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-wasting, or as toddlers with virilization. Females have atypical genitalia.
"Nonclassic," or late-onset 21OHD, 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 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 forms of CAH 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 patients with classic CAH are classified as "salt-wasting," while 33 percent of classic patients have the "non-salt-wasting" or "simple virilizing" form, reflecting the degree of aldosterone deficiency [4].
The nonclassic form of CAH is estimated to be one of the most common autosomal recessive diseases. Among White persons, the prevalence of these forms of the disorder may be as high as 1 in 1000 to 1 in 100 [11,12]. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Prevalence'.)
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 [13]. (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 [14].
There may be a survival advantage for heterozygote carriers who have a small, but significantly greater, adrenal response to corticotropin (ACTH) than noncarriers [15].
Humans have two CYP21A genes, a nonfunctional pseudogene (CYP21A1P or CYP21P) and the active gene (CYP21A2 or CYP21), both located in a 35-kilobase region of chromosome 6p21.3 within the major human leukocyte antigen (HLA) histocompatibility locus [16-19]. The pseudogene produces a truncated enzyme with no activity because it lacks eight bases from codons 110-112, resulting in a stop codon [18,19].
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 to 30 percent of CYP21A2 mutations described to date [1,7,20].
●Other hybrid CYP21A1P/CYP21A2 gene products have decreased, not absent, enzyme activity. A patient who is heterozygous for this hybrid gene product and a typical large gene deletion may have nonclassic or simple virilizing 21OHD [21,22].
●CAH-X syndrome, a variant of CAH, results from unequal crossover exchanges between CYP21A2 and CYP21A2P and neighboring genes that can occur due to the high recombination rate in the HLA region. The neighboring TNXB gene encodes tenascin-X, an extracellular matrix protein that plays a role in connective tissue and collagen deposition. Hybrid TNXA/TNXB genes lead to complete deletion of the CYP21A2 gene. Patients with CAH who carry a TNXA/TNXB gene have features characteristic of hypermobility-type Ehlers-Danlos syndrome, a presentation called CAH-X syndrome [23]. Heterozygosity for a TNXA/TNXB chimera (TNXA/TNXB on one allele) may cause clinical features of a connective tissue dysplasia, while homozygosity (a TNXA/TNXB gene on both alleles) results in a more severe phenotype [24,25]. Approximately 15 percent of patients with CAH have CAH-X syndrome; this prevalence has been similarly reported in cohort studies worldwide including in the United States (278 patients), China (424 patients), and Argentina (337 patients) [26-28]. Clinical manifestations of Ehlers-Danlos syndromes are reviewed in detail elsewhere. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)
Altered regions of the CYP21A1P 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 [29,30].
●These microconversion events represent acquisition of smaller segments of the CYP21A1 sequence by the CYP21A1P gene and result in deleterious point mutations that reduce enzyme activity [3,18-20]. They are present in approximately 70 percent of patients with defined genetic abnormalities.
●Over 200 pseudogene-independent mutations have been reported in genetic databases, and most of these rare mutations are sporadic [31-33].
●Eighteen gene conversion mutations account for nearly all affected alleles in various ethnic groups [3]. The remaining 5 percent of patients with defined abnormalities have one or more of the point mutations thus far identified, most being compound heterozygotes.
●Approximately 1 to 2 percent of CYP21A2 mutations arise de novo [34].
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 [35]. 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 [36,37].
Genotypically, women with the nonclassic form may be either compound heterozygotes (for example, with a classic mutation on one allele and a nonclassic mutation on the second allele) or homozygous with two nonclassic alleles. Relatives of women with this attenuated form of CAH 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 [3,38-51]. With the exception of severe CYP21A2 mutations, clinical phenotypes sometimes overlap along a continuum of disease severity. Other genes can modify steroid action, salt balance, or androgen sensitivity and thereby influence the clinical manifestations of CAH [52,53]. 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 [39]:
●The salt-wasting form of the disorder is most often associated with large deletions or intron 2 mutations that affect splicing and result in no enzyme activity. The correlation between genotype and phenotype for severe mutations (0 to 1 percent activity) is strong, whereas greater phenotypic variability exists for intermediate and less severely affected genotypes [54].
