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, the enzyme encoded by the CYP21A2 gene.
Patients with "classic" or the most severe form of CAH due to 21-hydroxylase deficiency (21OHD) present during the neonatal period and early infancy with adrenal insufficiency with or without salt-losing, or as toddlers with virilization. Females have genital ambiguity.
"Nonclassic," or late-onset 21OHD, presents later in life with signs of androgen excess and without neonatal genital ambiguity. 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 CAH due to CYP21A2 mutations will be reviewed here. The diagnosis and treatment of classic 21OHD in adults and in children and an overview of nonclassic and unusual CAHs are discussed elsewhere. (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" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias".)
PREVALENCE — The most common cause of congenital adrenal hyperplasia (CAH) worldwide, accounting for >90 percent of cases, is 21-hydroxylase deficiency (21OHD) [1]. Based upon neonatal screening studies that detect classic CAH, 21OHD is one of the more common inherited disorders. Data from approximately 6.5 million newborn infants screened worldwide show an estimate of approximately 1 in 15,000 livebirths [4,5]. Prevalence varies according to race and geographic area. This number varies from as low as 1 in 28,000 in the Chinese population [6], to 1 in 5000 to 23,000 live births in White persons [7,8], to as high as 1 in 280 in the Yupik people in Alaska [9] and 1 in 2100 among people in the French island of La Reunion [5].
In the United States, the prevalence is lower in African Americans than in White Americans (1 in 42,000 versus 1 in 15,500, respectively) [10].
Approximately 67 percent of classic patients are classified as "salt-losing," while 33 percent of classic patients have "non-salt-losing" or the "simple virilizing" form, reflecting the degree of aldosterone deficiency [4].
The nonclassic form is one of the most common autosomal recessive diseases, and the frequency is ethnic specific. Among White persons, the prevalence of these forms of the disorder may be as high as 1 in 1000 to 1 in 100 [9-11], with the prevalence being even higher (1 to 2 percent) among Mediterranean, or Hispanic, Yugoslavic, and Eastern European Jewish persons (3 to 4 percent) [1]. The rates of nonclassic congenital adrenal hyperplasia (NCCAH) in Eastern European Jewish persons, may actually be lower than 3 to 4 percent. In a genotyping study of 200 unrelated healthy Eastern European Jewish and 200 White subjects, the estimated prevalence of disease was similar in both groups (approximately 0.5 percent) [12].
Most patients with the nonclassic form will not be identified by standard screening studies, because they are based upon detection of very high levels of 17-hydroxyprogesterone [13]. The frequency of heterozygote carriers has been reported to be approximately 1 in 60 to 80 in some studies [6,9] but closer to 1 in 10 in another study using mutation analysis in a European population [14]. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
PATHOPHYSIOLOGY — The defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol in patients with 21-hydroxylase deficiency (21OHD) 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 [15]. (See "Adrenal steroid biosynthesis" and 'Genotype versus phenotype' below.)
GENETICS — As with the other forms of congenital adrenal hyperplasia (CAH), 21-hydroxylase deficiency (21OHD) is transmitted as an autosomal recessive disorder [16].
There may be a survival advantage for heterozygote carriers who have a small, but significantly greater, adrenal response to corticotropin (ACTH) than normal subjects [17].
Humans have two CYP21A genes, a nonfunctional 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 [18-21]. The pseudogene produces a truncated enzyme with no activity because it lacks eight bases from codons 110-112, resulting in a stop codon [20,21].
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 CYP21P gene or a nonfunctioning CYP21P/CYP21 fusion gene (macroconversion) account for approximately 20 percent of CYP21A2 mutations described to date [1,7,22].
●Other hybrid CYP21A1/CYP21A2 gene products have decreased, not absent, enzyme activity. A patient who is heterozygous for this and a typical large gene deletion may have nonclassic 21OHD [23].
●Altered regions of the CYP21A1 gene can be transferred to the CYP21A2 gene though nonreciprocal gene conversion. This is a process by which a segment of genetic material is transferred to a closely related gene, altering its sequence [24,25].
●These microconversion events represent acquisition of smaller segments of the CYP21A1 sequence by the CYP21A2 gene and result in deleterious point mutations that reduce enzyme activity [3,20-22]. 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 [3,26-28]. The remaining 5 percent of patients with defined abnormalities have one or more of the 60 point mutations thus far identified, most being compound heterozygotes [3,28-33].
