Pediatric
Cushing's
Cushing's syndrome in
children
By: Meg
Keil, MS, CRNP
How is Cushing's
syndrome (CS) in children different than in adults?
- CS in children
is rare. An estimated 10 to 15 of every million people are affected
a year and only about ten percent of these new cases occur in
children.
- For pre-pubertal
children, and certainly for toddlers, adrenal tumors (e.g. adenoma,
carcinoma, or bilateral hyperplasia) are a more common cause of
CS. In older children, pituitary adenomas are a more common cause
of CS. Ectopic (a site other than pituitary or adrenal) sources
of CS are extremely rare in children. Overall, there is a female
to male predominance, which decreases with younger age.
- There is
no single symptom shared by every child with CS. It is common
for children with CS to show an increase in rate of weight gain
accompanied by a decrease in growth rate (linear height). Figure
A shows a growth chart that is typically seen in children with
CS. Other problems that may occur in children with CS include:
rounded face, reddened
 cheeks,
acne, headache, excess hair growth (fine downy hair on cheeks,
arms, and legs), purplish-pink stretch marks (more common in older
children), darkened skin around neck and armpit areas, easy bruising,
development of pubic hair at a younger age than usual, irregular
or absent menstrual periods, and high blood pressure. Figure B
shows a photograph of a girl with CS standing next to her twin
brother who does not have CS.Compared to adults with CS, symptoms
that are less commonly seen in children include: sleep disruption,
mental changes, and muscle weakness. Although many adults with
CS report change in mental status that affect their job performance,
children with CS do not usually report problems with school performance.
What should I do if I think my child might have CS?
- Schedule
an appointment with a pediatrician or pediatric endocrinologist
immediately. Take pictures that show what your child looked like
prior to the start of the symptoms of possible CS. As with adults
with possible CS, the diagnosis is not always easy.
- The diagnosis
of CS is based on a review of your child's medical history (including
possible exposure to medications or other substances that contain
steroids), physical examination, review of growth data (growth
chart), and laboratory tests. Ask your child's doctor to review
your child's growth chart with you. If the growth chart shows
an increase in the rate of weight gain and decrease in the rate
of linear growth (height velocity) during the same time period,
then further evaluation and monitoring is needed to determine
the cause.
How is CS
diagnosed?
It is important for children to be evaluated by a pediatric endocrinologist
who is experienced with CS, since some of the tests require adjustment
for the pediatric patient. When the diagnosis of CS is suspected,
it is important to document hypercorticolism (high cortisol levels).
The best way
to screen for elevated cortisol levels in children is a 24 hour
urine collection for urinary free cortisol (UFC) determination.
Frequently, more than one 24hour urine collection is advised for
screening. If the results of the 24-hour UFC show elevated values,
then a referral to a pediatric endocrinologist is advisable. It
is important to remember that in order to correctly interpret the
results of the 24-hour UFC, the result must be "corrected"
for the child's body size ( or 'body surface area', a mathematical
formula that is based on the child's height and weight). High UFC
values can be caused by other conditions, such as physical and emotional
stress, obesity, pregnancy, chronic exercise, depression, etc. These
conditions may cause what is known as pseudo-Cushing's syndrome.
Although this is more common in adults, it is frequently seen in
children, especially in obese children or adolescents with other
medical or psychological problems.
Salivary cortisol
levels (collecting saliva in a tube at midnight and in the morning)
are also used as a screening test. Normally, the cortisol level
in the body is very low at midnight (when we are in the deepest
of the sleep phases), and higher in the morning. With CS, the body
loses the diurnal pattern (day vs. night) and the cortisol levels
at midnight are higher than expected; often not very different from
the early morning cortisol level.
Another screening
test is the low-dose dexamethasone test, which involves giving one
milligram of dexamethasone (adjusted for the child's weight) and
measuring the morning cortisol level in the blood. Results of a
study done at N.I.H. show that in the morning, the cortisol level
should be less than 5mcg/dL. Recent data in adults suggests a value
less than 1.8mcg/dL rules out Cushing's. The low-dose dexamethasone
test has not been validated extensively in children.
Once the diagnosis
of CS is confirmed, additional testing is needed to determine the
cause. If possible, it is best to have the diagnostic evaluation
done in a pediatric endocrine center experienced with the evaluation
of CS. Testing is done to determine whether the CS is due to an
adrenal, pituitary, or ectopic cause (ACTH dependent or not). It
is beyond the scope of this article to review in detail the various
diagnostic tests used in the evaluation of CS. Some tests are done
to confirm the diagnosis of CS and some tests are done to distinguish
the specific cause of CS. Please refer to the CSRF web site for
more specific information about these tests.