●Patients with the simple virilizing form have low but detectable enzyme activity (ie, 1 to 5 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 [55]. Heterozygotes may have mild biochemical abnormalities [15,56,57], but no clinically important endocrine disorder.
Genetic testing — The utility of genotype in the management of CAH is uncertain, and genetic testing is not routinely recommended. Genotyping is indicated if the diagnosis remains equivocal following hormonal evaluation or to guide genetic counseling especially in those seeking fertility [54,58].
Diagnostic CYP21A2 genotyping should only be performed by accredited laboratories. CYP21A2 genotyping is error prone due to the presence of the pseudogene and complex gene duplications, deletions, and rearrangements, often resulting in challenging interpretation of results [59]. Parental samples are often needed to accurately determine if disease-causing mutations are on the same or different alleles [59]. Parental genotyping is also needed to determine whether a child's disease-causing mutations are de novo or inherited and assess parental risk of having future affected children. Genetic counseling should accompany CYP21A2 genotyping and is important for family planning. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Role of genetic testing'.)
Individuals carrying the p.Gln318stop (p.Q318X) variant often have duplication of the CYP21A2 gene [60]. When this mutation is detected it is important to establish the number of gene copies in order to accurately distinguish between the carrier and disease state [61].
The nature of the identified mutations (salt-wasting, simple virilizing, or nonclassic) is important because this informs the decision regarding prenatal diagnosis during future pregnancies [59]. When available, in vitro fertilization with preimplantation genetic testing can reduce the risk of having an affected child [62]. (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
CLINICAL MANIFESTATIONS
Presentation — The clinical spectrum of disease ranges from the most severe to mild forms, depending on the degree of 21-hydroxylase deficiency (21OHD) [54]. Three main clinical phenotypes have been described: classic salt-wasting, classic simple virilizing (non-salt-wasting), and nonclassic (late onset):
●Females with the classic form (salt-wasting and simple virilizing) present with atypical genitalia. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
●Males with the salt-wasting 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 simple virilizing 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 [58,63]. 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 35 studies showed that the mean adult height of patients with classic CAH was 1.4 standard deviations (10 cm) below the population mean [64]. 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'.)
Behavior and psychological health — 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 [65,66] and have more interest in male-typical activities and careers [67].
●Women with both classic and nonclassic CAH are more likely to self-identify as lesbian or bisexual people compared with women without CAH [68].
●Adolescent and adult women with CAH may have greater aggressive tendencies than unaffected healthy women [69,70].
Swedish registry studies showed that patients with classic CAH have higher prevalence of anxiety, depression, alcohol misuse, suicidality, and adjustment disorders compared with controls [71,72]. In a retrospective cohort study, patients with CAH (n = 605) were found to have increased mortality and depression compared with matched controls (n = 562) [73]. Females with salt-wasting CAH are especially at risk for mental health issues. Alterations in the hypothalamic-pituitary-adrenal axis including endogenous cortisol deficiency and treatment-associated glucocorticoid excess might contribute to the elevated risk of mental health disorders in individuals with CAH.
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-wasting adrenal crises with abnormal electrolytes and/or hypoglycemia as neonates are at risk for cognitive impairment [74]. 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) [75]. 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-wasting group had the lowest IQ scores.
An IQ advantage has also been reported in a number of studies of CAH [76], 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) [77-79]. However, in a study of 24 women with salt-wasting or simple virilizing 21OHD undergoing detailed cognitive testing, there were no differences in overall IQ, visuospatial processing, or verbal learning and memory [80].
Female reproduction — Fertility rates in women with classic forms of 21OHD are low [81]. Possible contributing factors include [82]:
●Hyperandrogenemia due to inadequate glucocorticoid therapy, thereby resulting in anovulatory cycles [81-83]. 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 [84].
●Structural factors related to genital malformations or suboptimal surgical reconstruction may leave the vaginal introitus inadequate and may contribute to altered reproductive self-image [84].
