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Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children

Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children
Literature review current through: Jan 2024.
This topic last updated: Oct 14, 2022.

INTRODUCTION — Defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol due to 21-hydroxylase deficiency (21OHD) accounts for more than 95 percent of cases of congenital adrenal hyperplasia (CAH) [1,2]. This conversion is mediated by the 21-hydroxylase enzyme, which is encoded by the CYP21A2 gene.

The pathophysiology, clinical manifestations, and diagnosis of classic CAH due to 21OHD in neonates and children are reviewed here. The treatment of classic 21OHD in infants and children is discussed separately. CAH in adults is also reviewed separately, as is nonclassic CAH. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

PREVALENCE — The most common cause of congenital adrenal hyperplasia (CAH) worldwide, accounting for >95 percent of cases, is 21-hydroxylase deficiency (21OHD) [1]. Based upon neonatal screening studies, 21OHD is one of the more common inherited disorders. Data from approximately 6.5 million newborn infants screened worldwide show an overall prevalence of approximately 1 in 15,000 livebirths [3,4]. However, prevalence rates vary by ethnicity and geographic area. This number ranges from as low as 1 in 28,000 in the Chinese population [5], to 1 in 5000 to 23,000 live births in the New Zealand White population [6,7], to as high as 1 in 2100 in the French island of La Reunion [4], and 1 in 280 among native Alaskan and Canadian Yupiks [8]. In the United States, the prevalence is lower in Black Americans than in White Americans (1 in 42,000 versus 1 in 15,500, respectively) [9].

The nonclassic form of 21OHD is one of the most common autosomal recessive diseases across ethnicities. Among White Americans, the prevalence of this form of the disorder may be as high as 1 in 200 [10]. Most patients with the nonclassic form will not be identified by standard single-test newborn screening, because screening programs target classic patients and are based upon detection of very high levels of 17-hydroxyprogesterone (17OHP) in the blood spot [2]. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

PATHOPHYSIOLOGY — The defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol in patients with 21-hydroxylase deficiency (21OHD) results in decreased cortisol synthesis, loss of negative feedback, and therefore increased corticotropin (ACTH) secretion (figure 1). The resulting adrenal stimulation leads to increased production of adrenal-derived androgens and a variable degree of aldosterone deficiency. The severity of disease relates to the degree to which the mutations compromise enzyme activity [11]. (See 'Genotype-phenotype' below.)

GENETICS — As with the other forms of congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency (21OHD) is transmitted as an autosomal recessive disorder [12]. There has been speculation of a survival advantage among heterozygotes to explain the relatively high frequency of CAH alleles in the population [13].

Humans have two CYP21A genes, a nonfunctional pseudogene (CYP21A1P) and the active gene (CYP21A2), both located in a 35-kilobase region of chromosome 6p21.3 within the major histocompatibility complex (HLA) locus [14-17]. The pseudogene produces a truncated enzyme with no activity because it lacks eight bases from codons 110 to 112, resulting in a stop codon [16,17].

The two CYP21A genes are more than 90 percent homologous. This high degree of homology facilitates recombination events during meiosis, with consequent exchanges of segments of DNA between the two genes.

Unequal crossover exchanges leading to deletions of large segments of the CYP21A1P gene or a nonfunctioning CYP21PA1/CYP21A2 fusion gene account for approximately 20 to 30 percent of CYP21A2 variants described [18,19].

Approximately 3 percent of hybrid CYP21A1P/CYP21A2 gene products have decreased, not absent, enzyme activity. A patient who is heterozygous for this and a typical large gene deletion may have a phenotype spanning nonclassic and simple-virilizing 21OHD [20,21].

Altered regions of the CYP21A1P gene can be transferred to the CYP21A2 gene through misalignment of homologous genes and nonreciprocal gene conversion during meiosis.

These microconversion events represent acquisition of smaller segments of the CYP21A1P sequence by the CYP21A2 gene and result in deleterious point mutations that reduce enzyme activity [16,17]. They are present in approximately 70 percent of patients with defined genetic abnormalities.

