Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency

INTRODUCTION — Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for more than 90 percent of cases of congenital adrenal hyperplasia (CAH) [1-3]. This conversion is mediated by 21-hydroxylase and is defective due to mutations in the CYP21A2 gene.

The diagnosis and treatment of nonclassic CAH (NCCAH) due to 21-hydroxylase deficiency are reviewed here. The genetics and clinical manifestations of the nonclassic form of 21-hydroxylase deficiency and the classic form of 21-hydroxylase deficiency are reviewed separately. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Clinical manifestations and diagnosis 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".)

BACKGROUND — Congenital adrenal hyperplasias (CAHs) are autosomal recessive disorders; 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for approximately 95 percent of cases.

●The most severely affected individuals with classic CAH due to 21-hydroxylase deficiency present during the neonatal period and early infancy with adrenal insufficiency and salt wasting or in the first few years of life with virilization. Females have ambiguous genitalia.

●Most individuals are identified through neonatal screening; the characteristic biochemical abnormality is a high serum concentration of 17-hydroxyprogesterone. Affected neonates have concentrations greater than 3500 ng/dL (105 nmol/L), with most exceeding 10,000 ng/dL (300 nmol/L).

Nonclassic CAH (NCCAH) is a less severe form of the disorder in which there is 20 to 50 percent 21-hydroxylase enzyme activity compared with 0 to 2 percent in the classic form. Salt wasting is absent, and affected females do not have ambiguous genitalia. The biochemical findings are less severe than those seen with classic 21-hydroxylase deficiency.

●NCCAH is more prevalent than classic CAH. It is one of the most common autosomal recessive diseases, and the frequency varies by ethnicity. Among the white populations, the prevalence of NCCAH may be as high as 1 in 1000 to 1 in 100, with the prevalence being even higher among Hispanics, Yugoslavs, and Ashkenazi Jews.

●NCCAH presents later in life with signs of androgen excess. Clinical features in late childhood include premature pubarche, acne, and accelerated bone age; adolescent and adult females present with hirsutism (60 percent), oligomenorrhea (54 percent), and acne (33 percent) [2,4-10]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Clinical manifestations'.)

●Approximately two-thirds of patients with nonclassic 21-hydroxylase deficiency carry a severe mutation. Therefore, patients pursuing fertility should consider genotyping. (See 'Genetic testing' below.)

WHO SHOULD BE TESTED? — Unlike patients with classic 21-hydroxylase deficiency, who are identified either through neonatal screening by detecting very high levels of 17-hydroxyprogesterone or by clinical findings (ambiguous genitalia, salt wasting), most patients with the nonclassic form will not be identified by neonatal screening. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

Therefore, testing for nonclassic 21-hydroxylase deficiency should be considered in children and adults with the typical clinical features of the disorder. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Clinical presentations'.)

●Children – Children with premature pubarche or accelerated growth velocity (crossing growth percentiles) with advanced bone age. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Children' and "Premature adrenarche".)

●Women – Women with oligomenorrhea and hyperandrogenism (acne and/or hirsutism) because the clinical presentation of the nonclassic form of congenital adrenal hyperplasia (NCCAH) can be indistinguishable from that of polycystic ovary syndrome (PCOS). (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Female reproduction' and "Clinical manifestations of polycystic ovary syndrome in adults".)

The prevalence of NCCAH in women who present with apparent PCOS is variable, depending upon the population studied. Testing for NCCAH is most important in higher-risk groups including Mediterranean, Hispanic, and Ashkenazi Jewish women. Some experts suggest testing for NCCAH only in high-risk populations, but we suggest measuring a basal 17-hydroxyprogesterone in all women who present with a PCOS-type picture [11]. (See 'Differential diagnosis' below and "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Female reproduction'.)

●Men – A subset of males with NCCAH present in childhood with premature pubarche, accelerated growth velocity, and advanced bone age; however, many males with NCCAH remain asymptomatic and are never diagnosed. Some men are identified because they are tested following the diagnosis of a family member. Although most men with the nonclassic form have normal testicular function and normal fertility, testicular adrenal rests and infertility have been reported in rare isolated case reports [12]. However, we do not suggest routine screening for NCCAH in men with infertility. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Men'.)