Among 130 Brazilian patients, 20 percent did not have a known mutation, suggesting that other mutations occur. A novel missense mutation was subsequently identified in three patients with suggestion of a founder effect [28]. No mutation was detected in the entire coding region of the gene and up to 1 kb of the 5'-flanking promoter region of the gene in one Mexican and three Japanese patients, suggesting that more distant mutations may occur [34,35]. In a second series of 182 unrelated patients with 21OHD, targeted CP21A2 mutation analysis failed to identify mutations in 19 patients (10.4 percent) [36]. On more extensive analysis, novel mutations and previously reported rare mutations were identified in 18 of the 19 subjects: nine previously reported mutations were identified in 12 probands and six novel mutations were identified in six probands (eg, 15 mutations in 18 patients).
Genotypically, women with the nonclassic form may be either compound heterozygotes (with a classic mutation and a variant allele) or homozygous with two variant alleles. Relatives of women with this attenuated form may have similar biochemical abnormalities, but no signs of androgen excess. Women who carry the classic (severe) 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 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 [3,11,29-32,37-44]. 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 [29]:
●The salt-losing form of the disorder is most often associated with large deletions or intron 2 mutations that affect splicing and result in no enzyme activity.
●Patients with simple virilizing form have low but detectable enzyme activity (ie, 1 to 2 percent) that supports sufficient aldosterone and glucocorticoid production. This most commonly results from point mutations leading to nonconservative amino acid substitutions such as Ile172Asp.
●Women with the nonclassic 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).
●Patients who are compound heterozygotes for two different CYP21A2 mutations usually have the phenotype associated with the less severe of the two genetic defects [26]. Heterozygotes may have mild biochemical abnormalities [17,45,46], but no clinically important endocrine disorder.
Despite these general correlations, the CYP21A2 mutation phenotype does not always correlate precisely with the genotype [8,31,32], 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 [29,30,41,42].
The utility of genotype in the management of the disease is unknown, and it is not routinely recommended. Genotyping is indicated if the diagnosis remains equivocal following hormonal evaluation or for genetic counseling especially in those seeking fertility [47]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Genotype-phenotype'.)
CLINICAL PRESENTATION — The clinical spectrum of disease ranges from the most severe to mild forms, depending on the degree of 21-hydroxylase deficiency (21OHD). Three main clinical phenotypes have been described: classic salt-losing, classic non-salt-losing (simple virilizing), and nonclassic (late onset):
●Females with the classic form (salt-losing and non-salt-losing) present with genital ambiguity. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
●Males with the salt-losing form who are not identified by neonatal screening present with failure to thrive, dehydration, hyponatremia, and hyperkalemia typically at 7 to 14 days of life.
●Males with the classic non-salt-losing form who are not identified by neonatal screening typically present at two to four years of age with early virilization (pubic hair, growth spurt, adult body odor).
●Nonclassic or late-onset 21OHD may present as hirsutism and menstrual irregularity in young women, early pubarche or sexual precocity in school-age children, or there may be no symptoms. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Infants/children
Atypical genitalia — Female infants with classic 21OHD are born with atypical genitalia. Female newborns have clitoral enlargement (picture 1), labial fusion, and formation of a urogenital sinus caused by the effects of androgen excess on development of the external genitalia in utero. Rarely, genital ambiguity may be so profound that inappropriate sex assignment is made at birth. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
Affected males are normal appearing at birth but may have subtle findings such as hyperpigmentation of the scrotum or an enlarged phallus.
The surgical management of children born with atypical genitalia is complex. 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 surgery, urology, psychosocial services, and genetics [48]. This topic is discussed in detail separately. (See "Management of the infant with atypical genital appearance (difference of sex development)", section on 'Clinical approach to 46,XX congenital adrenal hyperplasia'.)
Growth — Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty and adult short stature. Exposure to high levels of sex hormones can induce early puberty and premature epiphyseal closure. Excess glucocorticoid exposure secondary to treatment may also suppress growth and contribute to adult short stature.
Retrospective studies have shown that the final height of treated patients is independent of the degree of control of adrenal androgen concentrations, suggesting that both hyperandrogenism and hypercortisolism play a role in the observed short stature. A meta-analysis of data from 18 centers showed that the mean adult height of patients with classic CAH was 1.4 standard deviations (10 cm) below the population mean [49]. Patients with nonclassic CAH have a more favorable height prognosis but are also at risk for loss of adult height. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Growth'.)
Sexual behavior — Studies of female patients with classic CAH suggest that exposure to excess androgens during prenatal development may influence the brain as evidenced by the following:
●Female patients with classic CAH have more male-typical childhood play than unaffected girls [50,51] and have more interest in male-typical activities and careers [52].
