Version July 2025
INTRODUCTION —
Congenital adrenal hyperplasias (CAHs) are autosomal recessive disorders. Approximately 95 percent of cases arise from 21-hydroxylase deficiency (21OHD) due to pathogenic variants in the CYP21A2 gene [1,2]. Loss of 21-hydroxylase activity leads to impaired conversion of 17-hydroxyprogesterone to 11-deoxycortisol and of progesterone to 11-deoxycorticosterone.
Most individuals with the more severe "classic" form of CAH due to 21OHD present during the neonatal period and early infancy with adrenal insufficiency or are diagnosed through neonatal screening. Females have atypical genitalia. "Nonclassic" 21OHD presents with signs of androgen excess later in life and without female atypical genitalia, although clitoromegaly may rarely occur. Clinical features in childhood may include premature pubarche and accelerated bone age. Adolescent females may present with hirsutism, menstrual irregularity, and acne, and some individuals with nonclassic 21OHD remain asymptomatic.
This topic will review the pathophysiology, clinical manifestations, diagnosis, and treatment of nonclassic 21OHD in children and adolescents. The clinical manifestations, diagnosis, and treatment of classic 21OHD in infants and children are reviewed separately, as are the classic and nonclassic forms of 21OHD in adults. Less common forms of CAH due to other enzyme deficiencies also are discussed elsewhere.
●(See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
●(See "Uncommon congenital adrenal hyperplasias".)
PATHOPHYSIOLOGY —
Impaired conversion of 17-hydroxyprogesterone to 11-deoxycortisol results in decreased cortisol synthesis and a compensatory increase in corticotropin (ACTH) secretion. The resulting adrenal stimulation leads to greater production of precursor adrenal steroids and hyperandrogenism. Disease severity reflects the degree to which the pathogenic variants compromise enzyme activity (figure 1).
●Classic 21OHD – In the more severe ("classic") form of 21-hydroxylase deficiency (21OHD), only 0 to 2 percent of 21-hydroxylase activity is preserved. Individuals with classic 21OHD typically present during the neonatal period and early infancy with adrenal insufficiency and salt wasting or during the first few years of life with virilization. Females have ambiguous genitalia.
●Nonclassic 21OHD – Nonclassic 21OHD is a mild form in which 5 to 20 percent of enzyme activity is preserved. Thus, in individuals with nonclassic 21OHD, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production; salt wasting and adrenal insufficiency are absent. In nonclassic 21OHD, increased ACTH production leads to excessive adrenal precursor steroid production, but biochemical and clinical hyperandrogenism are milder than in classic 21OHD.
PREVALENCE —
The nonclassic form of 21-hydroxylase deficiency (21OHD) is one of the most common autosomal recessive diseases across ethnicities. The prevalence ranges from 1 in 200 to 1 in 1000 [3-7]. Most individuals with the nonclassic form will not be identified by newborn screening, because screening programs target classic 21OHD and are based on detection of very high levels of 17-hydroxyprogesterone in the blood spot [1].
In children who present with premature pubarche (premature development of pubic hair), the prevalence of nonclassic 21OHD is approximately 4 to 5 percent [8-12], which is similar to the estimated worldwide prevalence of nonclassic 21OHD among women presenting with symptoms and signs of androgen excess (4.2 percent, 95% CI 3.2-5.4 percent) [13].
Males with nonclassic CAH are diagnosed less often than females because adrenal androgen excess is less likely to cause symptoms in males once puberty begins [14,15]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Prevalence'.)
GENETICS
Types of genetic variants — As with the other forms of congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency (21OHD) is transmitted as an autosomal recessive disorder. 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 (HLA) locus [16-22].
The two CYP21A genes are more than 90 percent homologous. This high degree of homology facilitates recombination and gene conversion events during meiosis, with consequent exchanges of deoxyribonucleic acid (DNA) segments between the two genes.