●Others – Other indications for biochemical testing for NCCAH include a family history of CAH [13] and patients with adrenal incidentaloma or bilateral adrenal masses with a history consistent with NCCAH. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Evaluation and management of the adrenal incidentaloma".)

DIAGNOSIS

17-hydroxyprogesterone — An early morning baseline 17-hydroxyprogesterone is a good screening test for nonclassic CAH and may obviate the need for an ACTH test.

●In children, a 17-hydroxyprogesterone level of >200 ng/dL (6 nmol/L) taken at 8:00 AM has 92 to 98 percent sensitivity and specificity for the diagnosis of nonclassic 21-hydroxylase deficiency [14-18]. The early morning timing is critical because the 17-hydroxyprogesterone level falls rapidly during the course of the day. Results are interpreted as follows:

•A normal level of 17-hydroxyprogesterone for prepubertal children (less than 115 ng/dL [3.5 nmol/L]) (table 1) excludes NCCAH with approximately 95 percent confidence.

•A slightly high level of 17-hydroxyprogesterone (between 115 and 200 ng/dL [4.1 to 6.0 nmol/L]) is atypical but consistent with premature adrenarche [14]. (See "Premature adrenarche".)

The patient should be followed clinically to determine if further testing is indicated (ie, for evidence of progressive puberty or virilization). If the clinical picture suggests progressive bone age advancement or virilization, an ACTH stimulation test should be performed. (See "Premature adrenarche".)

•A moderately elevated level of 17-hydroxyprogesterone (eg, between 200 and 1500 ng/dL [6.0 to 45 nmol/L]) suggests possible NCCAH. An ACTH stimulation test is recommended to confirm the diagnosis.

•A very elevated 17-hydroxyprogesterone level (>1500 ng/dL [45 nmol/L]) is diagnostic of NCCAH.

●In adult women, the diagnosis of NCCAH is strongly suggested by a basal 17-hydroxyprogesterone value greater than 200 ng/dL (6 nmol/L) and confirmed with an ACTH stimulation test.

For initial screening, a morning (7:30 to 8 AM) serum sample for 17-hydroxyprogesterone concentration should be obtained during the follicular phase of the menstrual cycle if the woman is cycling regularly. For women with amenorrhea or infrequent menses, the sample can be drawn on a random day.

If the basal sample is >200 ng/dL (6 nmol/L), a high-dose (250 mcg) ACTH stimulation test, the gold standard for diagnosis, should then be performed. The response to ACTH is exaggerated in NCCAH, and a serum 17-hydroxyprogesterone value exceeding 1500 ng/dL (43 nmol/L) [5,6] confirms the diagnosis. Rarely, stimulated values at 60 minutes in affected patients range between 1000 ng/dL (30 nmol/L) and 1500 ng/dL (43 nmol/L) [4]. This range is inconclusive, and the diagnosis should be confirmed with genotyping of the CYP21A2 gene [19].

When a lower post-ACTH cutoff for 17-hydroxyprogesterone (>1000 ng/dL) is used, the false-positive rate is high. In a study of 21 women with a stimulated serum 17-hydroxyprogesterone >1000 ng/dL (30 nmol/L), only 5 out of 21 cases had the diagnosis confirmed by 24-hour urinary steroid profiling and genotyping. Four others were heterozygotes, and 12 had no mutation. This observation supports our approach to diagnosis; a 17-hydroxyprogesterone >1500 ng/dL (43 nmol/L) after ACTH stimulation confirms the diagnosis. For patients with equivocal results (values between 1000 ng/dL [30 nmol/L] and 1500 ng/dL [43 nmol/L]), we perform genotyping to distinguish between a heterozygote carrier and an affected patient [20,21]. A more detailed description of the ACTH stimulation test (for adrenal insufficiency) is found separately). (See "Diagnosis of adrenal insufficiency in adults", section on 'Standard high-dose ACTH stimulation test'.)

●The biochemical criteria used for diagnosis in men are the same as those used for women. Adult men are typically asymptomatic but may be diagnosed during a family evaluation [13].

●Beyond infancy, there are no age-related differences in the diagnosis of NCCAH based upon high-dose (250 mcg) ACTH stimulation testing.

The biochemical findings in patients with classic 21-hydroxylase deficiency are more severe. Untreated patients with classic congenital adrenal hyperplasia (CAH) have basal 17-hydroxyprogesterone concentrations greater than 3500 ng/dL (105 nmol/L) [1], with most exceeding 10,000 ng/dL (300 nmol/L) [3,4]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Diagnosis'.)

