Clinical Diagnosis

21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) is suspected in the following:

• Females who are virilized at birth, or who become virilized postnatally, or who have precocious puberty or adrenarche. Virilization affects maturation, growth (leading to tall stature), and sex hormone-sensitive areas (external genitalia, skin, and hair) (leading to secondary sexual characteristics).
• Males with virilization in childhood (i.e., pseudoprecocious puberty)
• Any infant with a salt-losing crisis in the first four weeks of life

Testing

Affected Untreated Individuals

17-hydroxyprogesterone (17-OHP). The diagnosis of 21-OHD CAH is confirmed by biochemical findings, such as an unequivocally elevated serum concentration of 17-OHP (see Figure 1):

Figure

Figure 1. 17-OHP nomogram for the diagnosis of steroid 21-hydroxylase deficiency (60-minute cotrosyn stimulation test). The data for this nomogram was collected between 1982 and 1991 at the Department of Pediatrics, the New York Hospital-Cornell Medical (more...)

• Classic 21-OHD CAH. >20,000 ng/dL
• Non-classic 21-OHD CAH. 2,000 to 15,000 ng/dL

Note: Normal ranges for sex and pubertal status vary by laboratory reflecting the methods utilized. In adult females, the normal ranges depend on phase of the menstrual cycle.

Plasma renin. Plasma renin activity (PRA):

• Is markedly elevated in individuals with the salt-wasting form of 21-OHD CAH;
• Can be elevated in some individuals with the simple virilizing form of 21-OHD CAH.

Direct measurement of active renin can also be used.

Note: PRA measures the enzyme activity of renin to generate angiotensin I; the active renin assay immunoradiometrically measures renin substrate (not activity) [Krüger et al 1996].

Other adrenal steroids. Serum concentrations of:

• Δ⁴-androstenedione and progesterone are increased in males and females with 21-OHD CAH;
• Testosterone and adrenal androgen precursors are increased in affected females and prepubertal males.

Note: In individuals with the salt-wasting form of 21-OHD CAH, the serum concentration of aldosterone is inappropriately low compared to the level of plasma renin activity (PRA) elevation.

ACTH stimulation test. The serum concentration of 17-OHP and Δ⁴-androstenedione measured at baseline and at 60 minutes after intravenous injection of a standard 250-µg bolus of synthetic ACTH (Cortrosyn^TM) are plotted on the nomogram in Figure 1. Although the ACTH stimulation test provides far more reliable diagnosis of 21-OHD CAH than a test of baseline values alone, the results should be confirmed with molecular genetic testing of CYP21A2.

Note: Performing an ACTH stimulation test may not be feasible because of the relatively large volume of blood required for a newborn, lack of an appropriate setting in a neonatal intensive care unit, and clinical instability of a sick newborn. Molecular genetic testing is more appropriate for diagnosis.

Electrolytes. Individuals with untreated or poorly controlled salt wasting may have a decreased serum concentration of sodium, chloride, and total carbon dioxide (CO₂), an increased serum concentration of potassium, and inappropriately increased urine concentration of sodium.

Karyotype. Females with 21-OHD CAH have a normal 46,XX karyotype; males with 21-OHD CAH have a normal 46,XY karyotype.

Molecular Genetic Testing

Gene. CYP21A2 is the only gene in which mutation is known to cause 21-OHD CAH.

Clinical testing

• Targeted mutation analysis. Molecular genetic testing of CYP21A2 for a panel of common mutations and gene deletions detects 80%-98% of disease-causing alleles in affected individuals. Many of these common mutations arise as a result of gene conversion (see Molecular Genetics).
  
