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PEDIATRICS Vol. 106 No. 6 December 2000, pp. 1511-1518
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ABSTRACT |
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Top
Abstract
References
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The Section on Endocrinology and the Committee on Genetics of the American Academy of Pediatrics, in collaboration with experts from the fields of pediatric endocrinology and genetics, developed this policy statement as a means of providing up-to-date information for the practicing pediatrician about current practice and controversial issues in congenital adrenal hyperplasia (CAH), including the current status of prenatal diagnosis and treatment, the benefits and problem areas of neonatal screening programs, and the management of children with nonclassic CAH. The reference list is designed to allow physicians who wish more information to research the topic more thoroughly.
Congenital adrenal hyperplasia (CAH) consists of a family
of disorders caused by reduced activity of enzymes required for cortisol biosynthesis in the adrenal cortex. The most common defect is
21-hydroxylase (21-OH) deficiency, which accounts for >90% of all
cases of CAH. Classic 21-hydroxylase deficiency is found in about 1:12
000 to 1:15 000 births; the frequency of nonclassic deficiency is
unknown, although it may occur in up to 3% of individuals in certain
groups. Clinical consequences of 21-OH deficiency arise primarily from
overproduction and accumulation of precursors proximal to the blocked
enzymatic step. These precursors are shunted into the androgen
biosynthesis pathway, producing virilization in the female fetus or
infant and rapid postnatal growth with accelerated skeletal maturation,
precocious puberty, and short adult stature in both males and females.
Approximately 75% of patients with classic 21-OH deficiency also have
a defect in their ability to synthesize aldosterone. Such patients,
especially undiagnosed male infants, may die during the newborn period
of shock resulting from salt wasting.
Recent advances in molecular genetic analysis allow for prenatal
diagnosis and treatment of at-risk fetuses. However, controversy remains regarding the efficacy and safety of prenatal intervention that
attempts to minimize prenatal virilization in girls. Other controversial issues include the optimal regimen for postnatal treatments and the effects of long-term corticosteroid therapy on final
height, sexual function, and fertility. Approximately 20 states include
screening for CAH as a part of their newborn screening profiles. The
cost-effectiveness of the programs in detecting patients who would not
have been diagnosed before clinical manifestation of CAH continues to
improve as new standards for levels of 17 This review is designed to provide current information on prenatal
diagnosis and treatment, the status of newborn screening, methods of
diagnosis of affected patients and heterozygote carriers, and newer
treatment approaches for CAH.
The objective of prenatal diagnosis and treatment of 21-OH
deficiency is the prevention of prenatal virilization in affected female infants and the early recognition of the potential for salt
wasting in the newborn infant.
Prenatal Diagnosis of 21-OH Deficiency
Prenatal prediction of CAH attributable to classic 21-OH
deficiency is possible by using a number of modalities: determination of amniotic fluid (AF) hormone levels, human leukocyte antigen (HLA)
typing of chorionic villus cells and/or AF cells, and molecular genetic
studies of chorionic villus cells and AF cells. Advances in molecular
genetic techniques have made molecular genetic studies the test of
choice.
Prenatal diagnosis of CAH was first reported in 1965, based on elevated
levels of AF 17-ketosteroids and pregnanetriol.1 In 1975, the association between an elevated 17-OHP concentration in AF and the
birth of an infant with salt-wasting CAH was reported.2
Subsequent reports have confirmed the usefulness of AF 17-OHP concentrations for the prenatal diagnosis of classic CAH attributable to 21-OH deficiency.3-13 Although amniocentesis has been
performed routinely during the second trimester in women at risk of
having an infant with CAH, elevated 17-OHP levels in AF obtained as
early as 9 to 13 weeks in pregnancies with an affected fetus have been
reported. Androstenedione levels ( Because the gene for 21-OH has been linked to the HLA system on
chromosome 6, prenatal prediction of CAH may be made by HLA typing of
cultured AF cells and cultured chorionic villus
cells.5,7,10,13-18 Use of chorionic villus cells permits
earlier identification of the affected fetus than is possible with
amniocentesis. In a pregnancy in which the fetus has an HLA type
identical to that of the index case with 21-OH deficiency, the fetus is
predicted to be affected. The fetus that shares 1 parental haplotype
with the index case is predicted to be a heterozygous carrier, and the
fetus with both haplotypes different from the index case is predicted
to be homozygous normal.