Differential diagnosis — Children with NCCAH present with premature pubarche, accelerated growth velocity, and advanced bone age. Therefore, other diagnostic considerations in children include causes of premature pubarche such as premature adrenarche, precocious puberty, and other forms of CAH. (See "Premature adrenarche".)

In adolescents and adult females, the clinical presentation of NCCAH can be indistinguishable from that of polycystic ovary syndrome (PCOS). However, PCOS is far more common than NCCAH; basal levels of 17-hydroxyprogesterone may overlap, but ACTH stimulation testing works well to distinguish between the two [22]. (See '17-hydroxyprogesterone' above and "Diagnosis of polycystic ovary syndrome in adults".)

Genetic testing — Genetic testing is not considered to be a primary diagnostic tool for NCCAH. However, it may be used when biochemical results are borderline or when genetic counseling is needed prior to conception. (See 'Heterozygote carriers' below and "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Risk of classic CAH in offspring'.)

Compound heterozygotes — Approximately two-thirds of patients with nonclassic 21-hydroxylase deficiency are compound heterozygotes and carry a severe and mild mutation on different alleles. Therefore, patients pursuing fertility should consider genotyping [16,23]. The overall risk of severe (classic) 21-hydroxylase deficiency in a child of a patient with the nonclassic form has been estimated at 2.5 percent, while the risk of nonclassic deficiency is approximately 15 percent [24]. Knowledge of the partner's genotype can help assess these risks. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Risk of classic CAH in offspring'.)

Heterozygote carriers — If it is important to document the presence of a carrier state for genetic counseling, CYP21A2 genotyping should be performed. Biochemical testing has been used to identify heterozygote carriers of NCCAH, but results may be misleading and do not correlate well with results of genotyping. ACTH-stimulated 17-hydroxyprogesterone levels may be exaggerated and even overlap with some nonclassic patients, but heterozygote carriers may also have adrenal androgen responses to ACTH that overlap the responses of normal subjects [7,8]. As an example, in one study of 31 heterozygote carriers, only five (16 percent) had a serum 17-hydroxyprogesterone value after ACTH stimulation greater than the peak value seen in 90 healthy control subjects (580 ng/dL [17.55 nmol/L]) [8].

There is no clear consensus as to whether heterozygote carriers are at increased risk of developing hyperandrogenic symptoms. In several studies of women with hirsutism, 8 to 13 percent were identified as carriers [25-27], similar to the rate seen in nonhirsute women in two of the studies [26,27]. However, no relative with a single mutation was clinically symptomatic in another study of 242 subjects [16].

APPROACH TO TREATMENT

Children — We suggest the following approach for children with nonclassic congenital adrenal hyperplasia (NCCAH), which is largely consistent with the Endocrine Society Guidelines on congenital adrenal hyperplasia (CAH) [28].

●Glucocorticoids should be administered to children with early-onset or rapid progression of pubarche (development of pubic hair) and/or accelerated growth velocity (crossing height percentiles) with bone maturation significantly advanced (two or more years advanced) to adversely affect adult height [28]. Premature pubarche is defined as the isolated appearance of sexual hair before the age of eight years in girls and nine years in boys. (See "Premature adrenarche".)

●In children, the glucocorticoid of choice is hydrocortisone 10 to 15 mg/m² divided into three daily doses. Higher doses may have adverse effects on growth and result in Cushingoid features. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)

●Asymptomatic children who are diagnosed genetically due to family genotyping studies do not require treatment [29].

●Premature pubarche without advanced bone maturation can be monitored every six months without treatment [28]. (See 'Monitoring treatment' below.)

●Treatment may be discontinued during early to mid-puberty for boys and two to three years postmenarche for girls [30]. In girls with persistent symptoms (such as menstrual irregularities or hirsutism), other treatment modalities (eg, oral contraceptives [OCs]) are usually preferred to avoid prolonged glucocorticoid use.

Women

●Hirsutism and acne in women – We suggest combined estrogen-progestin OCs as first-line therapy for hyperandrogenic symptoms and management of oligomenorrhea. Antiandrogens can be added if the response to OCs is inadequate. Glucocorticoid therapy should only be used for those who do not respond to or cannot tolerate OC and antiandrogen therapies [31].

