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Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Literature review current through: Jan 2024.
This topic last updated: Apr 10, 2023.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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.

  1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245.
  2. Pang SY, Wallace MA, Hofman L, et al. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 1988; 81:866.
  3. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003; 349:776.
  4. Pang, S, Clark, A. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Newborn screening and its relationship to the diagnosis and treatment of the disorder. Screening 1993; 2:105.
  5. Therrell BL. Newborn screening for congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30:15.
  6. Lee HH, Kuo JM, Chao HT, et al. Carrier analysis and prenatal diagnosis of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency in Chinese. J Clin Endocrinol Metab 2000; 85:597.
  7. New MI, White PC. Genetic disorders of steroid hormone synthesis and metabolism. Baillieres Clin Endocrinol Metab 1995; 9:525.
  8. Cutfield WS, Webster D. Newborn screening for congenital adrenal hyperplasia in New Zealand. J Pediatr 1995; 126:118.
  9. Pang S, Murphey W, Levine LS, et al. A pilot newborn screening for congenital adrenal hyperplasia in Alaska. J Clin Endocrinol Metab 1982; 55:413.
  10. Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 1998; 101:583.
  11. Hannah-Shmouni F, Morissette R, Sinaii N, et al. Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med 2017; 19:1276.
  12. New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006; 91:4205.
  13. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005; 365:2125.
  14. Pignatelli D, Carvalho BL, Palmeiro A, et al. The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne) 2019; 10:432.
  15. Witchel SF, Lee PA, Suda-Hartman M, et al. Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1997; 82:2097.
  16. Carroll MC, Campbell RD, Porter RR. Mapping of steroid 21-hydroxylase genes adjacent to complement component C4 genes in HLA, the major histocompatibility complex in man. Proc Natl Acad Sci U S A 1985; 82:521.
  17. White PC, Grossberger D, Onufer BJ, et al. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A 1985; 82:1089.
  18. White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A 1986; 83:5111.
  19. Higashi Y, Yoshioka H, Yamane M, et al. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A 1986; 83:2841.
  20. Miller WL. Clinical review 54: Genetics, diagnosis, and management of 21-hydroxylase deficiency. J Clin Endocrinol Metab 1994; 78:241.
  21. L'Allemand D, Tardy V, Grüters A, et al. How a patient homozygous for a 30-kb deletion of the C4-CYP 21 genomic region can have a nonclassic form of 21-hydroxylase deficiency. J Clin Endocrinol Metab 2000; 85:4562.
  22. Chen W, Xu Z, Sullivan A, et al. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem 2012; 58:421.
  23. Merke DP, Chen W, Morissette R, et al. Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2013; 98:E379.
  24. Burch GH, Gong Y, Liu W, et al. Tenascin-X deficiency is associated with Ehlers-Danlos syndrome. Nat Genet 1997; 17:104.
  25. Chen W, Perritt AF, Morissette R, et al. Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia. Hum Mutat 2016; 37:893.
  26. Lao Q, Brookner B, Merke DP. High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia. J Mol Diagn 2019; 21:924.
  27. Marino R, Garrido NP, Ramirez P, et al. Ehlers-Danlos Syndrome: Molecular and Clinical Characterization of TNXA/TNXB Chimeras in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2021; 106:e2789.
  28. Gao Y, Lu L, Yu B, et al. The Prevalence of the Chimeric TNXA/TNXB Gene and Clinical Symptoms of Ehlers-Danlos Syndrome with 21-Hydroxylase Deficiency. J Clin Endocrinol Metab 2020; 105.
  29. Miller WL. Gene conversions, deletions, and polymorphisms in congenital adrenal hyperplasia. Am J Hum Genet 1988; 42:4.
  30. Cooper DN, Ball EV, Krawczak M. The human gene mutation database. Nucleic Acids Res 1998; 26:285.
  31. The Human Gene Mutation Database. Available at: https://www.hgmd.cf.ac.uk/ac/index.php (Accessed on March 09, 2023).
  32. CYP21A2 allele nomenclature. Available at: https://www.pharmvar.org/gene/CYP21A2 (Accessed on March 09, 2023).
  33. ClinVar archive of reported human genetic variations. Available at: https://www.ncbi.nlm.nih.gov/clinvar/ (Accessed on March 09, 2023).
  34. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management. Endocr Rev 2022; 43:91.
  35. Billerbeck AE, Mendonca BB, Pinto EM, et al. Three novel mutations in CYP21 gene in Brazilian patients with the classical form of 21-hydroxylase deficiency due to a founder effect. J Clin Endocrinol Metab 2002; 87:4314.