Genotype versus phenotype — Specific variants of the CYP21A2 gene do not always predict clinical phenotype, suggesting that other genes may influence the clinical presentation of 21OHD [23-27]. Nonetheless, genotype and phenotype exhibit general correlations. Individuals with CYP21A2 pathogenic variants can be grouped according to the predicted effect of the variant on 21-hydroxylase enzymatic activity. In some instances, the phenotype straddles the classic-nonclassic boundary. This is especially true for the p.Pro30Leu (P30L) nonclassic variant [2,28]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Genotype-phenotype'.)
Individuals diagnosed with 21OHD are most often compound heterozygotes for two different CYP21A2 pathogenic variants with a phenotype associated with the less severe of the two genetic variants [2]. Heterozygote carriers have one pathogenic variant and one normal allele. Such individuals may have mild biochemical abnormalities but generally do not develop clinical evidence of hyperandrogenism [16-18,29].
CLINICAL FEATURES
Children — Unlike classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), which often presents in the neonatal period, symptoms of nonclassic 21OHD develop over time, hence the formerly used term "late-onset" CAH [7,30,31]. Children present with signs of hyperandrogenism in the absence of adrenal insufficiency. Some individuals with nonclassic 21OHD are identified by family genetic studies and remain asymptomatic. The clinical presentation of children with classic 21OHD is discussed separately. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
In children, clinical features of nonclassic 21OHD may include:
●Premature pubarche, oily skin, acne, or adult-type body odor. In children (male and female) with nonclassic 21OHD, premature pubarche is the most common presentation. Premature pubarche is defined as the isolated appearance of sexual hair before the age of eight years in girls and nine years in boys. The clinical presentation may be indistinguishable from premature adrenarche [32]. (See "Premature adrenarche", section on 'Differential diagnosis'.)
●Accelerated growth velocity, which may be accompanied by advanced bone age (advanced ≥2 SD for age). Children with nonclassic 21OHD may enter puberty early, causing early epiphyseal closure that may lead to short stature as an adult. However, short stature is not a consistent feature in adults with nonclassic 21OHD [33-35].
●Acne or clitoromegaly (females). These findings are rare in children with nonclassic 21OHD.
Adolescents
●Females – Adolescent females with nonclassic 21OHD most commonly present with hirsutism, oligomenorrhea, and/or acne [36]. The clinical presentation is often similar to that of polycystic ovary syndrome (PCOS). (See "Treatment of polycystic ovary syndrome (PCOS) in adolescents".)
Additional clinical features may include clitoromegaly, alopecia, or primary amenorrhea [37].
●Males – Adolescent males with 21OHD remain asymptomatic because symptoms of adrenal androgen excess are clinically inapparent. Whereas males with classic 21OHD are at high risk for testicular masses (testicular adrenal rest tumors), these tumors are rare in males with nonclassic 21OHD [38,39].
DIAGNOSTIC EVALUATION
Whom to test — Testing for nonclassic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) should be performed in children and adolescents with the typical clinical features of the disorder.
●Children – Testing for nonclassic 21OHD should be performed in children with premature pubarche and/or accelerated growth velocity, who also have advanced bone age (≥2 SD). Virilization is rare in nonclassic 21OHD. Accelerated growth velocity is defined as growth that crosses a percentile line on the growth chart. Children with isolated premature pubarche without bone age advancement can be followed clinically. (See "Premature adrenarche".)
●Adolescents – Testing for nonclassic 21OHD is indicated in adolescent females who present with signs of androgen excess (hirsutism, oligomenorrhea, acne). We perform testing in all adolescent females with a clinical presentation consistent with polycystic ovary syndrome (PCOS). Adolescent and adult females with nonclassic 21OHD present with signs of hyperandrogenism that may be clinically indistinguishable from PCOS [14,37]. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome (PCOS) in adolescents".)