Eighteen such gene conversion mutations account for nearly all affected alleles in various ethnic groups [22,23]. However, over 200 CYP21A2 mutations are known [1,24]. Most patients are compound heterozygotes.

Genotypically, individuals with the nonclassic form may be either compound heterozygotes (with a classic severe mutation and a less deleterious nonclassic variant allele) or homozygous with two mild variant alleles. Affected relatives may be minimally symptomatic, but have similar biochemical and genetic abnormalities. Women with nonclassic CAH who carry a classic mutation have an increased risk of giving birth to a child with classic CAH. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Genotype-phenotype — It is not always possible to predict the phenotype of these patients from the specific mutation(s) of the CYP21A2 gene, but there are general correlations between genotype and phenotype [1,25-39]. Patients with CYP21A2 mutations can be divided into groups according to the predicted effect of the mutation on 21-hydroxylase enzymatic activity, as determined by site-directed mutagenesis and expression and in vitro analysis of enzymatic activity [28]:

The "salt-wasting" form of the disorder (most severe) is most often associated with large deletions or mutations that result in no enzyme activity. Seventy-five percent of patients with classic 21OHD have this form. (See 'Spectrum of disease' below.)

Twenty-five percent of patients with classic 21OHD have the "simple-virilizing" form (less severe) with low but detectable enzyme activity (1 to 2 percent) that supports some aldosterone production. This form most commonly results from point mutations leading to nonconservative amino acid substitutions such as Ile172Asp. A mutation in intron 2 that variably impairs splicing (g.A/C656G) manifests with a range of classic 21OHD phenotypes.

Of note, the terms "salt-wasting" and "simple-virilizing" have fallen out of favor. (See 'Spectrum of disease' below.)

Individuals with the nonclassic form (least severe) retain 5 to 20 percent of normal enzymatic activity (eg, with point mutations leading to conservative amino acid substitutions such as Val281Leu).

Patients who are compound heterozygotes for two different CYP21A2 mutations have the phenotype associated with the less severe of the two genetic defects. Heterozygotes may have mild biochemical abnormalities [40-42], but no clinically important endocrine disorder. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Despite these general correlations, the CYP21A2 mutation phenotype does not always correlate precisely with the genotype, suggesting that other genes influence the clinical manifestations. In general, there appear to be high concordance rates between genotype and phenotype in patients with the most severe and the mildest forms of the disease, but less genotype-phenotype correlation in moderately affected patients [25,36,37].

CLINICAL PRESENTATION

Spectrum of disease — The clinical spectrum of disease ranges from the most severe to mild forms, depending upon the degree of enzyme deficiency as described above (see 'Genotype-phenotype' above). Infants with classic congenital adrenal hyperplasia (CAH) have been historically subdivided into the "salt-wasting" and "simple-virilizing" forms. However, the use of the terms "salt-wasting" and "simple-virilizing" have fallen out of favor, and the clinical phenotypes overlap (eg, all patients lose salt and girls with either type have atypical genitalia). Thus, patients diagnosed with 21-hydroxylase deficiency (21OHD) should be categorized as having either classic or nonclassic CAH.

Nonclassic 21OHD may present as early pubarche or sexual precocity in school-age children, hirsutism and menstrual irregularity in young women, or there may be no symptoms. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Infants

Atypical genitalia

Females – 46,XX infants with classic 21OHD are typically born with atypical genitalia characterized by clitoral enlargement (picture 1), labial fusion, and formation of a urogenital sinus caused by the effects of in utero androgen excess on the development of the external genitalia. Rarely, virilization may be so profound that genital atypia is unrecognized, and male sex assignment (with undescended testes) is made at birth in a 46,XX patient. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

The surgical management of girls born with atypical genitalia is complex and is reviewed separately. Some groups have advocated avoiding genital surgery until the child is old enough to make an informed decision. Surgery should be done only in medical centers with substantial experience, and management ideally should be done by a multidisciplinary team that includes specialists in pediatric endocrinology, pediatric urology (or in some centers, general surgery or gynecology), psychosocial services, and genetics [2,43]. Long-term outcome data in those who have undergone surgery and those who have not are needed. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Clinical approach to 46,XX congenital adrenal hyperplasia'.)