The preferred technique for prenatal diagnosis is molecular genetic
analysis using DNA extracted from chorionic villus cells or amniocytes
for analysis of CYP21B, C4 and HLA class I and II genes.18-23 Advances in these molecular techniques have
made genetic characterization more reliable and rapid,24
such that in most centers the analysis of fetal P450c21B
genes from chorionic villus cells or amniocytes has largely replaced hormonal and HLA analysis in the prenatal diagnosis of CAH attributable to 21-OH deficiency.25 Causative mutations can now be
identified on 95% of chromosomes using Southern blot analysis and
selective amplification of the CYP21B gene by polymerase
chain reaction, followed by allele-specific hybridization with
oligonucleotide probes for a panel of 9 known CYP21B
mutations.26 A newly developed, rapid, allele-specific
polymerase chain reaction has been used for prenatal
diagnosis.27 Mutations not detected by this approach can
be characterized by direct sequencing of CYP21B
genes.28,29 Determination of satellite markers also may be
informative. De novo mutations, found in patients with CAH but not in
parents, are found in 1% of disease-causing CYP21B
mutations.28 Accurate prenatal prediction requires the
correct molecular genetic analysis of the index case and molecular
genetic analysis and complete hormonal profiling of the parents.
Prenatal Treatment of CAH Attributable to 21-OH Deficiency
Prenatal treatment of CAH to prevent the virilization of an
affected female fetus has been considered desirable by a number of
investigators.2,30-33 Because masculinization of the
external genitalia begins at about 6 to 7 weeks of gestation (8 to 9 weeks after the last menstrual period),34,35 suppression
of the fetal pituitary-adrenal axis at no later than 6 weeks of
gestation theoretically could prevent ambiguity of the external
genitalia in the female fetus with classic CAH, whereas therapy after
that time would prevent progression of virilization.
Successful prenatal treatment to ameliorate or prevent virilization of
a female fetus with classic CAH attributable to 21-OH deficiency was
first reported in 1984.36 In 2 pregnancies at risk for
classic salt-wasting CAH, the mothers were treated with hydrocortisone
and dexamethasone, respectively. Subsequent amniocentesis demonstrated
that both infants were girls and had HLA types identical to those of
their affected siblings, and treatment was continued to term. At birth,
the external genitalia were normal in the infant whose mother was given
dexamethasone and minimally virilized in the infant whose mother
received hydrocortisone. Postnatally, the diagnosis of 21-OH deficiency
was confirmed in both infants.36 There are reports of >50
affected female infants in whom prenatal treatment with dexamethasone
has been attempted. The dose of dexamethasone has ranged between 0.5 and 2 mg/d in 1 to 4 divided doses. Treatment was begun as early as the
4th week of pregnancy to as late as the 16th week. In some cases,
treatment was interrupted for 5 to 7 days before amniocentesis, and, in
a few cases, treatment was discontinued at 21 to 26 weeks.18,21-23,37-53
Fetal Outcome
Of the total number of cases for which data are available,
treatment was considered successful for almost three fourths of the
female infants; approximately one third had normal genitalia, and two
thirds were described as being mildly virilized with clitoromegaly, partial labial fusion, or both. In slightly more than one fourth of all
female infants treated, therapy was unsuccessful, and the infants had
marked genital virilization.