●Other indications
•Individuals with genetic testing results consistent with 21OHD – Some individuals may be identified as possibly having 21OHD through family genetic studies. It is important to confirm the diagnosis with hormonal testing because genotyping may be equivocal due to the complexity of the CYP21A2 locus [1].
•Adrenal incidentaloma – We perform biochemical testing for 21OHD in all individuals with a unilateral adrenal incidentaloma and hyperandrogenism. We also perform biochemical testing in those with bilateral adrenal enlargement/masses; in this setting, testing for nonclassic 21OHD is part of the evaluation for primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of bilateral adrenal lesions. (See "Cushing syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'PBMAH presenting as bilateral incidentalomas'.)
Most individuals with unilateral or bilateral adrenal incidentalomas have exaggerated serum 17-hydroxyprogesterone responses to cosyntropin (ACTH [corticotropin]) stimulation [7]. However, in such individuals, the prevalence of germline CYP21A2 variants is low. Nonetheless, adrenal enlargement and/or tumors are common findings in individuals with all forms of 21OHD [40]. Routine evaluation of incidentally discovered adrenal tumors/enlargement is reviewed separately. (See "Evaluation and management of the adrenal incidentaloma" and "Clinical presentation and evaluation of adrenocortical tumors".)
•Suspected misdiagnosis – In some individuals with a prior diagnosis of 21OHD, misdiagnosis may be suspected based on family history or clinical presentation. If the individual is not receiving glucocorticoid treatment, measuring a morning 17-hydroxyprogesterone level should be the next step in evaluation. (See 'Initial testing (morning 17-hydroxyprogesterone level)' below.)
However, in individuals receiving glucocorticoid therapy, biochemical evaluation is less reliable. In this setting, genotyping of CYP21A2 should be performed. (See 'Genetic testing (limited role)' below.)
Initial testing (morning 17-hydroxyprogesterone level) — An early morning, unstimulated serum 17-hydroxyprogesterone level is a cost-effective screening test for nonclassic 21OHD (algorithm 1).
Sample collection — Blood should be collected no later than 8:30 AM. In adolescent females with regular menstrual cycles, the sample should be obtained during the follicular phase of the cycle. For other children, including adolescent females with amenorrhea or infrequent menses, the sample can be drawn on a random morning. The early morning timing is critical because the 17-hydroxyprogesterone level falls rapidly over the course of the day. When the blood sample is obtained later in the day, a normal 17-hydroxyprogesterone level does not exclude CAH. Values are reasonably comparable for the different assay techniques [1]. Nevertheless, it is important to know the normative reference ranges for the clinical laboratory because hormone measurements are assay specific.
Interpretation — The interpretation of the serum 17-hydroxyprogesterone is the same in males and females. (Related Lab Interpretation Monograph(s): "High 17-hydroxyprogesterone in adults".)
≤200 ng/dL (6 nmol/L) — If the basal, morning serum 17-hydroxyprogesterone value is ≤200 ng/dL (6 nmol/L), nonclassic 21OHD is unlikely. The need for additional monitoring and/or evaluation depends on the value and the patient's age and clinical symptomatology. (See "Premature adrenarche", section on 'Additional testing for selected patients'.)
If clinical suspicion for nonclassic 21OHD remains high, a cosyntropin (ACTH) stimulation test is recommended, especially if the screening basal 17-hydroxyprogesterone level is >82 ng/dL (2.5 nmol/L) or in the highest quartile of the age-specific reference range [14]. A retrospective study of 238 prepubertal children with precocious pubarche found a basal morning 17-hydroxyprogesterone threshold of 200 ng/dL had 100 percent (95% CI 69-100) sensitivity and 99 percent (95% CI 96-100) specificity for identifying nonclassic 21OHD [11]. In a study of 280 individuals (median age 17.6 years) with hormonal and genetic data consistent with nonclassic 21OHD, 2.1 percent had a basal 17-hydroxyprogesterone level <200 ng/dL [15]. (See 'Additional testing (ACTH stimulation test)' below.)