  Note: The majority of individuals from heterogeneous populations with 21-OHD CAH are compound heterozygotes [Krone et al 2000].
• Deletion/duplication analysis. A variety of methods such as Southern blot analysis, homozygosity testing for single nucleotide polymorphisms, quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH can be used to detect this and other large (exonic, multiexonic, and whole-gene) deletions or duplications.
  • Approximately 20% of mutant alleles are deleted for a 30-kb gene segment that encompasses the 3' end of the CYP21A1P pseudogene, all of the adjacent C4B complement gene, and the 5' end of CYP21A2 (see Molecular Genetics).
  • In one recent study 7% of CYP21A2 alleles in the population studied were duplications [Parajes et al 2008].
• Sequence analysis of the coding region and flanking intronic regions detects the common mutations in addition to rarer alleles that are not identified by targeted mutation analysis. Note: Exonic and multiexonic deletions are often not detected by sequence analysis and require deletion/duplication analysis.

Table 1. Summary of Molecular Genetic Testing Used in 21-OHD CAH

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Gene Symbol	Test Method	Mutations Detected 1	Mutation Detection Frequency by Test Method 2	Test Availability
CYP21A2	Targeted mutation analysis	See footnote 3	~80%-98%	Clinical
	Deletion / duplication analysis 4	Exonic, multiexonic, and whole-gene deletions
	Sequence analysis	Sequence variants 5	>80%-98%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. See Molecular Genetics.

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Mutation panels vary by laboratory. Common mutations often included: c.293-13A>G; c.293-13C>G, p.Pro31Leu, p.Ile173Asn, exon 6 mutation cluster p.(Ile237Asn, Va238Glu, Met240Lys), p.Val282Leu, p.Leu308PhefsX6, p.Gln319X, p.Arg357Trp, p.Pro454Ser, p.Gly111ValfsX21, and the 30-kb chimeric pseudogene

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results

• Sequence analysis. For issues to consider in interpretation of sequence analysis results, click here.
• Targeted mutation analysis. Issues to consider in interpretation of targeted mutation analysis:
  • A large-scale gene conversion (see Molecular Genetics) can replace a large segment of functional CYP21A2 sequence with a segment of the CYP21A1P pseudogene that is nonfunctional as a result of more than one deleterious mutation [Mao et al 2002]. Thus, when targeted mutation analysis detects multiple mutations, it is possible that the mutations are either in trans configuration (i.e., are on separate chromosomes, one inherited from each parent) or in cis configuration (i.e., are on the same chromosome and thus represent only one mutant allele rather than two; most likely arising from gene conversion). To avoid diagnostic errors, studying both parents as well as the proband is recommended to confirm the mutations and to determine if they are in cis configuration or trans configuration.
  • Another potential cause of misdiagnosis is CYP21A2 duplication [Koppens et al 2002]. This could result in false positives during carrier screening of individuals who are not obligate carriers. A person carrying a functional gene and a duplicated copy with a mutation on the same chromosome may be incorrectly labeled a carrier. Such individuals may be identified by deletion/duplication analysis or haplotype analysis (research testing only).

Testing Strategy

To confirm the diagnosis in newborns (after the first day of life) (a) with elevated 17-OHP concentration detected as positive newborn screening, (b) at risk for classic 21-OHD CAH, or (c) with ambiguous genitalia, the following are indicated:

• Complete history
• Complete physical examination
• Ultrasound examination of the pelvis and adrenal glands
• Karyotype or FISH for X- and Y-chromosome detection
• Measurement of serum concentration of 17-OHP and adrenal androgens
• Molecular genetic testing of CYP21A2 to confirm or exclude the diagnosis of 21-OHD CAH
  
  Note: (1) Marked elevation of 17-OHP concentration is usually adequate to confirm diagnosis of classic 21-OHD CAH presenting in the newborn period. (2) An ACTH stimulation test can also be performed to confirm the diagnosis; however, the relatively large volume of blood required often precludes use of this test.
• Measurement of plasma renin activity (PRA) and serum electrolyte concentrations while monitoring for signs and symptoms of adrenal crisis

To confirm the diagnosis in a proband with non-classic 21-OHD CAH

• A 60-minute ACTH stimulation test or
• A single early-morning (before 8 AM) measurement of plasma 17-OHP concentration (baseline values in affected individuals are not always elevated) and
• Molecular genetic testing of CYP21A2

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prognostication for an affected individual relies on genotype/phenotype correlation. If a genotype associated with salt wasting is identified, administration of salt-retaining hormone (9α-fludrohydrocortisone) and salt supplementation may avert a salt-wasting crisis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in CYP21A2.