The variability of the results has been attributed to a number of
factors: inadequate dosage, interruption of treatment, delay in
initiating treatment, variability in maternal metabolic clearance, and
variability of placental metabolism of the administered
glucocorticoid.23,50 Variability in onset of fetal sexual
differentiation and maternal noncompliance to therapy also must be
considered.23,50
Spontaneous abortion, fetal demise during late pregnancy, intrauterine
growth retardation, liver steatosis, hydrocephalus, agenesis of the
corpus callosum, and hypospadias with unilateral cryptorchidism51 have been reported occasionally when
mothers received short-term treatment in unaffected pregnancies, as
well as in affected pregnancies in which the mother received prolonged
corticosteroid treatment. These events generally have not been
considered related to the treatment or to the disease
itself.17,45,49,50 In a report of intrauterine growth
retardation in an infant treated successfully for CAH, however, it was
concluded that intrauterine growth retardation still should be
considered "a possible fetal complication of
treatment."46 In long-term follow-up of most infants
treated throughout the pregnancy or treated prenatally until
midgestation,17,44-50 development seems to be normal, and
growth has been consistent with the family pattern and that of the
other affected siblings.17,41,42,44,45 Rare adverse
events, including failure to thrive and psychomotor and psychosocial
delay in development, have been observed.51 Long-term
follow-up is limited, however, and detailed neuropsychological evaluations have not been reported.
In a preliminary report, cognitive and behavioral development of young
children aged 6 months to 5.5 years treated prenatally with
dexamethasone because of risk for CAH was assessed by standard questionnaires completed by the mothers. The development of those children was compared with the development of children from untreated pregnancies at risk for CAH.52 No significant differences
in cognitive abilities or behavior problems were
identified.50 However, the demonstration of an increased
frequency of neurologically silent white matter abnormalities and
temporal lobe atrophy in children and adults with CAH indicates that
the long-term effects of glucocorticoids on the central nervous system
are not fully known and must be evaluated carefully.54
Although experimental treatment given to animals cannot be directly extrapolated to humans, high doses of dexamethasone administered to rhesus monkeys toward the end of gestation were associated with abnormalities of the fetal brain consisting of neuronal
degeneration of hippocampal, pyramidal, and dentate
regions.55 Other animal studies have focused on long-term
cardiovascular risks of prenatal dexamethasone treatment.
Intrauterine growth retardation, lower kidney weight,
oligonephronia, and the development of hypertension in adulthood
have been demonstrated in rat pups whose mothers received dexamethasone
prenatally.56-58 These studies underscore the need for
careful long-term outcome studies of prenatal dexamethasone treatment,
in which treated mothers and infants are followed up to determine
possible ill effects in later adult life.
Maternal Complications of Prenatal Treatment
Maternal adverse effects of dexamethasone may be serious
and long-lasting.23,44 Reported adverse effects include
edema, excessive weight gain, irritability, nervousness, mood swings,
hypertension, glucose intolerance, chronic epigastric pain,
gastroenteritis, cushingoid facial features, increased facial hair
growth, and severe striae with permanent
scarring.17,18,23,40,44-47,49,50
In a European survey, adverse effects occurred in approximately one
third of women who were treated until delivery and for whom data were
available.48 Marked weight gain, reported in approximately
25%, was the most common problem.48 The maternal adverse
effects prompted decreasing the dosage or discontinuing treatment and
may have resulted in nonadherence with therapy and unsatisfactory
genital outcome for the infant.40,49 Transient symptoms of
glucocorticoid deficiency on tapering or discontinuing treatment have
been reported rarely.17,41 A recent report indicated that
one third of the mothers who received dexamethasone treatment during
pregnancy would not elect treatment in a future
pregnancy.51
Current Recommendations for Prenatal Diagnosis and Treatment
Prenatal diagnosis and treatment is performed most commonly in
families with a previously affected child with CAH with a defined genetic defect.
Informed consent, in which the risks of possible maternal adverse
effects, variable genital outcome, and possible but presently unknown
long-term effects of dexamethasone treatment on the treated children
are discussed, should be obtained from all parents seeking genetic
counseling before prenatal diagnosis and treatment. Mothers with
previous medical or mental conditions that may be aggravated by
dexamethasone, such as psychosis, hypertension, overt diabetes, gestational diabetes, or toxemia, should not be treated or should be
treated only with extreme caution. Patients should be referred to
centers with expertise in the prenatal management of pregnancies at
risk for CAH. Treatment should be initiated by the fifth week of
gestation with dexamethasone, at a dose of approximately 20 to 25 µg/kg per day, given in 2 or 3 divided doses. Chorionic villus
sampling during the 9th to 10th week of gestation for prenatal diagnosis should be performed with karyotyping, and, optimally, HLA, CYP21B, and C4 gene analysis of chorionic
villus cells. If chorionic villus sampling is performed during the 10th
to 11th week, a small amount of AF can be obtained for hormonal
analysis as well, to gain some measure of fetal adrenal suppression. If the fetus is a boy or an unaffected girl, treatment is discontinued. If
the fetus is an affected girl, or if prenatal diagnosis by chorionic
villus sampling is unsuccessful or not performed, treatment is
continued. If necessary, for further clarification, amniocentesis can
be performed at 15 weeks with genetic analysis of amniocytes and
hormonal determination in the AF. If the fetus is an affected girl,
treatment is continued to term. It is important to note that if the
mother is receiving treatment with dexamethasone, hormonal analysis of
AF is unreliable for prenatal diagnosis. Furthermore, because only 1 of
8 infants will be an affected girl, 7 of 8 infants will be treated
unnecessarily for at least 12 weeks.
