Version May 2024
INTRODUCTION — Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for more than 90 percent of cases of congenital adrenal hyperplasia (CAH). This conversion is mediated by 21-hydroxylase, the enzyme encoded by the CYP21A2 gene.
Patients with "classic," or the most severe form of CAH due to 21-hydroxylase deficiency, present during the neonatal period and early infancy with adrenal insufficiency. "Nonclassic," or late-onset 21-hydroxylase deficiency, presents later in life with signs of androgen excess and without atypical genitalia. Clinical features in childhood may include premature pubarche and accelerated bone age; adolescent and adult females may present with hirsutism, menstrual irregularity, infertility, and acne. Some patients with nonclassic CAH remain asymptomatic.
The pathophysiology, genetics, and clinical manifestations of the nonclassic form of CAH due to 21-hydroxylase deficiency are reviewed here. The diagnosis and treatment of nonclassic 21-hydroxylase deficiency and the classic form of CAH due to 21-hydroxylase deficiency are reviewed separately. (See "Diagnosis and treatment of nonclassic (late-onset) 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 "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "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".)
PREVALENCE — Based upon neonatal screening studies that detect classic congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency is a common inherited disorder. The prevalence based upon such studies has been estimated to be approximately 1 in 14,200 live births, ranging from 1 in 28,000 in the Chinese population to 1 in 280 in the Yupik people. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Prevalence'.)
The nonclassic form (late-onset) is one of the most common autosomal recessive diseases, and the frequency is ethnic-specific. Among White individuals, the prevalence of the nonclassic form may be as high as 1 in 1000 to 1 in 100 [1-3], with the prevalence being even higher among Mediterranean, Hispanic, and Eastern European Jewish women [4,5]. Most patients with the nonclassic form will not be identified by the neonatal screening studies, which are based upon detection of very high levels of 17-hydroxyprogesterone [6].
Women with the nonclassic form typically present with oligomenorrhea and hyperandrogenism and, therefore, may be indistinguishable from polycystic ovary syndrome (PCOS). The prevalence of nonclassic CAH in women who present with apparent PCOS is variable, depending upon the population studied. As an example, in two different regions of Turkey, the prevalence ranged from 9.5 to 66 percent [7,8]. In the United States, the disorder occurs in approximately 1 to 4 percent of White women with clinical evidence of androgen excess [4,9,10]. (See "Clinical manifestations of polycystic ovary syndrome in adults".)
The frequency of heterozygote carriers has been reported to be about 1 in 60 to 80 in some studies [1,11], but closer to 1 in 10 in another study using mutation analysis in a European population [12].
In children who present with premature pubarche (premature development of pubic hair), the prevalence of nonclassic CYP21A2 deficiency has been reported to be very low [13], or as high as 30 percent, in high-risk ethnic groups [14]. In an unselected population of 31 such patients, none were found to have the disorder [15].
The prevalence in men with idiopathic oligospermia is not established. However, in one study of Jewish men presenting to an infertility clinic, there were no cases found in either 222 subjects with abnormal semen analysis or a concurrent control group of 262 men with normal semen analysis [16].
PATHOPHYSIOLOGY — The defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol in patients with CYP21A2 deficiency results in decreased cortisol synthesis and therefore increased corticotropin (ACTH) secretion (figure 1). The resulting adrenal stimulation leads to increased production of androgens. The severity of disease relates to the degree to which the mutations compromise enzyme activity. In patients with the nonclassic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production, at the expense of excessive androgen production.
GENETICS — As with the other forms of congenital adrenal hyperplasia (CAH), CYP21A2 deficiency is transmitted as an autosomal recessive disorder. Humans have two CYP21A genes, a non-functional pseudogene (CYP21A1 or CYP21P) and the active gene (CYP21A2 or CYP21), both located in a 35-kilobase region of chromosome 6p21.3 within the major histocompatibility locus.
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 deoxyribonucleic acid (DNA) between the two genes.
●Large or unequal cross-over exchanges can result in a large deletion of the active gene, or a non-functioning hybrid gene. Patients who are homozygous or heterozygous for such mutations have classic forms of CAH.