Males – 46,XY infants with classic CAH have normal-appearing genitalia at birth but may have subtle findings such as hyperpigmentation of the scrotum or an enlarged phallus. If not identified by neonatal screening, some males present at 2 to 4 years of age with early pubarche, a growth spurt, and adult body odor.

Males with the salt-wasting form who are not identified by neonatal screening may present with failure to thrive, dehydration, hyponatremia, and hyperkalemia typically at 7 to 14 days of life. (See 'Adrenal crisis' below.)

Adrenal crisis — In the United States and many other countries, neonatal screening for classic 21OHD is mandated, so almost all infants are diagnosed at birth (with some exceptions). The majority of patients with classic 21OHD have clinically relevant mineralocorticoid deficiency and are at risk for adrenal crisis. If 21OHD remains undiagnosed and hence not treated, adrenal crisis (also historically referred to as "salt-wasting" crisis) may occur. Vomiting, diarrhea, hypotension, and hypovolemic shock can occur, typically between 10 to 20 days of age. Laboratory findings suggesting adrenal crisis include hyperkalemia with or without hyponatremia, metabolic acidosis, and hypoglycemia [11]. The management of adrenal crisis in this setting is reviewed separately (table 1). (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Adrenal crisis'.)

Children — Children with 21OHD are at risk for bone age advancement, early puberty, premature epiphyseal closure, and adult short stature, from the early exposure to high levels of sex hormones. Excess glucocorticoid exposure secondary to treatment may also suppress growth and contribute to adult short stature.

Retrospective studies have shown that adult height of treated patients is not solely dependent on the control of adrenal androgen concentrations, suggesting that both hyperandrogenism and glucocorticoid exposure contribute to the observed short stature. A meta-analysis of data from 18 centers showed that the mean adult height of patients with classic 21OHD was 1.4 standard deviations (10 cm) below the population mean [44]. Patients with nonclassic 21OHD have a more favorable height prognosis but in some cases show reduced adult height. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Growth'.)

Affected children may have signs of androgen excess if diagnosed late or if excess adrenal androgens persist due to poor disease control. Symptoms include early pubic hair, growth acceleration with advanced bone age, early onset of adult body odor, and acne. Children with nonclassic 21OHD may have signs of androgen excess at various ages but they present at older ages and are less symptomatic than children with the classic form. Women with nonclassic 21OHD can experience hirsutism, acne, menstrual irregularities, and subfertility. Postpubertal males with nonclassic CAH are often asymptomatic.

DIAGNOSIS

Newborn screening — The diagnosis of classic 21-hydroxylase deficiency (21OHD) is based upon a very high serum concentration of 17-hydroxyprogesterone (17OHP), the normal substrate for 21-hydroxylase (figure 1); this diagnosis is almost always made soon after birth as routine newborn screening is now mandatory in many countries, including the United States [1,2,45]. The screening test for 17OHP is measured using a filter paper blood sample obtained by a heel puncture, preferably between two and four days after birth. The assay used in most programs is a fluoroimmunoassay (DELFIA) [46]. (See 'Interpretation of results' below.)

Interpretation of results — The characteristic biochemical abnormality for diagnosis at any age in patients with 21OHD is a very high serum concentration of 17OHP in a randomly timed blood sample. Most affected neonates have random heel-stick blood spot concentrations greater than 3500 to 5000 ng/dL (105 to 150 nmol/L) [1]. All have concentrations greater than 1000 ng/dL (30 nmol/L). One must compare screening results with the reference laboratory's own standard values for gestational age and/or birth weight.

Nonclassic 21OHD is generally not detected with single-test newborn screening or random serum steroid levels. The biochemical findings are less severe in the nonclassic form of the disorder. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Additional confirmatory laboratory testing should be performed once the diagnosis is suspected based on screening, described below. (See 'Additional testing for infants with equivocal results' below.)

