Clinical characteristics.

21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21-OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.

Diagnosis/testing.

The diagnosis of classic 21-OHD CAH is established in newborns with characteristic clinical features, elevated serum 17-OHP, and elevated adrenal androgens. The diagnosis of non-classic 21-OHD is established by comparison of baseline serum 17-OHP and ACTH-stimulated serum 17-OHP or early morning elevated 17-OHP. Identification of biallelic pathogenic variants in CYP21A2 confirms the clinical diagnosis and allows for family studies.

Management.

Treatment of manifestations: Classic 21-OHD CAH: glucocorticoid replacement therapy, which needs to be increased during periods of stress. Salt-wasting form: mineralocorticoid 9α-fludrohydrocortisone therapy and often sodium chloride. Females who are virilized at birth may require feminizing genitoplasty and/or vaginal dilation. Symptomatic individuals with non-classic 21-OHD CAH may require treatment.

Prevention of primary manifestations: Newborn screening programs aim to identify infants with classic 21-OHD CAH in order to initiate glucocorticoid and mineralocorticoid treatment prior to a potentially life-threatening salt-wasting crisis.

Surveillance: Monitor:

• Efficacy of glucocorticoid and mineralocorticoid replacement therapy every three to four months while children are actively growing, and less often thereafter;
• For testicular adrenal rest tumors in males every three to five years after onset of puberty;
• Weight, bone mineral density, fertility, cardiovascular and metabolic risks in adults.

Evaluation of relatives at risk: It is appropriate to measure 17-hydroxyprogesterone (17-OHP) of at-risk sibs to facilitate early diagnosis and treatment.

Genetic counseling.

21-OHD CAH is inherited in an autosomal recessive manner. Most parents are heterozygous for a pathogenic variant. Approximately 1% of pathogenic variants are de novo; thus, 1% of probands have only one parent who is heterozygous. In some instances during evaluation of a proband, a parent not previously known to be affected may be found to have biallelic pathogenic variants and the non-classic form of 21-OHD CAH. At conception, if the parents of a proband are both known to be heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.

Suggestive Findings

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

• 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 masculinization in childhood (i.e., premature adrenarche)
• Any infant with a salt-losing crisis in the first four weeks of life. 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.
• An infant with elevated 17-OHP concentration detected as positive newborn screening

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

Establishing the Diagnosis

21-OHD CAH. The diagnosis is established in a newborn with the following laboratory findings:

• Serum 17-OHP is markedly elevated.
• Adrenal androgens are elevated; Δ⁴-androstenedione, 21 deoxycortisol, and progesterone are increased in males and females with 21-OHD CAH; Testosterone and adrenal androgen precursors (Δ⁴-androstenedione, DHEA) are increased in affected females and prepubertal males.
• Plasma renin activity is markedly elevated in individuals with the salt-wasting form of 21-OHD CAH.
  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. A reduced ratio of aldosterone to PRA indicates impaired aldosterone synthesis and can differentiate those individuals with the salt-wasting form of CAH from those with the simple virilizing form of CAH after the newborn period [Nimkarn et al 2007].
• Identification of biallelic pathogenic variants in CYP21A2 (See Table 2.)

Non-classic 21-OHD CAH. The diagnosis is established in a proband based on the results of ONE of the two following laboratory tests (see Figure 1 and Table 1):

Figure 1.

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

• 60-minute ACTH stimulation test. The serum concentration of 17-OHP measured at baseline and at 60 minutes after intravenous injection of a standard 250-µg bolus of synthetic ACTH (Cortrosyn™) are plotted on the nomogram in Figure 1.
• 17-hydroxyprogesterone (17-OHP). A single early-morning (<8AM) measurement of plasma 17-OHP concentration (baseline values in affected individuals are not always elevated; see Table 1)
  Note: Normal ranges of 17-OHP for sex and pubertal status vary by laboratory, reflecting the methods used. In adult females, normal ranges depend on the phase of the menstrual cycle.