>200 and ≤1000 ng/dL (6 and 30 nmol/L) — A moderately elevated 17-hydroxyprogesterone level (>200 to ≤1000 ng/dL [6 to 30 nmol/L]) suggests possible nonclassic 21OHD. However, this level is also consistent with a carrier state. An ACTH stimulation test should be performed to verify the diagnosis. (See 'Additional testing (ACTH stimulation test)' below.)
In prepubertal children, an 8:00 AM 17-hydroxyprogesterone level >200 ng/dL (6 nmol/L) has 92 to 98 percent sensitivity and specificity for nonclassic 21OHD [11,15,41-43].
>1000 ng/dL (30 nmol/L) — A 17-hydroxyprogesterone level >1000 (30 nmol/L) is diagnostic of nonclassic 21OHD.
Most laboratories use mass spectrometry-based assays to measure 17-hydroxyprogesterone. However, if immunoassay was used, additional evaluation is warranted when 17-hydroxyprogesterone values are >1000 to 2000 ng/dL (30 to 61 nmol/L). Additional evaluation includes measuring an ACTH-stimulated 17-hydroxyprogesterone level and/or genotyping of the CYP21A2 gene.
Individuals with classic 21OHD typically have basal 17-hydroxyprogesterone concentrations >3500 ng/dL (105 nmol/L) [44], with most exceeding 10,000 ng/dL (300 nmol/L) [45,46], and bone age is several years advanced. If the clinical history and biochemical testing are suspicious for classic CAH, an ACTH stimulation test with cortisol measurement should be performed for further evaluation. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Interpretation of results'.)
Additional testing (ACTH stimulation test) — If the basal 17-hydroxyprogesterone level is indeterminate, the next step in evaluation is measuring serum 17-hydroxyprogesterone after ACTH stimulation (algorithm 2).
Procedure — ACTH stimulation testing can be performed any time of day and, in cycling females, during any phase of the menstrual cycle. Serum 17-hydroxyprogesterone and cortisol levels are measured at baseline and 60 minutes after administration of ACTH (250 mcg). The diagnosis of nonclassic CAH is based on the stimulated 17-hydroxyprogesterone level. Serum cortisol is measured to confirm that the test was performed properly and to identify patients with impaired cortisol production. Mildly reduced cortisol production has been found in approximately 30 percent of patients with nonclassic 21OHD [42,47,48].
If subnormal cortisol production is identified on basal or stimulated cortisol testing, patients should receive stress-dose glucocorticoids during times of major physiologic stress (eg, febrile illness, major trauma, surgery). (See 'Stress-dose glucocorticoids' below.)
Interpretation — Beyond infancy, age does not impact the diagnosis of nonclassic 21OHD based on high-dose (250 mcg) ACTH stimulation testing. The diagnostic criteria are the same for males and females. The interpretation of stimulated cortisol levels is reviewed separately. (See "Diagnosis of adrenal insufficiency in adults", section on 'ACTH stimulation tests'.)
Stimulated serum 17-hydroxyprogesterone values are interpreted as follows:
●≤1000 ng/dL (≤30 nmol/L) – A stimulated 17-hydroxyprogesterone level ≤1000 ng/dL excludes the diagnosis of nonclassic 21OHD. Rare false-negative results may occur following recent glucocorticoid therapy. For individuals exposed to recent or current glucocorticoid therapy, genetic testing may be warranted.
●>1000 ng/dL (30 nmol/L) – A stimulated 17-hydroxyprogesterone level >1000 (30 nmol/L) is diagnostic of nonclassic 21OHD.
Rarely, elevation in 17-hydroxyprogesterone up to 2000 ng/dL (60 nmol/L) is found in heterozygous carriers for classic 21OHD or some individuals with adrenal incidentalomas [14]. Patients with PBMAH also may have elevated 17-hydroxyprogesterone levels due to partial 21OHD; however, in such patients, biochemical evidence of hypercortisolism is usually present. (See "Cushing syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'PBMAH presenting as bilateral incidentalomas'.)