●The exchange of smaller amounts of material can result in hybrid CYP21A1/CYP21A2 gene products with reduced but not absent enzyme activity. A patient who is heterozygous for this and a typical large gene deletion may have nonclassic CYP21A2 deficiency [17]. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Genetics'.)
Genotype versus 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. Patients with CYP21A2 mutations can be divided into groups according to the predicted effect of the mutation on 21-hydroxylase enzymatic activity. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Genotype versus phenotype'.)
Women with the late-onset form may be either compound heterozygotes (with a classic mutation and a variant allele) or homozygotes with two variant alleles, allowing for 20 to 60 percent of normal enzymatic activity (eg, with point mutations leading to conservative amino acid substitutions such as Val281Leu).
Women who are compound heterozygotes for two different CYP21A2 mutations usually have the phenotype associated with the less severe of the two genetic defects [18].
Obligate heterozygote carriers (with one normal allele) may have mild biochemical abnormalities [19-21], but no clinically important endocrine disorder.
Despite these general correlations, the CYP21A2 deficiency phenotype does not always correlate precisely with the genotype, suggesting that other genes influence the clinical manifestations. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Genotype versus phenotype'.)
Prenatal diagnosis, neonatal screening and genotyping for CYP21A2 deficiency are discussed separately. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
CLINICAL PRESENTATIONS
Children — Children with nonclassic congenital adrenal hyperplasia (CAH) present after the neonatal period with signs of hyperandrogenism, without adrenal insufficiency. Clinical features may include:
●Premature pubarche. Children with nonclassic CYP21A2 deficiency typically differ from children with ordinary premature adrenarche in having a bone age advanced more than 2.0 SD for age. (See "Premature adrenarche", section on 'Differential diagnosis'.)
●Medication-resistant cystic acne [22].
●Accelerated growth with tall stature as children.
However, these children may enter puberty early, with early epiphyseal closure, leading to short stature as an adult, although short stature is not a consistent feature [4,23,24]. The management of children is discussed separately. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
Female reproduction — Adolescent and adult women have acne, hirsutism, and menstrual irregularity that are indistinguishable from polycystic ovary syndrome (PCOS) [25-27].
In one study of 220 females with nonclassic CAH, the clinical presentation varied by the age of the patient [27]:
●Nearly all patients younger than 10 years presented with premature pubarche; clitoromegaly and acne were less common (20 percent).
●The presenting clinical features in adolescents and adult women included hirsutism (59 percent), oligomenorrhea (54 percent), acne (33 percent), infertility (13 percent), clitoromegaly (10 percent), alopecia (8 percent), and primary amenorrhea (4 percent).
●The prevalence of hirsutism increased significantly with age, from 70 percent in adolescents to 90 percent in 40- to 49-year-old women. When present, the degree of hirsutism was similar at all ages.
The following features may help distinguish nonclassic CAH and PCOS [27,28]:
●Nonclassic CAH is uncommon in African-American and Hispanic-Puerto Rican women [29,30].
●Insulin resistance may be more severe, but probably not more common in polycystic ovarian syndrome [27,28].
●Polycystic ovaries on ultrasound are less common in nonclassic CAH (40 versus 70 percent) [27,28].
●Obesity is more common in women with polycystic ovary disease [10].
In a questionnaire-based study, women with nonclassic CAH show increased masculinization (defeminization) when compared with normal women [31,32]. These attributes were more extreme in women with the classic form of the disease.
Fertility — Women with the classic form of CAH due to 21-hydroxylase deficiency have low fertility rates that correlate with the severity of the mutation. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Female reproduction'.)
In contrast, subfertility is milder in women with the nonclassic form of 21-hydroxylase deficiency. Many women conceive spontaneously, while others have anovulatory infertility that responds to glucocorticoids alone or combined with clomiphene citrate [33,34]. (See "Ovulation induction with clomiphene citrate".)