A contiguous gene syndrome involving CYP21A2 and TNX led to a combination of Ehler-Danlos syndrome, hypermobility type and 21-OHD CAH [Burch et al 1997, Schalkwijk et al 2001].

Natural History

21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) occurs in a classic form and a non-classic form (Table 2).

In classic 21-OHD CAH prenatal exposure to potent androgens such as testosterone and Δ⁴-androstenedione at critical stages of sexual development virilizes the external genitalia of genetic females, often resulting in genital ambiguity at birth. The classic form is further divided into the simple virilizing form (~25% of individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting CAH caused by 21-OHD CAH are at risk for life-threatening salt-wasting crises.

Individuals with the non-classic form of 21-OHD CAH have only moderate enzyme deficiency and present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.

Genotype-Phenotype Correlations

In more than 95% of individuals with 21-OHD CAH, genotype can be used to predict disease severity. Salt-wasting, simple virilizing, or non-classical phenotypes can be predicted in an individual who undergoes molecular genetic testing. In general, an individual's phenotype correlates with the greatest degree of residual enzyme activity from a mutant allele (i.e., the expressed phenotype reflects the mutation with the less severe phenotypic effect of two alleles).

However, for reasons that are not understood, genotype does not always predict phenotype either within mutation-identical groups [Krone et al 2000] or within the same family (i.e., sibs with 21-OHD CAH who have the same mutations can have different phenotypes).

Alleles can be grouped as severe or mild, based on residual enzyme activity (Table 3).

• Salt-wasting 21-OHD CAH usually has the most severe mutations (e.g., homozygous deletions).
• Phenotypes with intermediate severity group are more variable within mutation groups than the phenotypes within severe or mild mutation groups [Krone et al 2000].
• Non-classic 21-OHD CAH usually has one mild allele or both mild alleles [Wilson et al 1995].

In the context of prenatal diagnosis, it is important to distinguish classic and non-classic genotypes in order to determine the need to offer prenatal treatment.

• In families in which the proband is a virilized female, predicting the risk of genital virilization in subsequent affected female fetuses is feasible.
• In families in which the proband is a male, predicting the risk of genital virilization in subsequent affected female fetuses based on genotype is not possible.

Classic 21-OHD CAH. The genotype for the classic form of 21-OHD CAH is predicted to be a severe mutation on both CYP21A2 alleles, with completely abolished enzyme activity determined by in vitro expression studies.

Note: The point mutation c.293-13A>G or c.293-13C>G, one of the most frequent mutations in classic 21-OHD CAH, causes premature splicing of the intron and a shift in the translational reading frame. Although most individuals who are homozygous for this mutation have salt-wasting 21-OHD CAH, variation in severity of salt wasting is observed. This genotype-phenotype non-concordance can be explained by increased alternate splicing that can occur when the normal splicing is abolished by the splice site mutation, allowing some protein production but with variable activity [Higashi et al 1988].

Non-classic 21-OHD CAH. Individuals with non-classic CAH are predicted to have two mild mutations or one mild and one severe mutation (i.e., to be compound heterozygotes). Approximately two-thirds of individuals with non-classic 21-OHD CAH are compound heterozygotes. Missense mutations p.Pro31Leu in exon 1 and p.Val282Leu in exon 7 reduce enzyme activity and are generally associated with this form of the disease. However, variation in the phenotype associated with one mild mutation can be observed:

• In a small number (<3%) of affected individuals with the p.Val282Leu or p.Pro31Leu mutation and a severe mutation, the classic phenotype was observed when a non-classic phenotype was expected.
• In a very small percent of affected individuals with the p.Ile173Asn mutation and a severe mutation, the non-classic phenotype (rather than the expected classic phenotype) was observed [Stikkelbroeck et al 2003].