If the history and clinical presentation support a diagnosis of 21OHD, no further diagnostic evaluation is needed. If the diagnosis remains equivocal, genotyping of the CYP21A2 gene can be performed [13,49]. (See 'Differential diagnosis' below and 'Genetic testing (limited role)' below.)
Genetic testing (limited role) — Genetic testing is not part of the routine diagnostic evaluation for children and adolescents with nonclassic 21OHD. However, genetic testing is helpful when the diagnosis remains equivocal after ACTH stimulation testing (eg, stimulated 17-hydroxyprogesterone level approximately 1000 ng/dL [30 nmol]). Genotyping also may be needed for individuals with recent or current exposure to exogenous glucocorticoids.
In adults with nonclassic 21OHD who are pursuing fertility, genetic testing is indicated for preconception counseling.
Differential diagnosis
Other causes of premature pubarche — Children with nonclassic 21OHD may present with premature pubarche, accelerated growth velocity, and advanced bone age. Therefore, nonclassic 21OHD should be differentiated from other causes of premature pubarche such as premature adrenarche and precocious puberty. If serum 17-hydroxyprogesterone levels exclude 21OHD, other causes of premature pubarche should be investigated. (See "Premature adrenarche", section on 'Differential diagnosis'.)
11-beta-hydroxylase deficiency — Like nonclassic 21OHD, nonclassic 11-beta-hydroxylase deficiency (11OHD) is a form of CAH characterized by elevated adrenal androgen and mildly elevated 17-hydroxyprogesterone levels. Children may present with premature pubarche, and adolescent females may have signs of hyperandrogenism and menstrual irregularity. However, in classic 11OHD, mineralocorticoid levels also are elevated and may lead to hypertension and/or hypokalemia early in life, whereas mineralocorticoid excess is not a feature of 21OHD. In nonclassic 11OHD but not 21OHD, 11-deoxycortisol levels are markedly elevated after ACTH stimulation. Genetic testing can confirm the diagnosis of 11OHD. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)
Polycystic ovary syndrome — In adolescent females, the clinical presentation of nonclassic 21OHD can be indistinguishable from that of PCOS. However, PCOS is far more common than 21OHD; basal levels of 17-hydroxyprogesterone may overlap, but ACTH stimulation testing effectively distinguishes between the two [50]. (See 'Additional testing (ACTH stimulation test)' above and "Diagnosis of polycystic ovary syndrome in adults".)
Classic 21OHD — Occasionally, patients with classic 21OHD are missed by newborn screening and are not diagnosed clinically in the newborn period. These patients produce small amounts of aldosterone and cortisol sufficient to escape adrenal crisis and maintain sodium balance. Affected children present with signs of androgen excess typically before age 4 years. The biochemical and clinical findings in patients with classic 21-hydroxylase deficiency are more severe. Untreated individuals with classic 21OHD have basal 17-hydroxyprogesterone concentrations >3500 ng/dL (105 nmol/L) [44], with most exceeding 10,000 ng/dL (300 nmol/L) [45,46]. Individuals with classic 21OHD also have cortisol deficiency with a subnormal serum cortisol response to ACTH stimulation. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Diagnosis'.)
MANAGEMENT
Children — We suggest the following approach for children with nonclassic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), which is largely consistent with the Endocrine Society Guidelines [1].
●Asymptomatic – Asymptomatic children who are diagnosed through family genotyping do not require treatment [1,51].
●Premature pubarche and advanced bone age – In children (females and males) with early-onset or rapid progression of pubarche (development of pubic hair) and accelerated growth velocity (crossing height percentiles) with advanced bone maturation (ie, ≥2 SD or two or more years advanced), glucocorticoid therapy should be initiated. The goal of glucocorticoid therapy is to mitigate the adverse effect of hyperandrogenism on adult height [1].