False-positive results — False-positive results from neonatal screening are common in premature and sick infants [47], or if sampling is done prior to 24 to 48 hours of life. Reference ranges based upon birth weight and gestational age improve the positive-predictive value of screening [48]. Second-tier screening with liquid chromatography followed by tandem mass spectrometry improve positive-predictive value [47]. DNA-based methods are not currently in widespread use.

Some cases of 11-beta-hydroxylase deficiency, P450 oxidoreductase deficiency, and 3-beta-hydroxysteroid dehydrogenase type 2 deficiency may be identified by newborn screening because 17OHP levels can be elevated in these rare disorders of steroidogenesis.

False-negative results

Some studies now suggest that there is a substantial risk of false-negative results for the neonatal screening for 21OHD, particularly in girls [49,50]. This was best illustrated in a population-based study of all newborns screened in Minnesota from 1999 to 2010. Of the 838,241 newborns screened, 52 were diagnosed with classic 21OHD, but 15 cases (9 girls, 6 boys) were missed, for a false-negative rate of 22.4 percent (95% CI 14-34). Among the nine females missed by screening, five had further evaluation and were diagnosed because they had atypical genitalia, but three others had atypical genitalia and were not diagnosed until three months to six years. Thus, newborns with findings suggestive of 21OHD (eg, atypical genitalia) should undergo further endocrine evaluation even if the neonatal screening test is negative. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

To minimize the problem of false-negative results, some states in the United States perform a second routine screening for 21OHD in all newborns between 8 to 14 days of life. While sensitivity and positive-predictive value might be improved by this approach, the data are not definitive, there are increased costs, and universal adoption of second screening has not been recommended [51]. Moreover, some later positive results reflect the nonclassic form of CAH, which is not usually treated if diagnosed presymptomatically in infancy.

Administration of antenatal glucocorticoids (eg, betamethasone), particularly multiple courses (administered to induce pulmonary maturation in pregnancies with expected preterm delivery), may decrease 17OHP levels in filter paper blood, increasing the risk of false-negative results [52].

Repeat screening for 21OHD at one to two weeks of age should therefore be performed in infants whose mothers have received multiple courses of antenatal glucocorticoids; salt loss should be carefully monitored in the interim between screening samples.

Infants with equivocal screening results should be referred to a pediatric endocrinologist for a thorough history (including evaluation of feeding pattern), family history, and physical examination with particular attention to weight gain and any atypical genital findings. Additional laboratory testing is often recommended beyond the baseline serum tests. (See 'Confirmatory serum testing' below.)

Confirmatory serum testing — Any infant with a positive result of the newborn screen or with any clinical manifestations suggesting the possibility of 21OHD (atypical genitalia or serum electrolyte abnormalities) should be further evaluated with the following:

A serum sample for 17OHP and cortisol at a minimum, preferably measured by tandem mass spectrometry.

Serum electrolytes, to assess for salt-wasting and risk of adrenal crisis, repeated every 24 to 48 hours until 21OHD is excluded.

After the confirmatory blood sample is obtained, treatment doses of glucocorticoid and mineralocorticoid should be initiated to prevent the potentially life-threatening manifestations of an adrenal crisis. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Positive newborn screen'.)

As noted, most affected neonates have random 17OHP concentrations greater than 3500 to 5000 ng/dL (105 to 150 nmol/L). Infants with elevations above the normal range, but below the levels observed in 21OHD, should be further evaluated to establish the cause. (See 'Additional testing for infants with equivocal results' below.)

A distinction between the salt-wasting and simple-virilizing forms of 21OHD is not necessary; clinical management is the same, and there is a continuum of disease severity (see 'Spectrum of disease' above). However, patients with the most complete enzyme deficiency typically have the highest 17OHP levels [53].

The majority of patients with classic 21OHD have clinically relevant mineralocorticoid deficiency and are at risk for volume depletion, hyponatremia, and hyperkalemia. Patients are also at risk for hypoglycemia during an adrenal crisis [11] (see 'Adrenal crisis' above). Elevated plasma renin activity indicates aldosterone deficiency but is difficult to assess in the newborn period.