The main reason that OCs are first-line therapy for most women with NCCAH, is because hirsutism typically requires long-term therapy, and glucocorticoids have a number of potential risks and side effects. The choice of an OC is the same as for any woman with hirsutism (eg. women with polycystic ovary syndrome). (See "Management of hirsutism in premenopausal women".)

Exogenous glucocorticoids, which suppress hypothalamic corticotropin-releasing hormone (CRH) production and, therefore, pituitary corticotropin (ACTH) and adrenal androgen production, are used long term to manage hirsutism and maintain ovulatory cycles in women with classic 21-hydroxylase deficiency (see "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults"). They have also been investigated as a therapy for hirsutism in women with NCCAH. In two trials of glucocorticoid therapy in women with NCCAH (one randomized, one nonrandomized), hydrocortisone [32] and dexamethasone [33] were more effective than an OC or an antiandrogen (cyproterone acetate), respectively, for suppressing serum adrenal androgen concentrations (dehydroepiandrosterone [DHEA] and DHEA sulfate [DHEAS]) but less effective for decreasing hirsutism scores.

OCs, which suppress ovarian androgens, also suppress ACTH and adrenal androgens [34-37]. As noted, they appear to be more effective for hirsutism than glucocorticoids [32,33].

Antiandrogens, such as spironolactone, are also effective, but we suggest against antiandrogen monotherapy because of their potential teratogenicity. In the United States, spironolactone is the most commonly used antiandrogen, while cyproterone acetate is typically used in other countries (not available in the United States). The management of hirsutism is reviewed in detail separately. (See "Management of hirsutism in premenopausal women".)

●Oligomenorrhea – If fertility is not desired, we suggest OC agents rather than glucocorticoid therapy for menstrual cycle management. Although glucocorticoids may restore ovulation and regular cycles, they do not provide contraception, and, as noted, they are associated with important risks and side effects.

●For women who cannot tolerate or take OCs or antiandrogen therapy, glucocorticoid therapy may be used for both hyperandrogenic symptoms and menstrual cycle management.

●Anovulatory infertility – We suggest glucocorticoid therapy as the initial treatment for ovulation induction in women with NCCAH [38]. Clomiphene citrate and other assisted reproduction techniques may be added if glucocorticoid therapy alone is ineffective [39].

Dexamethasone is not inactivated by placental 11-beta-hydroxysteroid dehydrogenase type 2 (fetal exposure occurs). Therefore, we suggest hydrocortisone, prednisone, or prednisolone for ovulation induction [28]. We typically start with prednisone 5 mg/day and add clomiphene citrate if ovulation has not occurred with prednisone alone. Alternatively, the prednisone dose can be increased to 7.5 mg/day before adding clomiphene. The general management of anovulatory infertility is reviewed elsewhere. (See "Overview of ovulation induction".)

●Glucocorticoid therapy may be discontinued when an adult woman no longer seeks fertility. Hyperandrogenic symptoms may persist, however, and require ongoing therapy. We suggest stopping glucocorticoid therapy and switching to OCs in women being treated only for oligomenorrhea and/or hyperandrogenism. If glucocorticoids must be used (if other treatment options are not tolerated or contraindicated), dexamethasone 0.25 mg given once daily or prednisone or prednisolone 4 to 6 mg per day divided into two doses are suggested starting doses [28,30]. The lowest dose that ameliorates the sign or symptom being treated should be used.

Men — Treatment is not necessary for men unless there is oligospermia (in a man desiring fertility). For the rare patient requiring treatment, we suggest starting with dexamethasone 0.25 mg given once daily or prednisone or prednisolone 4 to 6 mg per day divided into two doses. While testicular adrenal rest tumors (TART) and infertility are common in men with classic CAH, they are thought to be very rare in men with NCCAH. Further studies are needed to evaluate fertility in men with NCCAH. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Male reproduction'.)

Stress-dose glucocorticoids — Stress doses of glucocorticoids are not required for patients with NCCAH unless they have been receiving glucocorticoid therapy, which could suppress their hypothalamic-pituitary-adrenal axis [2,40].