•Glucocorticoid regimen – In children, the preferred glucocorticoid regimen is hydrocortisone 10 to 15 mg/m2 divided into three daily doses, although lower doses may be effective. Higher doses may have adverse effects on growth and result in Cushingoid features. Glucocorticoid regimens are the same as for children with classic 21OHD, but doses required for ameliorating the androgen excess are often lower. (See "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children: Treatment", section on 'Glucocorticoid (all patients)'.)
Glucocorticoid treatment is monitored primarily through clinical assessments. (See 'Glucocorticoid therapy' below.)
•Treatment duration – Treatment may be tapered and discontinued during early to mid-puberty for males and two to three years postmenarche for females [52]. In adolescent females with persistent hyperandrogenic symptoms or oligomenorrhea, combined estrogen-progestin oral contraceptives (COCs) are usually preferred to avoid prolonged glucocorticoid use. (See 'Adolescents' below.)
Very limited data suggest that aromatase inhibitor therapy may prove an alternative to glucocorticoid treatment in selected children with nonclassic 21OHD and advanced bone age. In one series of three female children with nonclassic 21OHD and early adrenarche, advanced bone age, and normal endogenous cortisol production, monotherapy with the aromatase inhibitor anastrozole normalized bone age Z-scores in all three patients, who ultimately achieved or surpassed their target height [53].
●Premature pubarche without advanced bone age – For children with premature pubarche but without advanced bone maturation, we defer treatment and monitor pubertal development and growth every six months [1]. (See 'Treatment monitoring' below.)
Adolescents
●Asymptomatic – Adolescents who are asymptomatic and diagnosed through family genotyping do not require treatment.
●Symptomatic females – In symptomatic adolescent females, treatment goals include managing hyperandrogenic signs and regulating menstrual cycles. Treatment regimens should be individualized and tailored to the individual's goals.
•COCs (preferred) – We suggest COCs as first-line therapy for hyperandrogenic symptoms and management of oligomenorrhea. COCs suppress ovarian androgen production, which may be more effective for attenuating hyperandrogenism than lowering corticotropin (ACTH) with glucocorticoid therapy [13]. COCs also are preferred therapy because hyperandrogenism typically requires long-term treatment, and glucocorticoids impart numerous potential risks and side effects with long-term use. The choice of COC is the same as for any premenopausal woman with hirsutism. (See "Management of hirsutism in premenopausal females".)
•Anti-androgen therapy – If clinical response to COCs is inadequate after six months, anti-androgen therapy can be added. Anti-androgens are effective, but we suggest against anti-androgen monotherapy because of potential teratogenicity. In the United States, spironolactone is the most used anti-androgen, whereas cyproterone acetate is typically used in other countries (though not available in the United States). The management of hirsutism is reviewed in detail separately. (See "Management of hirsutism in premenopausal females".)
•Oral contraceptive intolerance or contraindications – For adolescent females who are not candidates for COCs or anti-androgen therapy, glucocorticoid therapy may be used for both hyperandrogenic symptoms and menstrual cycle management. Glucocorticoid therapy should only be used for those who do not respond to or cannot tolerate COC and anti-androgen therapies [54].
When a decision is made to initiate glucocorticoid therapy, we prefer treatment with hydrocortisone 10 to 15 mg/m2 divided into three daily doses. For adolescent females who are still growing, glucocorticoid regimens are the same as for children with classic 21OHD, but doses required for ameliorating the androgen excess are often lower. (See "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children: Treatment", section on 'Glucocorticoid (all patients)'.)
For adolescent females who have completed linear growth, longer-acting glucocorticoid regimens could be considered, similar to adults with classic 21OHD, but lower doses may be effective. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Hydrocortisone (preferred glucocorticoid)'.)