●In one report, 31 women with CAH (mean age 25 years) recalled more cross-sex role behavior and fewer sexual experiences with men than 15 unaffected relatives of the same age [53]. In contrast, there was no difference in the relationship status between the two groups (eg, married/cohabitating versus single).
●Adolescent and adult women with CAH may have greater aggressive tendencies than unaffected healthy women [54,55].
●Overall, patients with CAH have favorable quality of life [56] and good psychological health [57].
Cognitive function — The effect of 21OHD on cognitive function is uncertain. Some studies suggest that patients with the most severe form of 21OHD and those who have experienced salt-losing adrenal crises with abnormal electrolytes and/or hypoglycemia as neonates are at risk for cognitive impairment [58]. This was illustrated in a study of 35 Danish women with CAH and healthy age-matched controls undergoing testing with the Wechsler Adult Intelligence Scale (WAIS) [59]. Women with CAH had significantly lower intelligence quotients (IQs) compared with controls (mean full-scale IQ 84.5 versus 99.1 and mean performance IQ 85.7 versus 101.3 in the CAH and control women, respectively). The salt-losing group had the lowest IQ scores.
Surprisingly, an IQ advantage has also been reported in a number of studies of CAH [60], possibly due to socioeconomic, genetic, or hormonal factors.
Some data have suggested that girls with CAH develop a more male-typical cognitive pattern (better performance on spatial tasks, worse performance on verbal tasks) [61,62]. However, in a study of 24 women with salt-losing or simple virilizing 21OHD undergoing detailed cognitive testing, there were no differences in overall IQ, visuospatial processing, or verbal learning and memory, suggesting that prenatal androgen exposure does not have an organizing effect on female cognition [63].
Conversely, 54 patients with CAH underwent a virtual water maze test that measures spatial cognition and has established performance sex-differences in healthy controls. Females with the most severe salt-wasting form of CAH and patients with advanced bone age during childhood displayed improved performance, similar to healthy males, suggesting that both in utero and long-term childhood exposure to excess testosterone has long-lasting effects on cognitive function [64].
Female reproduction — Fertility rates in women with classic forms of 21OHD are low [65]. Possible contributing factors include [66]:
●Hyperandrogenemia due to inadequate glucocorticoid therapy, thereby resulting in anovulatory cycles [65-69]. The androgen excess is not simply due to corticotropin (ACTH) hypersecretion; other factors include mild hyperresponsiveness of ACTH to corticotropin-releasing hormone stimulation, reduced catalytic activity of the 21-hydroxylase enzyme, and abnormal gonadotropin dynamics with excess ovarian production of progesterone, 17-hydroxyprogesterone, and androgens [70].
●Structural factors related to genital malformations or suboptimal surgical reconstruction may leave the vaginal introitus inadequate and may contribute to impaired reproductive self-image [71].
●Fertility rates are related to the severity of the mutation [72]. Pregnancy rates of 60 to 80 percent and 7 to 60 percent of women have been reported in women with classic non-salt-losing and classic salt-losing CAH, respectively [65,69].
In women with classic 21OHD who do conceive, their unaffected female offspring do not have genital virilization, but careful management with monitoring of androgen levels during gestation is indicated [73].
Adrenal rest tumors in the ovary are rare [74], unlike in male patients, who often have testicular adrenal rest tumors (see 'Testicular adrenal rests' below). In addition to the ovary, adrenal rest tumors have been found in the paraovarian/adnexal area. The tumors are difficult to identify by imaging, and most have been identified during surgery or at autopsy. Imaging with 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) localized rest tissue in three women [75-77] (including one with Nelson syndrome); in one case, tumors were only visible after administration of cosyntropin [76]. The etiology appears related to sustained elevations in ACTH.
Male reproduction — Reproductive function may be impaired in men with 21OHD. Affected boys or young men may have no symptoms or signs of androgen excess. However, they may have testicular masses composed of adrenal tissue.
Testicular adrenal rests — Testicular adrenal rest tumors, which are testicular masses composed of adrenal-like tissue, are common in male patients with 21OHD [78-80].
Confirmation that these tumors resemble adrenal tissue comes from a study of eight adult patients who underwent testis-sparing surgery [81]. Adrenal-specific steroid secretion was documented with preoperative spermatic vein sampling, and expression of adrenal-specific enzymes and ACTH receptors was confirmed in tumor tissue.
