonstrate your unconditional love for your child. Children—especially
overweight children—need support, acceptance, and encouragement from
their parents.
Build self-esteem by focusing on all of your child’s 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.
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.
Don’t 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 nutrition—and they will be more likely to try new
foods if they helped make them!
Develop Healthy Eating Habits
Since children (and adults!) have a natural preference for sweet and high fat
foods, it’s 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.
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.
Participation 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!
Ehrhardt (1975) studied 17 female CAH patients: age 4.3 to 19.9
years,
CAH appears to have a significant effect on gender role behaviours.
Patients exhibit significantly more male-typical behaviours than unaffected
siblings.
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
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.
BMD si CAH