Stress-dose glucocorticoids
●Individuals on glucocorticoid therapy – For children and adolescents with nonclassic 21OHD who are on exogenous glucocorticoid therapy, adrenal insufficiency is possible due to iatrogenic hypothalamic-pituitary-adrenal axis suppression [1,55]. Such individuals should receive extensive counseling about the risks of adrenal insufficiency and management of glucocorticoid dosing during periods of acute stress (eg, febrile illness, trauma, surgery). Stress-dose glucocorticoid regimens for children and adolescents are reviewed in detail separately. (See "Treatment of adrenal insufficiency in children", section on 'Stress conditions' and "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children: Treatment", section on 'Measures to prevent adrenal crisis in all'.)
●Individuals not on glucocorticoid therapy – Children and adolescents with nonclassic 21OHD who are not on exogenous glucocorticoid therapy do not require stress-dose glucocorticoids unless partial cortisol insufficiency has been identified. Approximately 30 percent of patients with nonclassic 21OHD [42,47,48] have a subnormal ACTH-stimulated cortisol level (ie, <14 to 18 mcg/dL [400 to 500 nmol/L] measured by mass spectrometry. Although adrenal crises have not been reported in these patients, stress-dose glucocorticoids are recommended during severe physiologic stress such as major surgery, major trauma, or childbirth. (See "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children: Treatment", section on 'Measures to prevent adrenal crisis in all'.)
TREATMENT MONITORING
Glucocorticoid therapy — Glucocorticoid overtreatment can impair growth, inhibit bone mass acquisition, and lead to excessive body weight gain. Thus, the lowest dose that achieves treatment goals should be used.
For children and adolescents who have not completed linear growth, growth velocity, weight, and bone age are used to guide glucocorticoid therapy. We perform clinical assessments every six months, and annual bone age is also helpful.
Biochemical assessments are less useful than in patients with classic 21OHD, especially if unstimulated adrenal androgen levels were not elevated on diagnosis. In children and adolescents on glucocorticoid therapy, serum concentrations of 17-hydroxyprogesterone, androstenedione, and testosterone should be monitored at least annually according to practice guidelines but target levels are unclear [1]. In general, androstenedione and testosterone levels should be in the reference range. In contrast, 17-hydroxyprogesterone levels should not be completely suppressed; suppressed levels of 17-hydroxyprogesterone generally indicate overtreatment.
For adolescents who have completed linear growth, glucocorticoid treatment monitoring is mostly clinical. Clinical assessment for amelioration of signs of androgen excess (hirsutism, menstrual cycle regularity) and monitoring for glucocorticoid excess is indicated. Most patients can be weaned from glucocorticoid therapy. (See 'Management' above.)
Non-glucocorticoid-based regimens — For female adolescents on combined estrogen-progestin oral contraceptives (COCs) with or without anti-androgen therapy, monitoring through clinical assessments should be performed every six months. Patients should be assessed for signs of hyperandrogenism (hirsutism, acne, body odor, sweating) and menstrual cycle regularity. Treatment regimens should be individualized to meet the patient's goals. (See "Management of hirsutism in premenopausal females".)
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 – Impaired conversion of 17-hydroxyprogesterone to 11-deoxycortisol in patients with 21-hydroxylase deficiency (21OHD) results in decreased cortisol synthesis and a compensatory increase in corticotropin (ACTH) secretion (figure 1). The resulting adrenal stimulation leads to greater production of precursor adrenal steroids and hyperandrogenism. (See 'Pathophysiology' above.)
●Prevalence – Nonclassic congenital adrenal hyperplasia (CAH) due to 21OHD is one of the most common autosomal recessive diseases. The prevalence ranges from 1 in 200 to 1 in 1000. In children who present with premature pubarche (premature development of pubic hair), the prevalence of nonclassic 21OHD is approximately 4 to 5 percent. (See 'Prevalence' above.)
●Clinical features – Children with nonclassic 21OHD present after the neonatal period with evidence of hyperandrogenism in the absence of adrenal insufficiency. (See 'Children' above.)