Nomenclature

Congenital adrenal hyperplasia (or its common abbreviation, CAH) preceded by the description of the specific enzyme defect (e.g., 21-hydroxylase deficiency) is the current and preferable term.

Terms used in the past for 21-OHD CAH include: adrenogenital syndrome (AG syndrome), C-21-hydroxylase deficiency, and congenital adrenocortical hyperplasia.

The non-classic form of 21-OHD CAH was previously referred to as the "attenuated" or "late-onset" form.

The salt-wasting form of 21-OHD CAH has also been called "salt-losing CAH."

Prevalence

Classic 21-OHD CAH. Analysis of data from almost 6.5 million newborns screened in different populations worldwide have demonstrated an overall incidence of 1:15,000 live births for the classic form of 21-OHD [Pang & Shook 1997, van der Kamp & Wit 2004].

Prevalence in specific populations:

• 1:300 in Yupik Eskimos of Alaska
• 1:5,000 in Saudi Arabia
• 1:10,000-1:16,000 in Europe and North America
• 1:21,000 in Japan
• 1:23,000 in New Zealand

Non-classic 21-OHD CAH. The prevalence of non-classic 21-OHD CAH in the general heterogeneous population of New York City was estimated to be 1/100. The highest ethnic-specific non-classic disease prevalence (1/27) is found among Ashkenazi Jews. Other ethnic groups exhibiting high non-classic disease prevalence are: Hispanics (1/40), Slavs (1/50), and Italians (1/300) [Speiser et al 1985].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH), the following evaluations are recommended:

To assess for salt wasting

• Plasma renin activity (PRA) or direct renin assay
• Serum electrolytes

To distinguish classic and non-classic forms of 21-OHD CAH

• Baseline 17-OHP, Δ⁴-androstenedione, cortisol, and aldosterone
• ACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline level

To assess the degree of prenatal virilization in females

• Careful physical examination of the external genitalia and its orifices
• Vaginogram to assess the anatomy of urethra and vagina

To assess the degree of postnatal virilization in both males and females

• Bone maturation assessment by bone age
• Serum concentration of adrenal androgens (unconjugated dehydroepiandrosterone [DHEA], Δ⁴-androstenedione, and testosterone)

Treatment of Manifestations

It is imperative to make the diagnosis of 21-OHD CAH as quickly as possible in order to initiate therapy and arrest the effects of cortisol deficiency and mineralocorticoid deficiency, if present.

A multidisciplinary team of specialists in pediatric endocrinology, pediatric urology/surgery, medical genetics, and psychology is essential for the diagnosis and management of the individual with ambiguous genitalia [Hughes et al 2006].

Prevention of Primary Manifestations

Salt-wasting crisis. Newborn screening programs aim to identify infants with classic 21-OHD CAH and to initiate treatment prior to a potentially life-threatening salt-wasting crisis.

See Treatment of Manifestations, Glucocorticoid replacement therapy and Mineralocorticoid replacement therapy.

Prevention of Secondary Complications

Short stature. Short stature may result from glucocorticoid-induced growth suppression caused by over-treatment with glucocorticoids or from advanced skeletal maturation caused by inadequate glucocorticoid treatment. Injections of human growth hormone alone or in combination with gonadotropin-releasing hormone (GnRH) may be used both to improve linear growth in individuals with 21-OHD CAH who have significant growth failure [Quintos et al 2001] and to improve final height [Lin-Su et al 2005].

Surveillance

The following evaluations should be performed every three to four months when children are actively growing. Evaluation may be less often thereafter. The frequency of evaluation should vary depending on individual needs.