Molecular testing. Identification of biallelic pathogenic variants in CYP21A2 (see Table 2) confirms the diagnosis and allows for family studies. Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of CYP21A2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  Note: 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 variant [Mao et al 2002]. Thus, when targeted analysis detects multiple pathogenic variants, it is possible that the pathogenic variants 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 mutated 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 pathogenic variants and to determine if they are in cis configuration or trans configuration.
• A multigene panel that includes CYP21A2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of 21-OHD CAH.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) occurs in a classic form and a non-classic form (Table 3).

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

A study by New et al [2013] that included the largest cohort of individuals with 21-OHD CAH demonstrated that the predictability of phenotype was less certain than previously thought. A direct genotype-phenotype correlation was found in approximately 50% of genotypes. The most unreliable predictions occurred in the simple virilizing form, where a wide phenotypic variety was observed with the same genotype. However, a strong correlation was noted for some genotypes that were exclusively found in salt-wasting and non-classic forms. For example, the Val281Leu pathogenic variant is exclusively associated with the non-classic form. In individuals with this form, the phenotype reflected the pathogenic variant with the less severe phenotypic effect of the two alleles.

Alleles can be grouped as severe or mild, based on residual enzyme activity (Table 4).

• Salt-wasting 21-OHD CAH usually has the most severe pathogenic variants (e.g., homozygous deletions).
• Non-classic 21-OHD CAH usually has one mild allele or both mild alleles.

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 less reliable.

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

Note: The single-nucleotide variants c.293-13A>G or c.293-13C>G, among the most frequent pathogenic variants in classic 21-OHD CAH, cause premature splicing of the intron and a shift in the translational reading frame. Although most individuals (>90%) who are homozygous for one of these pathogenic variants 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 variant, allowing some protein production but with variable activity [Higashi et al 1988].

Among affected individuals who were compound heterozygotes for the pathogenic single-nucleotide variant p.Ile173Asn and a second severe variant, 76% had the simple virilizing phenotype while 23% had the salt wasting phenotype [New et al 2013]. It is postulated that subtle variations in transcription regulation or downstream protein translation may account for reduced 21-OH enzyme activity.

Non-classic 21-OHD CAH. Individuals with non-classic CAH are predicted to have two mild variants or one mild and one severe variant. Approximately two-thirds of individuals with non-classic 21-OHD CAH are compound heterozygotes. Pathogenic missense variants 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 variant can be observed:

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

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

Nomenclature

Terms used in the past for 21-OHD CAH include adrenogenital syndrome (AG syndrome) 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 has demonstrated an overall incidence of 1:15,000 live births for the classic form of 21-OHD [van der Kamp & Wit 2004].

Prevalence in specific populations:

• 1:300 in Yup'ik 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 at 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 and needs 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)
• Serum electrolytes

To distinguish classic from 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)

Consultation with a clinical geneticist and/or genetic counselor is recommended for those individuals with a new diagnosis of 21-OHD CAH.

Treatment of Manifestations

Clinical practice guidelines for the treatment of individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency have been published [Speiser et al 2010] (full text).

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, clinical genetics, and psychology is essential for the diagnosis and management of the individual with ambiguous genitalia [Hughes et al 2006]. A pioneer project of CAH comprehensive care centers was implemented [Auchus et al 2010]. Two CAH comprehensive care centers which can provide multidisciplinary care from diagnosis through all stages of growth and development have been designated in the United States.

Prevention of Primary Manifestations

Salt-wasting crisis. Newborn screening programs aim to identify infants with classic 21-OHD CAH in order to initiate glucocorticoid and mineralocorticoid 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. Evidence derived from observational studies suggests that the final height of individuals with CAH treated with glucocorticoids is lower than the population norm and lower than expected given parental height [Muthusamy et al 2010]. See Therapies Under Investigation for a discussion of treatment of short stature in individuals with CAH.

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 [Speiser et al 2010].

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 of 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.

Monitoring fertility and metabolic risks in adults. In affected adults, periodic measurements and/or monitoring of the following should be performed:

• Fecundity and fertility
• Weight
• Lipid profile
• Blood pressure
• Bone mineral density

Imaging studies. No routine adrenal imaging or bone mineral density is recommended [Speiser et al 2010].

Agents/Circumstances to Avoid

Physical stress such as febrile illness, gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma can precipitate an adrenal crisis in individuals with classic CAH. Increased doses of glucocorticoids are recommended in these situations.