Newborn screening unavailable — Prior to the availability of newborn screening, or in areas where screening is still unavailable, some affected females presented with adrenal crisis at one to two weeks of age (if atypical genitalia was not identified). Historically, boys presented as neonates with a salt-wasting adrenal crisis (hyponatremia, hyperkalemia, and failure to thrive) or later as toddlers with signs of puberty (simple-virilizing form). Phallic enlargement and scrotal hyperpigmentation are sometimes present in newborn males with the "simple-virilizing" form. With the advent of neonatal screening programs, affected males are typically diagnosed before they develop clinical symptoms [2].

ADDITIONAL TESTING FOR INFANTS WITH EQUIVOCAL RESULTS

ACTH stimulation test

A cosyntropin (ACTH) stimulation test is indicated to rule out rare disorders of steroidogenesis. However, if the diagnosis of 21-hydroxylase deficiency (21OHD) is highly probable (ie, random 17-hydroxyprogesterone [17OHP] >5000 ng/dL, and electrolyte abnormalities or atypical genitalia in female infant are present), treatment should be instituted immediately and not withheld in order to perform a cosyntropin test.

Although a cosyntropin stimulation test is the gold standard to diagnose all forms of congenital adrenal hyperplasia (CAH), it is not always necessary to make the diagnosis of classic 21OHD; infants with classic 21OHD have levels of basal adrenocortical hormone and cortisol precursors that are already markedly elevated due to a highly stimulated adrenal cortex.

To assess borderline cases, the standard high-dose (250 mcg cosyntropin) test, not the low-dose (1 mcg) test, should be used. This is preferred over genetic testing and can be done in an outpatient setting by a pediatric endocrinologist.

Other steroid intermediates

To define the metabolic defect in infants, serum concentrations of 11-deoxycortisol, 17-hydroxypregnenolone, cortisol, androstenedione, and dehydroepiandrosterone (DHEA) should also be measured, listed in order of priority. As noted, 17OHP might be elevated in rare types of CAH, such as P450 oxidoreductase deficiency, 11-hydroxylase deficiency and 3-beta-hydroxysteroid dehydrogenase deficiency [54-56]. (See 'False-positive results' above.)

Other abnormalities that may be present in either form (but mostly in the classic form) include high serum concentrations of androstenedione, 3-alpha-androstanediol glucuronide, testosterone, 21-deoxycortisol, and progesterone, and increased urinary excretion of metabolites of cortisol precursors, particularly pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids. (Pregnanetriol and its glucuronide are the major metabolites of 17OHP, and 17-ketosteroids are metabolites of androgens such as testosterone.) (See "Adrenal steroid biosynthesis".)

Role of genetic testing — Genetic testing can be used if the biochemical testing is equivocal or for purposes of genetic counseling, but it is costly. Although screening for the 12 most common mutations may miss mutations in up to 10 percent of 21OHD patients [18], if at least one mutation is detected, the patient can be evaluated further. Parental testing is often needed to confirm genotype [57]. CYP21A2 mutation analysis is not helpful in diagnosing other enzyme deficiencies as a possible cause of CAH. For infants with atypical genitalia, but negative results of 17OHP screening, targeted genotyping for CYP21A2 or a panel of CAH candidate genes, in combination with imaging, can help to identify other causes of genital atypia. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Subsequent evaluation'.)

Genotyping is not used as a first-line diagnostic test, because multiple mutations on some alleles can make it difficult to distinguish affected patients from carriers [57]. In this situation, parental CYP21A2 genotyping can determine whether heterozygous disease-causing variants are in trans or in cis (on the same or different alleles), thus determining the genotype. Genotyping is indicated if the diagnosis remains equivocal following hormonal evaluation or for genetic counseling, especially in those seeking fertility [58].