●Fertility rates are related to the severity of the mutation [85]. Pregnancy rates of 60 to 80 percent and 7 to 60 percent of women have been reported in women with classic simple virilizing and classic salt-wasting CAH, respectively [83].
In women with classic 21OHD who do conceive, their unaffected female offspring do not have genital virilization, but careful management and an increase in glucocorticoid dose as the pregnancy progresses is indicated [62]. The management of fertility and pregnancy in women with CAH is reviewed separately. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Pregnancy'.)
Adrenal rest tumors in the ovary are rare [86], unlike in male patients, who often have testicular adrenal rest tumors. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
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 [87-89].
Confirmation that these tumors resemble adrenal tissue comes from a study of eight adult patients who underwent testis-sparing surgery [90]. 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 [91-93]. 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 [93]. A similar prevalence was reported in a second report of 19 boys (mean age 5.6 years, range 2 to 10 years) [94]. 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) [88,89,95].
●They are more common in patients with the salt-wasting form than the simple virilizing form, as the former tend to have poorer control and higher ACTH concentrations [96]. However, a correlation between ACTH levels and tumor growth is not always seen [87,88].
●They are typically bilateral and vary in size from 2 to 40 mm in diameter [89].
●They may lead to obstruction of seminiferous tubules, gonadal dysfunction, and infertility. (See 'Infertility' below.)
●Some, but not all, regress during glucocorticoid therapy [97]. 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".)
Screening for testicular adrenal rest tumors and adrenal rest management are reviewed elsewhere. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults".)
Infertility — Some men with 21OHD are fertile as adults, but others have evidence of Leydig cell failure or impaired spermatogenesis [88,89,98]. 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 6 men and 7 of 11 men had abnormal semen analyses [88]. In a second report of 30 men, those with adrenal rests in the testes were more likely to be infertile [87].
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 healthy individuals [99]. 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 [100], and stress doses of hydrocortisone did not improve the response [101]. Thus, 21OHD compromises both the development and subsequent functioning of the adrenomedullary system in severely affected individuals. The combination of cortisol deficiency and epinephrine deficiency puts patients at risk for hypoglycemia with illness or fasting, and impaired adrenomedullary function increases risk of illness in infants with CAH [102,103]. In contrast, adrenomedullary function in response to exercise was found to be normal in five untreated patients with nonclassic CAH [104].
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 [105]. 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 [1,106].
●Insulin resistance has been reported in patients with both classic [107] and nonclassic [108] 21OHD. Hyperandrogenism, glucocorticoid therapy, and epinephrine deficiency have all been implicated as possible risk factors for insulin resistance [13,107,108]. Hyperleptinemia has also been reported [107,109].
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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●Basics topics (see "Patient education: Congenital adrenal hyperplasia (The Basics)")
SUMMARY
●Prevalence – 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. (See 'Prevalence' above.)
●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. (See 'Genotype versus phenotype' above.)
●Genetic testing – Genotyping is indicated if the diagnosis remains equivocal following hormonal evaluation or for genetic counseling. Diagnostic CYP21A2 genotyping should only be performed by accredited laboratories. Parental genotyping is often needed to accurately determine genotype. Genetic counseling should accompany CYP21A2 genotyping and is important for family planning.
●Clinical presentation – Classic 21OHD results in one of two clinical syndromes: a salt-wasting form and the simple virilizing form. Girls with both forms present as neonates with atypical genitalia. Boys, if not diagnosed by neonatal screening, present as neonates with a salt-wasting adrenal crisis characterized by hyponatremia, hyperkalemia, and failure to thrive (salt-wasting form) or as toddlers with signs of puberty (simple virilizing form). (See 'Clinical manifestations' above.)
●Female reproduction – Reproductive abnormalities are common in females and include structural abnormalities due to androgen excess in utero and anovulatory menstrual cycles. (See 'Female reproduction' above.)
●Male reproduction – In adult men, testicular masses (adrenal rests), Leydig cell dysfunction, and abnormal semen analyses may be seen. (See 'Male reproduction' 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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