Maternal monitoring for physical, hormonal, and metabolic changes
should begin at the initiation of treatment and should be continued
throughout the pregnancy. The serum estriol level to evaluate adequacy
of fetal adrenal suppression and the fasting blood glucose level should
be determined monthly, and an oral glucose tolerance test should be
performed during the second and third trimesters. In the presence of
excessive weight gain, increased blood pressure, and glucose
intolerance or other adverse effects, prompt intervention should be
instituted. Consideration should be given to reducing the dosage of
dexamethasone during the second and third trimesters.
Maternal treatment seems to prevent or reduce virilization in
approximately 75% of affected female fetuses but has not been uniformly successful in all pregnancies. Its efficacy and safety remain
to be fully defined. It should be offered only to patients who have a
clear understanding of the possible risks and benefits and who are able
to comply with the need for close monitoring throughout pregnancy and
the need for long-term follow-up of the infants, children, and adults
treated prenatally.
The major objectives of newborn screening for CAH attributable to
21-OH deficiency are to identify infants at risk for the development of
life-threatening adrenal crisis and to prevent the incorrect male sex
assignment of affected female infants with ambiguous genitalia. The
former is particularly important for affected boys whose initial
manifestation may be adrenal crisis. In addition, early identification
will permit the monitoring and treatment of affected infants and
children to prevent postnatal exposure to excessive androgens and the
accompanying clinical manifestations. In 1977, newborn screening for
21-OH deficiency became possible after development of the method to
measure 17-OHP in a heel-stick capillary blood specimen on filter
paper. A pilot newborn screening program was developed in Alaska
shortly thereafter. National and regional screening programs now have
been developed worldwide, and in almost 20 states.59-61
Data on >8 million neonates screened are available. The disorder occurs in 1 of 21 000 newborns in Japan, 1 of 10 000 to 16 000 in
Europe and North America, and 1 of 300 in Yupik Eskimos of Alaska.
About 75% of affected infants have the salt-losing, virilizing form,
and 25% have the simple virilizing form of the disorder. The
nonclassic form is not detected reliably by newborn screening.
Newborn Screening Procedures and Cost Analysis
Neonatal screening for CAH requires the following procedures for
optimal efficiency and effective screening results: 1) early sample
collection, ideally between 2 and 3 days of life; 2) immediate and
reliable analysis of 17-OHP levels after sample collection; 3)
optimally chosen 17-OHP cutoff levels that distinguish affected from
unaffected newborns; 4) immediate and clear communication of
presumptive positive results to the appropriate health care professional and to family members; and 5) diagnostic confirmation of
newborns with positive screening results.
All CAH newborn screening programs use the measurement of 17-OHP in a
filter paper blood spot sample obtained by the heel-stick technique as
used for newborn screening of other disorders. The concurrent screening
test procedures for disorders such as phenylketonuria and congenital
hypothyroidism, which were established before the initiation of CAH
screening, seem to have influenced the age at which CAH screening
samples were collected in many programs. Although most screening
samples for CAH had been collected between 3 and 5 days after
birth,59,62 recent practices of early discharge from the
nursery and increased numbers of deliveries at birthing centers have
resulted in many screening samples being collected at 1 to 2 days after
birth. This may result in an increased number of false-positive tests.