Adolescent females may present with hirsutism, oligomenorrhea, and acne. Adolescent males are asymptomatic. (See 'Adolescents' above.)
●Diagnosis
•Whom to test – Testing for nonclassic 21OHD is indicated in the following individuals:
-Children with premature pubarche and/or accelerated growth velocity with advanced bone age or rapid progression of symptoms
-Adolescent females who present with oligomenorrhea and signs of hyperandrogenism
•Initial testing – An early morning serum 17-hydroxyprogesterone level is a cost-effective screening test for nonclassic 21OHD. Blood should be collected at or before 8:30 AM (algorithm 1). In adolescent females with regular menstrual cycles, the sample should be obtained during the follicular phase of the cycle. (See 'Initial testing (morning 17-hydroxyprogesterone level)' above.)
If the basal, morning serum 17-hydroxyprogesterone value is ≤200 ng/dL (6 nmol/L), nonclassic 21OHD is unlikely, whereas a 17-hydroxyprogesterone level >1000 ng/dL (30 nmol/L) confirms underlying 21OHD. (See 'Interpretation' above.)
•Additional testing – If the basal 17-hydroxyprogesterone level is indeterminate, the next step in evaluation is measuring serum 17-hydroxyprogesterone after cosyntropin (ACTH) stimulation (algorithm 2). Serum 17-hydroxyprogesterone and cortisol levels are measured at baseline and 60 minutes after administration of ACTH (250 mcg). Serum cortisol is measured to confirm that the test was performed properly and to identify unrecognized partial cortisol deficiency. (See 'Additional testing (ACTH stimulation test)' above.)
●Management – Asymptomatic children and adolescents who are diagnosed through family genotyping do not require treatment.
•Children – In children with nonclassic 21OHD who have signs of hyperandrogenism and advanced bone age, glucocorticoid therapy is warranted to mitigate the adverse effect of hyperandrogenism on adult height. (See 'Children' above.)
-Choice of glucocorticoid – For children with nonclassic 21OHD, we suggest hydrocortisone as the glucocorticoid of choice (Grade 2C). A typical hydrocortisone regimen is 10 to 15 mg/m2 divided into three daily doses. (See 'Children' above.)
-Duration of therapy – We typically discontinue glucocorticoid treatment during early to mid-puberty for boys and two to three years post-menarche for girls. In adolescent females with persistent signs of hyperandrogenism, other treatment modalities are usually preferred to avoid prolonged glucocorticoid use. (See 'Children' above and 'Adolescents' above.)
•Adolescents
-Females – For adolescent females with nonclassic 21OHD who have signs of hyperandrogenism (eg, hirsutism, acne), we suggest combined estrogen-progestin oral contraceptives (COCs) as first-line therapy (Grade 2C). If the response to COCs is inadequate after six months, anti-androgens may be added. (See 'Adolescents' above and "Management of hirsutism in premenopausal females".)
We also use COCs rather than glucocorticoids as first-line therapy for menstrual cycle management. (See 'Adolescents' above.)
For adolescent females who cannot tolerate or have contraindications to COCs, glucocorticoid therapy may be used for both hyperandrogenic symptoms and menstrual cycle management. (See 'Adolescents' above.)
•Stress-dose glucocorticoids – Stress doses of glucocorticoids are required for individuals who receive glucocorticoid therapy, which could suppress the hypothalamic-pituitary-adrenal axis and cause central adrenal insufficiency. Stress doses of glucocorticoids are also recommended during severe physiologic stress (major surgery, major trauma, childbirth) for individuals who have partial cortisol insufficiency evident on ACTH stimulation testing. (See 'Stress-dose glucocorticoids' above.)
●Monitoring – Treatment monitoring should be performed at least every six months, depending on the clinical status. Management is based primarily on clinical assessments. (See 'Treatment monitoring' above.)
ACKNOWLEDGMENT —
The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States government or its components.\