The clinical features of testicular rest tumors include:
●They are usually diagnosed between the ages of 10 and 20 years but may be found as early as age five [82-84]. In one report of 34 boys with classic 21OHD between the ages of 2 and 18 years who were undergoing testicular ultrasonography, eight (24 percent) were diagnosed with testicular adrenal rests; two of the boys were age seven [84]. A similar prevalence was reported in a second report of 19 boys (mean age 5.6 years, range 2 to 10 years) [85]. Inhibin B and anti-müllerian hormone concentrations were lower in patients compared with age-matched controls, suggesting that gonadal dysfunction was also present.
●Ultrasound studies suggest that the majority of adolescent and adult males with 21OHD have testicular adrenal rests (18 of 21 [86 percent] and 16 of 17 [94 percent] in two reports) [79,80,86].
●They are more common in patients with the salt-losing form than the simple virilizing form, as the former tend to have poorer control and higher ACTH concentrations [87]. However, a correlation between ACTH levels and tumor growth is not always seen [78,79].
●They are typically bilateral and vary in size from 2 to 40 mm in diameter [80].
●They may lead to obstruction of seminiferous tubules, gonadal dysfunction, and infertility. (See 'Infertility' below.)
●Some, but not all, regress during glucocorticoid therapy [88,89]. A minority of patients with large adrenal rest tumors eventually requires surgery for pain relief. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Testicular adrenal rest tumors'.)
Because of the high prevalence of testicular adrenal rests and their association with infertility in male patients with 21OHD, we suggest screening testicular ultrasonography in adolescence or early adulthood [80].
Infertility — Most men with 21OHD are fertile as adults, but others have evidence of Leydig cell failure or impaired spermatogenesis [79,80,90]. As noted above, testicular adrenal rests may be associated with seminiferous tubule obstruction, gonadal dysfunction, and infertility. (See 'Testicular adrenal rests' above.)
In one study of 17 adolescent and adult men, serum testosterone concentrations were low in six, and seven had abnormal semen analyses [79]. In a second report of 30 men, those with adrenal rests in the testes were more likely to be infertile [78].
Epinephrine deficiency — Adrenomedullary function is compromised in patients with classic CAH, as illustrated in a study of 38 children with classic 21OHD. Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower than in normal subjects [91]. In three patients who underwent bilateral adrenalectomy, the adrenal medulla was poorly formed and the cells contained few vesicles.
In a second study, the epinephrine response to exercise was significantly reduced in patients with classic 21OHD compared with healthy volunteers [92], and stress doses of hydrocortisone did not improve the response [93]. Thus, 21OHD compromises both the development and subsequent functioning of the adrenomedullary system in severely affected cases. The combination of cortisol deficiency and epinephrine deficiency puts patients at risk for hypoglycemia with illness or prolonged fasting [92]. Adrenomedullary function has not been studied in patients with nonclassic CAH.
Other findings — Other clinical findings that have been described include adrenal incidentalomas, pituitary adenomas, insulin resistance, and hyperleptinemia.
●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 [1], 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 [94]. 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 [1].
●Pituitary microadenomas or empty sella may be found, but symptomatic corticotroph tumors have not been reported [1,95].
●Insulin resistance has been reported in patients with both classic [96] and nonclassic [97] 21OHD. Hyperandrogenism, glucocorticoid therapy, and epinephrine deficiency have all been implicated as possible risk factors for insulin resistance [15,96,97]. Hyperleptinemia has also been reported [96,98].
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".)
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SUMMARY — Over 95 percent of cases of congenital adrenal hyperplasia (CAH) are due to 21-hydroxylase deficiency (21OHD) due to CYP21A2 mutations. It is one of the most common known autosomal recessive disorders.
●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.
●The utility of genotype in the management of the disease is unknown, and it is not routinely recommended. Genotyping is indicated if the diagnosis remains equivocal following hormonal evaluation or for genetic counseling.
●Classic 21OHDresults in one of two clinical syndromes: a salt-losing form and the simple virilizing form. Girls with both forms present as neonates with atypical genitalia. Boys present as neonates with a salt-losing adrenal crisis (salt-losing form) (hyponatremia, hyperkalemia, and failure to thrive) or as toddlers with signs of puberty (simple virilizing form).
●Reproductive abnormalities are common in females and include structural abnormalities due to androgen excess in utero and anovulatory menstrual cycles.
●In adult men, testicular masses (adrenal rests), Leydig cell dysfunction, and abnormal semen analyses may be seen.
●Nonclassic or late-onset 21OHD may present as hirsutism and menstrual irregularity in young women, early pubarche or sexual precocity in school-age children, or there may be no symptoms. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
●The diagnosis and treatment of classic 21OHD are reviewed separately. (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" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children".)
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.