The majority of screening programs worldwide use a single screening
test without retesting of questionable 17-OHP levels.62
This single-screen method offers the advantage of expedited results but
may cause inaccurate classification in borderline cases. A small number
of programs perform a second screening test of the initial sample to
confirm borderline cases identified in the first screening.62 Although relatively time-intensive, this
approach provides greater accuracy than the single-screen method. One
program (Manitoba, Canada) collects and tests a second sample on
request when 17-OHP levels are elevated above the cutoff level in the
initial test.62 A number of programs mandate 2 screenings
and routinely obtain and test a second sample.62-64 In
addition to detecting infants with the salt-wasting form of CAH and
preventing life-threatening adrenal crisis by using results of the
first screening, this approach is optimal for minimizing false-negative
results by detecting newborns with the simple virilizing and mild forms
of the disorder on the second screening who may not have been
identified initially.59
Laboratory Screening Assay Methods and Cutoff Levels
Three principal assay techniques are used for the initial
screening of CAH in neonates: radioimmunoassay, enzyme-linked
immunosorbent assay, and time-resolved fluoroimmunoassay. These assays
measure the 17-OHP concentration in a filter paper blood spot sample
obtained by the heel-stick technique without prior extraction or
purification. The 17-OHP levels measured by direct fluoroimmunoassay
are significantly higher than levels measured by radioimmunoassay after
extraction. Screening fluoroimmunoassay may overestimate 17-OHP levels
in low birth weight infants weighing <1500 g.65 Although
theoretically 17-OHP concentrations in newborns should be comparable
regardless of the assay method, there is considerable variation in
cutoff levels from one program to another. The 17-OHP cutoff levels
that divide positive from negative screening test results have been
established at greater than the 99th percentile of the mean level in
healthy newborns or on the basis of a normal range established in that
program or on the experience of other programs.62 Other
sources of variation include the different antibodies and reagents used
in the assay systems, varying thickness and density of the filter paper
used for sample collection, and, most significantly, the ethnic
background of the reference newborns.
Reliability of Screening Tests
The reliability of each screening program is based on evaluation
of both the false-negative and false-positive rates. There have been
extraordinarily few false-negative results in newborn screening
worldwide.62 The majority of reported false-positive
results have been caused by low birth weight and premature birth, in
which the 17-OHP levels are invariably higher. Therefore, separate
normative reference levels should be established based on birth weight
or gestational age to minimize an otherwise unacceptably high
false-positive rate. In 1 study, application of multitiered
weight-adjusted 17-OHP cutoff levels compared with a 2-tiered criterion
reduced the number of false-positive results requiring immediate
follow-up testing by >50%, and the rate was reduced by >90% among
low birth weight infants.65 Two-tier weight-adjusted
cutoff levels are being used by many programs with acceptable
false-positive rates,62 but further modification of the
test cutoff levels and recall procedures is necessary in programs with
persistently high false-positive rates.
As more adequate reference data have been developed, 17-OHP cutoff
levels in low birth weight infants have been adjusted, and the
false-positive rates in preterm screening populations have
improved.62,65,66 Issues relating to false-positive
results, however, including the cost of evaluating false-positive cases
and the undesirable psychological effect on patients' families,
continue to be problematic. Therefore, periodic review of 17-OHP cutoff
levels is essential to minimize false-positive and false-negative rates
and ensure high sensitivity and specificity of neonatal screening tests
for CAH. Genotyping for mutations in CYP21B causing CAH has
been suggested as an adjunct to newborn screening.67
In classic 21-OH deficiency, serum levels of 17-OHP are markedly
elevated. However, 17-OHP levels are normally high during the first 2 to 3 days after birth and may range as high as levels found in affected
patients. By the third day, however, levels in healthy infants fall,
and those in affected infants rise to clearly diagnostic levels. Ill,
unaffected infants and premature infants may have elevated levels of
17-OHP. Serum concentrations of testosterone in girls and
androstenedione in boys and girls also are elevated in affected
infants. Salt losers may have low serum sodium and chloride levels,
inappropriately increased urine sodium levels, and elevated levels of
serum potassium and serum urea nitrogen. However, hyponatremia and
hyperkalemia are usually not present before 7 days of age. Plasma
levels of renin are elevated, and the serum aldosterone level is
inappropriately low for the renin level.