Ultrasound — Bedside ultrasound detection of a uterus in an infant with ambiguous or atypical external genitalia can provide an important early clue to the diagnosis of virilizing CAH. Detailed adrenal ultrasonography is another potential adjunctive test for 21OHD in neonates with atypical genitalia and/or life-threatening salt loss before hormonal or genetic test results are available. In a retrospective analysis of 52 children with atypical genitalia or salt-wasting crises, abnormal adrenal ultrasonography (ie, adrenal limb width >4 mm, lobulated surface, or abnormal echogenicity) had 92 percent sensitivity and 100 percent specificity in differentiating 25 neonates and children with untreated 21OHD from eight children with the disorder who had been treated and 19 children with other conditions [59]. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

PRENATAL DIAGNOSIS — Prenatal diagnosis can be considered when a fetus is known to be at risk because of an affected sibling or when both partners are known to be heterozygous for one of the severe mutations, thus predicting a one-in-eight chance of female genital atypia. If 21-hydroxylase deficiency (21OHD) is identified by prenatal diagnosis, confirmatory steroid testing should be performed two to three days after birth. After obtaining a blood sample to confirm the diagnosis, treatment should be initiated. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

Molecular analysis of CYP21A2 genes is now the method of choice for prenatal diagnosis. Molecular analysis of fetal CYP21A2 genes in amniocytes or chorionic villus samples is used as a screening method. Preimplantation genetic testing of embryos and selection of only genetically unaffected embryos for transfer is useful in preplanning for potentially at-risk pregnancies [60]. These tests are available commercially but are expensive and not fully covered by insurers in the United States.

Noninvasive fetal cell-free DNA testing of the mother's plasma has correctly identified fetal 21OHD status as early as five weeks gestation in 14 families [61]. This prenatal cell-free DNA screening could be used in conjunction with prenatal therapy to reduce risk of dexamethasone exposure to unaffected fetuses. However, because long-term risks are unknown, prenatal dexamethasone therapy is considered an experimental approach and is recommended to be done only in a research setting [2,62]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prenatal therapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

SUMMARY AND RECOMMENDATIONS

Pathophysiology – Defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol due to 21-hydroxylase deficiency (21OHD) accounts for more than 95 percent of cases of congenital adrenal hyperplasia (CAH) [1,2]. This conversion is mediated by the 21-hydroxylase enzyme, which is encoded by the CYP21A2 gene. (See 'Introduction' above.)

Prevalence – Based upon neonatal screening studies, the prevalence of this disorder varies widely according to ethnicity and geographic area. (See 'Prevalence' above.)

Clinical presentation – The clinical spectrum of disease ranges from the most severe to mild forms, depending upon the degree of enzyme deficiency. Infants with classic CAH have been historically subdivided into "salt-wasting" and "simple-virilizing" forms. However, the use of the terms "salt-wasting" and "simple-virilizing" are considered less useful now. (See 'Genotype-phenotype' above and 'Spectrum of disease' above.)

Diagnosis – Almost all infants are diagnosed at birth because of mandated neonatal screening. Female infants with classic 21OHD are typically born with atypical genitalia (picture 1). Boys usually have normal-appearing genitalia. Both girls and boys are at potential risk for adrenal crisis depending upon the severity of their enzyme deficiency. (See 'Adrenal crisis' above.)

Neonatal screening: Measurement of 17OHP – In many countries, neonatal screening for 21OHD is performed routinely in all newborns and begins with measurement of 17OHP in a dried, filter paper blood spot. The diagnosis of classic 21OHD is based upon a very high serum concentration of 17OHP, the normal substrate for 21-hydroxylase. Most affected neonates have random heel-stick blood spot concentrations greater than 3500 to 5000 ng/dL (105 to 150 nmol/L). Confirmatory testing and additional testing needed when results are equivocal are reviewed above. (See 'Newborn screening' above and 'Confirmatory serum testing' above.)

False-positive results – False-positive results from neonatal screening are common in premature infants, and many screening programs have established reference ranges that are based upon weight and gestational age. False-negative results may occur as a result of maternal antenatal glucocorticoid use. (See 'Interpretation of results' above.)

Genotyping – Genotyping is not used as a first-line diagnostic test. Its role is described above. (See 'Role of genetic testing' above.)