Monitoring treatment — Standards have not been established for monitoring glucocorticoid therapy in adults with nonclassic 21-hydroxylase deficiency. In both children and women, concentrations of 17-hydroxyprogesterone, androstenedione, and testosterone should be measured in women, with the goal of normalizing androstenedione and testosterone levels. Adrenal androgen secretion should not be completely suppressed; suppressed levels of 17-hydroxyprogesterone generally indicate overtreatment, and elevation of 17-hydroxyprogesterone to two or three times the upper limit of normal is acceptable.

In children, one goal of treatment is normalization of height velocity; hence, growth charts should be maintained.

For women with classic CAH trying to conceive, monitoring progesterone is useful, and progesterone <2 nmol/L (<0.6 ng/mL) is associated with improved fertility in women with classic CAH [41,42]. It is unclear whether this is also true in women with NCCAH.

One should be alert to symptoms and signs of Cushing's syndrome. Patients should have measurements of bone mineral density periodically to look for bone loss [43]. The lowest dose that ameliorates symptoms should be used.

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

●Nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive diseases, and the frequency varies by ethnicity. (See 'Background' above.)

●Candidates for testing are described above. We suggest screening all women who present with oligomenorrhea and hyperandrogenism (suggestive of polycystic ovary syndrome [PCOS]) with a basal follicular phase 17-hydroxyprogesterone level as the clinical presentation of NCCAH in women is indistinguishable from PCOS. (See 'Who should be tested?' above.)

A basal, morning serum 17-hydroxyprogesterone value (drawn in the early follicular phase in cycling women) greater than 200 ng/dL (6 nmol/L) strongly suggests the diagnosis. (See '17-hydroxyprogesterone' above.)

●The diagnosis is confirmed by an exaggerated serum 17-hydroxyprogesterone response to high-dose corticotropin (ACTH) (250 mcg) ≥1500 ng/dL (≥43 nmol/L). Rarely, stimulated values at 60 minutes in affected patients range between 1000 ng/dL (30 nmol/L) and 1500 ng/dL (43 nmol/L). This range is inconclusive, and the diagnosis should be confirmed with genotyping of the CYP21A2 gene. (See '17-hydroxyprogesterone' above.)

●We suggest treating children with NCCAH with signs of hyperandrogenism and bone maturation significantly advanced to adversely affect adult height (Grade 2C) (see 'Children' above). For children, we suggest hydrocortisone 10 to 15 mg/m² divided into three daily doses. (See 'Children' above.)

●For children with NCCAH receiving glucocorticoid therapy during childhood, we suggest discontinuing treatment during early to mid-puberty for boys and two to three years post-menarche for girls (Grade 2C) (see 'Children' above). In girls with persistent symptoms (such as menstrual irregularities or hirsutism), other treatment modalities (eg, oral contraceptives [OCs]) are usually preferred to avoid prolonged glucocorticoid use.

●For most adult women with nonclassic 21-hydroxylase deficiency who are not pursuing fertility, we suggest OCs as first-line therapy for hyperandrogenic symptoms (hirsutism). Antiandrogens can be added after six months if the response to OCs is inadequate (Grade 2C). (See 'Women' above and "Management of hirsutism in premenopausal women".)

●For women who cannot tolerate or take OCs or antiandrogen therapy, glucocorticoid therapy may be used for both hyperandrogenic symptoms and menstrual cycle management. For sexually active women, hydrocortisone, prednisone, or prednisolone are suggested because dexamethasone crosses the placenta. (See 'Women' above.)

●We also suggest OCs over glucocorticoids as first-line therapy for menstrual cycle management (Grade 2C). (See 'Women' above.)

●For women with nonclassic 21-hydroxylase deficiency with anovulatory cycles who desire fertility, we suggest glucocorticoids as initial therapy for ovulation induction (Grade 2C). In women who do not ovulate with glucocorticoid therapy alone, we suggest adding clomiphene citrate (Grade 2C). (See 'Women' above.)

●We suggest not treating the majority of adult men with NCCAH with glucocorticoid therapy, as they are almost always asymptomatic. Testicular rests and infertility are very rare in this population (Grade 2B).

●Stress doses of glucocorticoids are not required for patients with NCCAH unless they have been receiving glucocorticoid therapy, which could suppress their hypothalamic-pituitary-adrenal axis. (See 'Stress-dose glucocorticoids' above.)

●Biochemical monitoring of therapy is described above. (See 'Monitoring treatment' above.)

DISCLOSURE — 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.