Efficacy of glucocorticoid replacement therapy is monitored by measurement of the following:

• Early-morning serum concentrations of 17-OHP, Δ⁴-androstenedione, and testosterone approximately every three months during infancy and every three to six months thereafter. (In some instances, measurement of urinary pregnantriols and 17 ketosteroids in a 24-hour urine sample may help assess hormonal control. However, the process of urine collection makes it less practical than a simple blood draw.)
• Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excess
• Bone age to assess osseous maturation (at 6- to 12-month intervals)

Efficacy mineralocorticoid replacement therapy is monitored by measurement of the following:

• Blood pressure
• Early morning plasma renin activity or direct renin assay in a controlled position (usually upright)

Monitoring for testicular abnormalities in males. Periodic imaging of the testes either by ultrasonography or MRI should begin after puberty and be repeated every three to five years.

Testing of Relatives at Risk

If prenatal testing for 21-OHD CAH has not been performed, it is appropriate to measure 17-OHP from newborn screening blood samples of at-risk sibs to facilitate early diagnosis and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Female genital ambiguity. Through molecular genetic testing of fetal DNA, defects in 21-OHD CAH synthesis can be diagnosed in utero. Genital ambiguity in female fetuses may be reduced or eliminated by suppressing fetal androgen production through administration of dexamethasone to the mother beginning early in gestation and continuing until delivery. Prenatal treatment should continue to be considered experimental and should only be used within the context of a formal IRB-approved clinical trial.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Pregnant females with classic 21-OHD CAH. Pregnant females who have classic salt-wasting 21-OHD CAH need to be monitored closely by an endocrinologist. Maintenance doses of glucocorticoid and mineralocorticoid usually need to be increased because adrenal androgens tend to increase during pregnancy. Despite excess production of maternal adrenal androgens, the genitalia of their female fetuses may not be virilized [Lo et al 1999].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Most parents are heterozygotes with one normal allele and one mutated allele.
• Heterozygotes are asymptomatic but may have slightly elevated 17-OHP levels when stimulated with ACTH, as compared to individuals with two normal alleles (see Carrier Detection).
• Approximately 1% of mutations occur de novo and thus, 1% of probands have only one parent who is heterozygous [Krone et al 2000].
• In some instances, a parent who was previously not known to be affected may be found to have the non-classic form of 21-OHD CAH. It is appropriate to evaluate both parents of a proband with molecular genetic testing and hormonal profiling to determine if either has non-classic 21-OHD CAH.

Sibs of a proband

• If the parents of a proband are both heterozygotes, each sib has a 25% chance of inheriting both altered alleles and being affected, a 50% chance of inheriting one altered allele and being an unaffected carrier, and a 25% chance of inheriting both normal alleles and being unaffected.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• If one parent of a proband is heterozygous and the other has 21-OHD CAH, each sib has a 50% chance of inheriting both mutated alleles and being affected and a 50% chance of inheriting one mutated allele and being a carrier.

Offspring of a proband

• An affected individual transmits one disease-causing allele to each child.
• Given the high carrier rate for 21-OHD CAH, it is appropriate to offer molecular genetic testing of CYP21A2 to the reproductive partner of a proband:
  • If the reproductive partner is determined not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH. (Since targeted mutation analysis does not detect 100% of altered alleles, there is a slight residual risk that the reproductive partner may carry a mutant allele that might be detected if the entire gene were sequenced.)
  • If the reproductive partner is determined to be heterozygous for an identified mutation, the risk to each child of being affected is 50%. The ability to predict the phenotype based on genotype is clinically useful most of the time, but still imperfect (accurate in about 95% of cases) (see Genotype-Phenotype Correlations).

Other family members of a proband. Sibs of the proband's obligate heterozygous parents are at a 50% risk of also being carriers.