Treatment – Treatment of classic 21OHD is reviewed separately. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

  1. Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med 2020; 383:1248.
  2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018; 103:4043.
  3. Pang, S, Clark, A. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Newborn screening and its relationship to the diagnosis and treatment of the disorder. Screening 1993; 2:105.
  4. Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30:15.
  5. Lee HH, Kuo JM, Chao HT, et al. Carrier analysis and prenatal diagnosis of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency in Chinese. J Clin Endocrinol Metab 2000; 85:597.
  6. New MI, White PC. Genetic disorders of steroid hormone synthesis and metabolism. Baillieres Clin Endocrinol Metab 1995; 9:525.
  7. Cutfield WS, Webster D. Newborn screening for congenital adrenal hyperplasia in New Zealand. J Pediatr 1995; 126:118.
  8. Pang S, Murphey W, Levine LS, et al. A pilot newborn screening for congenital adrenal hyperplasia in Alaska. J Clin Endocrinol Metab 1982; 55:413.
  9. Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998; 101:583.
  10. Hannah-Shmouni F, Morissette R, Sinaii N, et al. Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med 2017; 19:1276.
  11. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005; 365:2125.
  12. Pignatelli D, Carvalho BL, Palmeiro A, et al. The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne) 2019; 10:432.
  13. Nordenström A, Svensson J, Lajic S, et al. Carriers of a Classic CYP21A2 Mutation Have Reduced Mortality: A Population-Based National Cohort Study. J Clin Endocrinol Metab 2019; 104:6148.
  14. Carroll MC, Campbell RD, Porter RR. Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man. Proc Natl Acad Sci U S A 1985; 82:521.
  15. White PC, Grossberger D, Onufer BJ, et al. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A 1985; 82:1089.
  16. White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A 1986; 83:5111.
  17. Higashi Y, Yoshioka H, Yamane M, et al. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A 1986; 83:2841.
  18. Finkielstain GP, Chen W, Mehta SP, et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2011; 96:E161.
  19. Lee HH, Chang JG, Tsai CH, et al. Analysis of the chimeric CYP21P/CYP21 gene in steroid 21-hydroxylase deficiency. Clin Chem 2000; 46:606.
  20. L'Allemand D, Tardy V, Grüters A, et al. How a patient homozygous for a 30-kb deletion of the C4-CYP 21 genomic region can have a nonclassic form of 21-hydroxylase deficiency. J Clin Endocrinol Metab 2000; 85:4562.
  21. Chen W, Xu Z, Sullivan A, et al. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem 2012; 58:421.
  22. Lajić S, Clauin S, Robins T, et al. Novel mutations in CYP21 detected in individuals with hyperandrogenism. J Clin Endocrinol Metab 2002; 87:2824.
  23. Stikkelbroeck NM, Hoefsloot LH, de Wijs IJ, et al. CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: six novel mutations and a specific cluster of four mutations. J Clin Endocrinol Metab 2003; 88:3852.
  24. Concolino P, Costella A. Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene. Mol Diagn Ther 2018; 22:261.
  25. Riedl S, Röhl FW, Bonfig W, et al. Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients. Endocr Connect 2019; 8:86.
  26. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003; 349:776.
  27. Ferenczi A, Garami M, Kiss E, et al. Screening for mutations of 21-hydroxylase gene in Hungarian patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 1999; 84:2369.
  28. Speiser PW, Dupont J, Zhu D, et al. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 1992; 90:584.
  29. Wedell A, Thilén A, Ritzén EM, et al. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab 1994; 78:1145.
  30. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995; 80:2322.
  31. Jääskeläinen J, Levo A, Voutilainen R, Partanen J. Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population. J Clin Endocrinol Metab 1997; 82:3293.
  32. Higashi Y, Hiromasa T, Tanae A, et al. Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem 1991; 109:638.
  33. Mornet E, Crété P, Kuttenn F, et al. Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet 1991; 48:79.