In the late-onset variant of CAH, basal circulating levels of 17-OHP
are not as high as in the classic form and may even be normal,
especially if the specimen is not obtained in the morning. Therefore,
for initial screening, blood specimens should be obtained between 7:30
and 8:30 AM. Elevated basal 17-OHP levels may suggest the
diagnosis, but an adrenocorticotropic hormone (ACTH) test with
measurement of serum cortisol and 17-OHP levels is necessary to confirm
the diagnosis. A significant rise in the 17-OHP level 60 minutes after
an intravenous bolus of 0.25 mg of ACTH (1-24) is diagnostic. The
17-OHP-cortisol ratio is markedly elevated, and there may be a blunted
or absent response in cortisol.
Administration of glucocorticoids inhibits excessive production of
androgens and prevents progressive virilization. A variety of
glucocorticoids (hydrocortisone, prednisone, dexamethasone) and dosage
schedules have been used for this purpose. Most often, hydrocortisone
(10-20 mg/m2 per 24 hours) is administered
orally in 3 divided doses. There have been recent problems with
consistent dosing with the liquid formulation of hydrocortisone.
Tablets may give more reliable levels. Infants usually require 2.5 to 5 mg 3 times daily and children, 5 to 10 mg 3 times daily. The morning
dose should be given as early as possible to blunt the early morning
corticotropin increase that begins during the predawn hours. Doses must
be individualized by monitoring growth, bone age, and hormonal levels.
Patients with disturbances of electrolyte regulation (salt losers) and elevated plasma renin activity require a mineralocorticoid and sodium
supplementation in addition to the glucocorticoid.
Maintenance therapy with fludrocortisone acetate (Florinef) (0.05-0.3
mg daily) and sodium chloride (1-3 g) is usually sufficient to
normalize plasma renin activity. Increased doses of glucocorticoid are
indicated during periods of stress, such as infection or surgery, for
salt-losing and non-salt-losing patients.
Non-salt-losing children, particularly boys, frequently are not
diagnosed until 3 to 7 years of age, at which time osseous maturation
may be 5 years or more in advance of chronologic age. Institution of
treatment slows growth and osseous maturation to more nearly normal
rates in some children. In others, especially if the bone age is 12 years or more, spontaneous gonadotropin-dependent puberty may occur as
therapy with hydrocortisone suppresses production of adrenal androgens
and permits release of pituitary gonadotropins if the appropriate level
of hypothalamic maturation is present. This form of superimposed true
precocious puberty may be treated with a long-acting potent luteinizing
hormone-releasing hormone analog.
Patients with nonclassic 21-OH deficiency do not always require
treatment. Many are asymptomatic throughout their lives, or symptoms
may develop during puberty, after puberty, or postpartum. Traditionally, therapy with lower amounts of glucocorticoid than those
required for patients with classic 21-OH deficiency have been used.
Indications for treatment include bone age advancement, severe acne,
hirsutism, menstrual irregularity, and infertility.
The protocol for monitoring these patients varies with personal
preference. Measurements of 24-hour urinary levels of 17-ketosteroids and pregnanetriol are unnecessary. Serum levels of 17-OHP,
androstenedione, testosterone, and renin, measured preferably between
7:30 and 8:30 AM, either before or shortly after taking the
morning medication, usually provide adequate indices of control. Recent
reports indicate that 17-OHP may be measured reliably and accurately at
home using filter paper techniques.68 Careful monitoring
for signs of cortisol and androgen excess, growth and weight gain,
pubertal development, and osseous maturation is important.
The administration of glucocorticoid must be lifelong for all patients
with classic forms of CAH. More potent glucocorticoids tend to suppress
growth more than hydrocortisone. However, after growth is completed,
prednisone, given once or twice daily, or dexamethasone, given as a
single dose at bedtime, may result in adequate suppression of
androgens.
Heterozygous carriers of 21-OH deficiency have been identified by
measuring the ratio of 17-OHP to 11-deoxycortisol or cortisol 60 minutes after an intravenous bolus injection of 0.25 mg of ACTH (1-24)
and, in families with an affected individual, by HLA genotyping.