Carrier Detection

Molecular genetic testing. Carrier testing using molecular genetic testing of CYP21A2 is possible for at-risk relatives when one or both disease-causing mutations have been identified in the family.

Hormonal testing. Although carriers may have slightly higher serum concentration of 17-OHP than non-carriers when stimulated with ACTH, overlap exists between heterozygotes and non-carriers. Thus, molecular genetic testing is the preferred method of carrier testing.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

High-risk pregnancies. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must have been identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. With the increase in use and improved resolution of prenatal ultrasonography, fetal genital and/or adrenal abnormalities may be detected more frequently than in the past [Saada et al 2004]. Pinhas-Hamiel et al [2002] detected genital ambiguity in 16 fetuses out of 10,000 who underwent prenatal ultrasound examination. Three of the 16 were ultimately diagnosed with 21-OHD CAH.

If ambiguous external genitalia are noted on routine ultrasound examination, a fetal karyotype, FISH for SRY, and ultrasound evaluation for müllerian structures should be obtained. A 46,XX karyotype in an SRY-negative fetus with a normal-appearing uterus should raise consideration of classic 21-OHD CAH. Amniocentesis to measure 17-hydroxyprogesterone (17-OHP) concentration in the amniotic fluid and/or molecular genetic testing of CYP21A2 may be appropriate.

The prenatal diagnosis of 21-OHD CAH can be valuable in the medical management of the newborn and in preparation of the family for the related medical and social issues of 21-OHD CAH.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American Academy of Pediatrics; Technical report: congenital adrenal hyperplasia. Section on Endocrinology and Committee on Genetics. Pediatrics. 2000;106:1511–8. [PubMed: 11099616]
2. 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. 2002;87:4048–53. [PubMed: 12213842]

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Suggested Reading

1. Bachelot A, Chakthoura Z, Rouxel A, Dulon J, Touraine P. Classical forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults. Horm Res. 2008;69:203–11. [PubMed: 18204267]
2. Donohoue PA, Parker KL, Migeon CJ. Congenital adrenal hyperplasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 159. New York, NY: McGraw-Hill. Available at www​.ommbid.com. Accessed 12-15-11.
3. Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update. 2004;10:469–85. [PubMed: 15514016]
4. Forest MG, Tardy V, Nicolino M, David M, Morel Y. 21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease. Ann Endocrinol (Paris). 2005;66:225–32. [PubMed: 15988383]
5. Gonçalves J, Friães A, Moura L. Congenital adrenal hyperplasia: focus on the molecular basis of 21-hydroxylase deficiency. Expert Rev Mol Med. 2007;9:1–23. [PubMed: 17466088]
6. New MI. An update of congenital adrenal hyperplasia. Ann N Y Acad Sci. 2004;1038:14–43. [PubMed: 15838095]
7. New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endo Metab. 2006;91:4222–31. [PubMed: 16912124]
8. New MI. 21-hydroxylase deficiency: classical & nonclassical congenital adrenal hyperplasia. In: Pediatric Endocrinology. Chap 8a. Updated 4-16-2006. Available for purchase at endotext​.org. Accessed 12-15-11.
9. Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia. Horm Res. 2007;67:53–60. [PubMed: 17047340]
10. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349:776–88. [PubMed: 12930931]

Author History

Brian Betensky, Weill Medical College of Cornell University (2004-2006)
Maria I New, MD (2001-present)
Saroj Nimkarn, MD (2006-present)
Andrea Putnam, MS; New York Weill Cornell Center (2001-2004)

Revision History

• 24 August 2010 (cd) Revision: edits to Management and Genetic Counseling
• 15 September 2009 (me) Comprehensive update posted live
• 7 September 2006 (me) Comprehensive update posted to live Web site
• 15 April 2004 (me) Comprehensive update posted to live Web site
• 26 February 2002 (me) Review posted to live Web site
• 15 June 2001 (mn) Original submission