However, the risk of spontaneous abortion (SAB) appears to be high in these women compared with normal women (≥25 percent versus 10 to 15 percent, respectively) [26,35-39]. Treatment with glucocorticoids may lower this risk, as illustrated in a study of 85 women with the nonclassic form who were pursuing pregnancy. Women who had received therapy with glucocorticoids in order to conceive (n = 36), had a lower risk of SAB than those who had not received glucocorticoids (n = 49; 6.5 versus 26.3 percent, respectively) [38].
Risk of classic CAH in offspring — Women with the late-onset form of nonclassic congenital adrenal hyperplasia (CAH) who seek fertility should be aware of the potential risk of giving birth to an infant with classic CYP21A2 deficiency. Women with the nonclassic disorder who carry at least one allele affected by a severe mutation and whose partner also carries the severe mutation are at risk of having an infant who is homozygous for the severe mutation (ie, classic CAH). This was illustrated in a report of 162 live births in 101 women with the late-onset form [35]. At birth, 4 (2.5 percent) and 24 (15 percent) of the 162 infants were diagnosed with the classic form and the late-onset nonclassic form, respectively.
If genetic screening has not been performed by a couple prior to conception, the birth of an affected infant should prompt consideration of genotyping and consideration of prenatal diagnosis in subsequent pregnancies.
However, genotyping for CYP21 mutations is not widely available, usually not covered by insurance, and does not detect all mutations; as a result, recommendations for screening protocols for these couples have not been established [40].
Prenatal diagnosis, neonatal screening, and genotyping for CYP21A2 deficiency are discussed separately. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Men — In males, it can be difficult to differentiate between simple virilizing forms of "classic" CYP21A2 deficiency and "non-classic" forms. Both can present in childhood with premature pubarche or adrenarche and eventual short stature. After puberty, nonclassic men usually present with acne or infertility. Asymptomatic individuals (obligate heterozygote carriers) may be diagnosed because of an affected family member.
Boys and men with classic CYP21A2 deficiency often develop testicular masses (testicular adrenal rest tumors). During adulthood, these are often associated with oligospermia and infertility. Although most men with the nonclassic form are thought to have normal testicular function and normal fertility, some do present with testicular adrenal rests and infertility [23,41,42].
In general, treatment is not necessary for men with nonclassic CYP21A2 deficiency who do not desire future fertility. However, in men with a testicular mass and/or oligospermia, glucocorticoid therapy should be given until fertility is no longer desired [43]. (See "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", section on 'Fertility'.)
Adrenal incidentalomas — Although 60 percent of patients with unilateral adrenal incidentalomas, and even more of those with bilateral incidentalomas, have exaggerated serum 17-hydroxyprogesterone responses to ACTH stimulation [4], the prevalence of germline CYP21A2 mutations is low. However, unilateral and bilateral adrenal incidentalomas were found in 10 of 12 patients with simple virilizing and five of seven patients with late-onset CAH, as well as 9 of 10 heterozygotic siblings [44]. Most tumors had a diameter of less than 2 cm, but three patients had masses more than 5 cm in size. Adrenal masses in children with CYP21A2 deficiency are usually benign [4].
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
●Prevalence – Nonclassic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive diseases, and the frequency is ethnic-specific (see 'Prevalence' above). The genetics of this disorder are discussed above. (See 'Genetics' above.)
●Clinical presentations
•Children – Children may present with precocious pubarche, medication-resistant acne, and accelerated growth. (See 'Clinical presentations' above.)
•Adolescent girls – Adolescent girls typically present with acne, hirsutism, and menstrual irregularity (oligoovulation), features that are indistinguishable from the polycystic ovary syndrome (PCOS). (See 'Female reproduction' above.)
•Adult women – Adult women also present with acne, hirsutism, and menstrual irregularity. In addition, anovulatory infertility is common in women who are untreated. Most conceive with ovulation induction (glucocorticoids alone or combined with clomiphene citrate), and the rate of early pregnancy loss appears to be no higher than normal after treatment begins. (See 'Fertility' above.)
•Men – Although most men with the nonclassic form are thought to have normal testicular function and normal fertility, some do present with testicular adrenal rests and infertility. (See 'Clinical presentations' 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.
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