Molecular characterization, alone or in combination with hormonal
measurements and HLA genotyping, should be used when available for
genetic counseling.
A number of clinical trials have been designed to evaluate the efficacy
of new treatment modalities. These modalities should be considered
experimental at this time.
Because it is recognized that patients with Addison's disease are more
easily and successfully treated than patients with CAH, adrenalectomy
for patients with salt-wasting 21-OH deficiency has been suggested as a
possible mode of therapy. This would eliminate the difficult problems
of achieving adequate suppression of adrenal androgens without giving
excessive glucocorticoid, and without the rapid advancement of bone age
and early virilization that occur with inadequate adrenal androgen
suppression. Adrenalectomy has been performed for treatment of 21-OH
deficiency. Long-term follow-up of a large number of patients will be
necessary to determine the safety and efficacy of this mode of
therapy.69
Preliminary use of a combination of an antiandrogen (to block androgen
effect) and an aromatase inhibitor (to block conversion of androgen to
estrogen) with a reduced hydrocortisone dose also has been
reported.70,71 Again, long-term studies are
required to determine if this regimen will further improve
the final outcome. The use of synthetic blockers of the
corticotropin-releasing hormone and corticotropin receptors theoretically could provide a pharmacologic adrenalectomy and may
provide additional future treatment options.
CAH is a chronic disease requiring lifelong monitoring and treatment.
The diagnosis and treatment are complex, requiring specific training
and expertise to individualize therapy. Thus, a pediatric endocrinologist ideally should be involved in the management of all
children and adolescents with CAH. A high index of suspicion should be
present in any infant with ambiguous genitalia and nonpalpable testes,
especially in the presence of increased pigmentation of nipples,
genitalia, and/or skin creases. A family history of early neonatal
deaths or previously affected family members adds to the risk of having
CAH. Markedly elevated levels of 17-OHP should prompt immediate
evaluation in any newborn infant. Pediatricians should call their state
department of health to determine if newborn screening for CAH is
available. New molecular techniques permit early prenatal diagnosis and
have made possible intervention to prevent prenatal virilization in
affected female infants. Early diagnosis through newborn screening may
avert salt-losing crises, particularly in affected boys, by permitting
early initiation of therapy. Although glucocorticoid therapy is the
mainstay of treatment, the outcome has not been optimal and therapeutic
regimens vary. New approaches to treatment, including adrenalectomy,
combination antiandrogen and aromatase inhibitors, and synthetic
blockers of corticotropin-releasing hormone and corticotropin receptors are under investigation. Support for families is available through a
national CAH group, The Magic Foundation, 1327 North Harlem Avenue, Oak
Park, IL, 60302 (http://www.magicfoundation.org).
Ad Hoc Writing Committee, 2000-2001
Jaime Frias, MD
Lenore S. Levine, MD
Sharon E. Oberfield, MD
Sonya Pang, MD
Janet Silverstein, MD
Section on Endocrinology, 2000-2001
Robert P. Schwartz, MD, Chairperson
Inger L. Hansen, MD
Francine Kaufman, MD
Surendra Kumar Varma, MD
Sharon E. Oberfield, MD
Janet Silverstein, MD
Liaisons
Lynn Levitsky, MD
Lawson Wilkins Pediatric Endocrinology Society
Mary Jean Suriano, RN
Pediatric Endocrinology Nursing Society
Staff
Laura Poulin, MPH
Committee on Genetics, 2000-2001
Christopher Cunniff, MD, Chairperson
Jaime L. Frias, MD
Celia Kaye, MD, PhD
John B. Moeschler, MD
Susan R. Panny, MD
Tracy L. Trotter, MD
Liaisons
Felix de la Cruz, MD, MPH
National Institutes of Health
James W. Hanson, MD
American College of Medical Genetics
Michele Lloyd-Puryear, MD, PhD
Health Resources and Services Administration
Cynthia A. Moore, MD, PhD
Centers for Disease Control and Prevention
John Williams III, MD
American College of Obstetricians and Gynecologists
Section Liaison
H. Eugene Hoyme, MD
Section on Genetics and Birth Defects
Staff
Lauri Hall
-hydroxyprogesterone
(17-OHP) in premature infants, very sick infants, and infants younger
than 24 hours decrease the rate of false-positive results.