Imaging studies
are an important tool in the diagnostic evaluation of CS. When CD
is suspected, magnetic resonance imaging (MRI) of the pituitary
(with contrast enhancement) should be performed. Generally, pituitary
MRI may detect only about half of ACTH producing pituitary tumors;
however, recently, at the National Institutes of Health, a new MRI
technique has been developed (SPGR-MRI) that may increase sensitivity
to 70-80%. Finally, computed tomography (CT) of the adrenal glands
is helpful in the evaluation of pituitary versus adrenal causes
of CS.
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Treatment
- Treatment
for CS depends on the specific cause of the cortisol excess. Referral
to a pediatric endocrinologist who is experienced with the diagnosis
and treatment of CS is very important. Prolonged exposure of the
body to excess cortisol levels has many negative effects, including:
obesity, loss of final height, high blood pressure, osteoporosis
and other orthopedic problems, diabetes, and increased susceptibility
to infections.
- Pituitary
tumors (adenomas) are usually treated by surgical removal, which
is known as transsphenoidal surgery (TSS). Due to the highly specialized
nature of this surgery, referral to a neurosurgeon who is experienced
with this procedure is recommended. In certain patients, treatment
with medication(s) that control or block cortisol production,
may be done on a short-term basis. In some patients, when surgery
has failed (or if they were not good candidates for surgery, which
is very rare in children but more frequent in adults), radiation
therapy is indicated.
- Adrenal
tumors and bilateral hyperplasia (bilateral adrenal nodular disease,
primary pigmented adrenal nodular disease) are treated surgically,
by either unilateral or bilateral adrenalectomy, as appropriate.
Will my
child lead a normal life after treatment for CS?
- Various
studies report that one year after surgical cure of CS most children
had lost weight and body mass and their height and growth velocity
had increased; however final adult height is often impaired (by
at least an inch or more).
- Risk factors
associated with TSS for removal of a pituitary adenoma include
temporary or permanent dysfunction of the pituitary gland. Therefore,
it is important for the child and adolescent to be monitored on
a routine basis by a pediatric endocrinologist to screen for any
problem with pituitary gland function, including hypothyroidism,
adrenal insufficiency, growth hormone insufficiency, pubertal
delay. After TSS for CS, daily cortisol replacement is necessary,
typically for a period of six to eighteen months, until the hypothalamic-pituitary-adrenal
axis (HPA) recovers, Many children often experience some symptoms
of steroid withdrawal during this period (e.g. fatigue, headache).
- Children
and adolescents who undergo bilateral adrenalectomy for treatment
of CS experience a recovery period that is similar to other patients
who undergo major abdominal surgery (depending on whether the
procedure is able to be performed by laproscopy or not). Because
both adrenals are removed, these children will require daily hormone
replacement (hydrocortisone and fludrocortisone) for the rest
of their life. In addition, the hydrocortisone dose will require
adjustment during illness episodes and significant physical stress
(e.g. surgery, trauma).
- Children
with an adrenal tumor that requires the removal of a single adrenal
need to take daily hydrocortisone replacement until the HPA axis
recovers, just like patients with surgically resected pituitary
tumors.
- Most children
and adolescents who are recovering from CS are able to resume
normal physical activities within several weeks to months. Many
children and adolescents recovering from CS experience changes
in cognitive performance that can be stressful for both the child
and the parents. The brain is affected by prolonged exposure to
abnormally high cortisol levels and once the cortisol levels are
normalized there is a period of readjustment. Symptoms reported
by some children and adolescents include difficulty concentrating
and problems with memory that may affect their academic performance
for an indeterminate period. It is important to provide appropriate
educational and psychological resources for the child or adolescent
during this period.
Editor's
Note: Meg Keil,MS, CRNP is a nurse practitioner at the NIH in
Bethesda, MD in the pediatric endocrinology division. She is
an associate investigator for two protocols for the evaluation
and treatment of pediatric Cushing's at NIH. (Dr. Constantine
Stratakis, a pediatric endocrinologist, is the principal investigator
for these protocols.) She can be reached at: 301-435-3391 or
email: meg_keil@nih.gov
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