Evaluation of Relatives at Risk

If prenatal testing for 21-OHD CAH has not been performed, it is appropriate to evaluate newborn sibs of a proband in order to facilitate early diagnosis and treatment.

• Serum 17-OHP concentration should be measured in addition to newborn screening.
• Molecular genetic testing is indicated if the pathogenic variants in the family are known.

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

Pregnancy Management

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 during pregnancy. 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 are not virilized [Lo et al 1999].

Therapies Under Investigation

Affected female fetus with 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. Noninvasive prenatal diagnostic methods for earlier diagnosis of affected female fetuses have been developed and may eliminate the unnecessary prenatal treatment of males and unaffected females [New et al 2014, Tardy-Guidollet et al 2014].

Treatment of short stature. Injections of human growth hormone alone or in combination with gonadotropin-releasing hormone (GnRH) may be used to improve height prognosis in individuals with 21-OHD CAH who have significant growth failure [Lin-Su et al 2011]. Aromatase inhibitors to slow bone age advancement have been used. However, these approaches are considered experimental treatment and should not be used outside of formally approved clinical trials [Speiser et al 2010].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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 (i.e., carriers of one CYP21A2 pathogenic variant).
• 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 CYP21A2 pathogenic variants 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

• At conception, if the parents of a proband are both heterozygotes, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• If one parent of a proband is heterozygous and the other has 21-OHD CAH, each sib has a 50% chance of inheriting both pathogenic variants and being affected and a 50% chance of inheriting one pathogenic variant and being a carrier.
• 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).

Offspring of a proband

• An affected individual transmits one pathogenic variant 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 found not to be a carrier, the child is at significantly decreased risk of having 21-OHD CAH.
  • If the reproductive partner is found to be heterozygous for a known pathogenic variant, 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 (see Genotype-Phenotype Correlations).

Other family members. Sibs of the proband's obligate heterozygous parents are at a 50% risk of also being carriers of a CYP21A2 pathogenic variant.

Carrier (Heterozygote) Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the CYP21A2 pathogenic variants in the family.

Note: Another potential cause of misdiagnosis is CYP21A2 duplication [Koppens et al 2002]. In one study, 7% of CYP21A2 alleles in the population studied were duplications [Parajes et al 2008]. The common duplication haplotype consists of the p.Gln319Ter pathogenic allele coexisting with a normal CYP21A2 allele on the same chromosome [Kleinle et al 2009]. 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 pathogenic variant on the same chromosome may be incorrectly labeled a carrier, which may lead to an erroneous prenatal diagnosis [Lekarev et al 2013]. Such individuals may be identified by deletion/duplication analysis or haplotype analysis.

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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies. Once the CYP21A2 pathogenic variants have been identified in an affected family member, molecular genetic prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for 21-OHD CAH are possible.

Noninvasive prenatal diagnostic methods for earlier diagnosis of affected female fetuses have been developed and may eliminate the unnecessary prenatal treatment of males and unaffected females [New et al 2014, Tardy-Guidollet et al 2014].

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 or chorionic villus sampling for molecular genetic testing of CYP21A2 may be appropriate. Biochemical prenatal testing has been studied but is not appropriate for diagnosis of this disorder.

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.

Published Guidelines / Consensus Statements

• 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. Available online. 2002. Accessed 2-14-22. [PubMed: 12213842]
• Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Pediatrics. 2006;118:e488–500. [PubMed: 16882788]
• Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC. Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133–60. [PMC free article: PMC2936060] [PubMed: 20823466]

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Author History

Brian Betensky, Weill Medical College of Cornell University (2004-2006)
Prasanna K Gangishetti, MBBS (2016-present)
Maria I New, MD (2001-present)
Saroj Nimkarn, MD (2006-present)
Andrea Putnam, MS; New York Weill Cornell Center (2001-2004)
Mabel Yau, MD (2016-present)

Revision History

• 4 February 2016 (sw) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 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 live
• 15 April 2004 (me) Comprehensive update posted live
• 26 February 2002 (me) Review posted live
• 15 June 2001 (mn) Original submission