PRENATAL DIAGNOSIS AND TREATMENT
4), which also are elevated in
pregnancies in which the fetus is affected with CAH, provide another
diagnostic measurement.
NEONATAL SCREENING
DIAGNOSIS
TREATMENT
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FOOTNOTES |
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The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.
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ABBREVIATIONS |
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CAH, congenital adrenal hyperplasia;
21-OH, 21-hydroxylase;
17-OHP, 17-hydroxyprogesterone;
AF, amniotic fluid;
HLA, human leukocyte antigen;
ACTH, adrenocorticotropic hormone.
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Statement of reaffirmation:
This article has been cited by other articles:
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  F. Votava, D. Torok, J. Kovacs, D. Moslinger, S. M Baumgartner-Parzer, J. Solyom, Z. Pribilincova, T. Battelino, J. Lebl, H. Frisch, et al. Estimation of the false-negative rate in newborn screening for congenital adrenal hyperplasia Eur. J. Endocrinol., June 1, 2005; 152(6): 869 - 874. [Abstract] [Full Text] [PDF]
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 K. Homma, T. Hasegawa, E. Takeshita, K. Watanabe, M. Anzo, T. Toyoura, K. Jinno, T. Ohashi, T. Hamajima, Y. Takahashi, et al. Elevated Urine Pregnanetriolone Definitively Establishes the Diagnosis of Classical 21-Hydroxylase Deficiency in Term and Preterm Neonates J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6087 - 6091. [Abstract] [Full Text] [PDF]
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Joint LWPES/ESPE CAH Working Group Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4048 - 4053. [Full Text] [PDF]
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M. Steigert, E. J. Schoenle, A. Biason-Lauber, and T. Torresani High Reliability of Neonatal Screening for Congenital Adrenal Hyperplasia in Switzerland J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4106 - 4110. [Abstract] [Full Text] [PDF]
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R. C. Olney, E. B. Mougey, J. Wang, D. I. Shulman, and J. E. Sylvester Using Real-Time, Quantitative PCR for Rapid Genotyping of the Steroid 21-Hydroxylase Gene in a North Florida Population J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 735 - 741. [Abstract] [Full Text] [PDF]
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 D. Torok, A. Muhl, F. Votava, G. Heinze, J. Solyom, J. Crone, S. Stockler-Ipsiroglu, and F. Waldhauser Stability of 17{alpha}-Hydroxyprogesterone in Dried Blood Spots after Autoclaving and Prolonged Storage Clin. Chem., February 1, 2002; 48(2): 370 - 372. [Full Text] [PDF]
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 E. D. Chambrier, C. Heinrichs, and F. E. Avni Sonographic Appearance of Congenital Adrenal Hyperplasia In Utero J. Ultrasound Med., January 1, 2002; 21(1): 97 - 100. [Full Text] [PDF]
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M. I. New, A. Carlson, J. Obeid, I. Marshall, M. S. Cabrera, A. Goseco, K. Lin-Su, A. S. Putnam, J. Q. Wei, and R. C. Wilson EXTENSIVE PERSONAL EXPERIENCE: Prenatal Diagnosis for Congenital Adrenal Hyperplasia in 532 Pregnancies J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5651 - 5657. [Abstract] [Full Text] [PDF]
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 C. A. Brosnan, P. G. Brosnan, J. M. Swint;, J. L. Frias, L. S. Levine, S. E. Oberfield, S. Pang, and J. Silverstein Analyzing the Cost of Neonatal Screening for Congenital Adrenal Hyperplasia Pediatrics, May 1, 2001; 107(5): 1238 - 1238. [Full Text]
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M. I. New;, J. Frias, L. S. Levine, S. E. Oberfield, S. Pang, and J. Silverstein Prenatal Treatment of Congenital Adrenal Hyperplasia: Author Differs With Technical Report Pediatrics, April 1, 2001; 107(4): 804 - 804. [Full Text] [PDF]
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