  34. Owerbach D, Ballard AL, Draznin MB. Salt-wasting congenital adrenal hyperplasia: detection and characterization of mutations in the steroid 21-hydroxylase gene, CYP21, using the polymerase chain reaction. J Clin Endocrinol Metab 1992; 74:553.
  35. Dardis A, Bergada I, Bergada C, et al. Mutations of the steroid 21-hydroxylase gene in an Argentinian population of 36 patients with classical congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 1997; 10:55.
  36. Krone N, Braun A, Roscher AA, et al. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab 2000; 85:1059.
  37. Deneux C, Tardy V, Dib A, et al. Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2001; 86:207.
  38. Balsamo A, Cicognani A, Baldazzi L, et al. CYP21 genotype, adult height, and pubertal development in 55 patients treated for 21-hydroxylase deficiency. J Clin Endocrinol Metab 2003; 88:5680.
  39. Grigorescu Sido A, Weber MM, Grigorescu Sido P, et al. 21-Hydroxylase and 11beta-hydroxylase mutations in Romanian patients with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2005; 90:5769.
  40. Witchel SF, Lee PA, Suda-Hartman M, et al. Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1997; 82:2097.
  41. Gutai JP, Kowarski AA, Migeon CJ. The detection of the heterozygous carrier for congenital virilizing adrenal hyperplasia. J Pediatr 1977; 90:924.
  42. Charmandari E, Merke DP, Negro PJ, et al. Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress. J Clin Endocrinol Metab 2004; 89:2228.
  43. 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.
  44. Muthusamy K, Elamin MB, Smushkin G, et al. Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab 2010; 95:4161.
  45. Kaye CI, Committee on Genetics, Accurso F, et al. Newborn screening fact sheets. Pediatrics 2006; 118:e934.
  46. Gonzalez RR, Mäentausta O, Solyom J, Vihko R. Direct solid-phase time-resolved fluoroimmunoassay of 17 alpha-hydroxyprogesterone in serum and dried blood spots on filter paper. Clin Chem 1990; 36:1667.
  47. White PC. Neonatal screening for congenital adrenal hyperplasia. Nat Rev Endocrinol 2009; 5:490.
  48. Pode-Shakked N, Blau A, Pode-Shakked B, et al. Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2019; 104:3172.
  49. Sarafoglou K, Banks K, Kyllo J, et al. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012; 307:2371.
  50. Varness TS, Allen DB, Hoffman GL. Newborn screening for congenital adrenal hyperplasia has reduced sensitivity in girls. J Pediatr 2005; 147:493.
  51. Chan CL, McFann K, Taylor L, et al. Congenital adrenal hyperplasia and the second newborn screen. J Pediatr 2013; 163:109.
  52. Gatelais F, Berthelot J, Beringue F, et al. Effect of single and multiple courses of prenatal corticosteroids on 17-hydroxyprogesterone levels: implication for neonatal screening of congenital adrenal hyperplasia. Pediatr Res 2004; 56:701.
  53. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983; 57:320.
  54. Coulm B, Coste J, Tardy V, et al. Efficiency of neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children born in mainland France between 1996 and 2003. Arch Pediatr Adolesc Med 2012; 166:113.
  55. Peter M, Janzen N, Sander S, et al. A case of 11beta-hydroxylase deficiency detected in a newborn screening program by second-tier LC-MS/MS. Horm Res 2008; 69:253.
  56. El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet 2017; 390:2194.
  57. Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. Eur J Hum Genet 2020; 28:1341.
  58. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:4133.
  59. Al-Alwan I, Navarro O, Daneman D, Daneman A. Clinical utility of adrenal ultrasonography in the diagnosis of congenital adrenal hyperplasia. J Pediatr 1999; 135:71.
  60. Simpson JL, Rechitsky S. Prenatal genetic testing and treatment for congenital adrenal hyperplasia. Fertil Steril 2019; 111:21.
  61. New MI, Tong YK, Yuen T, et al. Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma. J Clin Endocrinol Metab 2014; 99:E1022.
  62. Hirvikoski T, Nordenström A, Wedell A, et al. Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: the Swedish experience and standpoint. J Clin Endocrinol Metab 2012; 97:1881.
Topic 145 Version 22.0

References

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