  36. Nimkarn S, Cerame BI, Wei JQ, et al. Congenital adrenal hyperplasia (21-hydroxylase deficiency) without demonstrable genetic mutations. J Clin Endocrinol Metab 1999; 84:378.
  37. Koyama S, Toyoura T, Saisho S, et al. Genetic analysis of Japanese patients with 21-hydroxylase deficiency: identification of a patient with a new mutation of a homozygous deletion of adenine at codon 246 and patients without demonstrable mutations within the structural gene for CYP21. J Clin Endocrinol Metab 2002; 87:2668.
  38. Ferenczi A, Garami M, Kiss E, et al. Screening for mutations of 21-hydroxylase gene in Hungarian patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 1999; 84:2369.
  39. Speiser PW, Dupont J, Zhu D, et al. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 1992; 90:584.
  40. Wedell A, Thilén A, Ritzén EM, et al. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab 1994; 78:1145.
  41. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995; 80:2322.
  42. Jääskeläinen J, Levo A, Voutilainen R, Partanen J. Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population. J Clin Endocrinol Metab 1997; 82:3293.
  43. Finkielstain GP, Chen W, Mehta SP, et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2011; 96:E161.
  44. Higashi Y, Hiromasa T, Tanae A, et al. Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem 1991; 109:638.
  45. Mornet E, Crété P, Kuttenn F, et al. Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet 1991; 48:79.
  46. Owerbach D, Ballard AL, Draznin MB. Salt-wasting congenital adrenal hyperplasia: detection and characterization of mutations in the steroid 21-hydroxylase gene, CYP21, using the polymerase chain reaction. J Clin Endocrinol Metab 1992; 74:553.
  47. Dardis A, Bergada I, Bergada C, et al. Mutations of the steroid 21-hydroxylase gene in an Argentinian population of 36 patients with classical congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 1997; 10:55.
  48. Krone N, Braun A, Roscher AA, et al. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab 2000; 85:1059.
  49. Deneux C, Tardy V, Dib A, et al. Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2001; 86:207.
  50. Balsamo A, Cicognani A, Baldazzi L, et al. CYP21 genotype, adult height, and pubertal development in 55 patients treated for 21-hydroxylase deficiency. J Clin Endocrinol Metab 2003; 88:5680.
  51. Grigorescu Sido A, Weber MM, Grigorescu Sido P, et al. 21-Hydroxylase and 11beta-hydroxylase mutations in Romanian patients with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2005; 90:5769.
  52. Gomes LG, Huang N, Agrawal V, et al. Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency. J Clin Endocrinol Metab 2009; 94:89.
  53. Kaupert LC, Lemos-Marini SH, De Mello MP, et al. The effect of fetal androgen metabolism-related gene variants on external genitalia virilization in congenital adrenal hyperplasia. Clin Genet 2013; 84:482.
  54. Merke DP, Auchus RJ. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med 2020; 383:1248.
  55. Lajić S, Clauin S, Robins T, et al. Novel mutations in CYP21 detected in individuals with hyperandrogenism. J Clin Endocrinol Metab 2002; 87:2824.
  56. Gutai JP, Kowarski AA, Migeon CJ. The detection of the heterozygous carrier for congenital virilizing adrenal hyperplasia. J Pediatr 1977; 90:924.
  57. Charmandari E, Merke DP, Negro PJ, et al. Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress. J Clin Endocrinol Metab 2004; 89:2228.
  58. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:4133.
  59. Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. Eur J Hum Genet 2020; 28:1341.
  60. Kharrat M, Riahi A, Maazoul F, et al. Detection of a frequent duplicated CYP21A2 gene carrying a Q318X mutation in a general population with quantitative PCR methods. Diagn Mol Pathol 2011; 20:123.
  61. Concolino P, Costella A. Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene. Mol Diagn Ther 2018; 22:261.
  62. Maher JY, Gomez-Lobo V, Merke DP. The management of congenital adrenal hyperplasia during preconception, pregnancy, and postpartum. Rev Endocr Metab Disord 2023; 24:71.
  63. Joint LWPES/ESPE CAH Working Group.. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 2002; 87:4048.
  64. Muthusamy K, Elamin MB, Smushkin G, et al. Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab 2010; 95:4161.
  65. Berenbaum, SA, Snyder, E. Early hormonal influences on childhood sex-typed activity and playmate preferences: implications for the development of sexual orientation. Dev Psychol 1995; 31:31.
  66. Dittmann RW, Kappes MH, Kappes ME, et al. Congenital adrenal hyperplasia. I: Gender-related behavior and attitudes in female patients and sisters. Psychoneuroendocrinology 1990; 15:401.
  67. Berenbaum SA. Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia. Horm Behav 1999; 35:102.
  68. Meyer-Bahlburg HF, Dolezal C, Baker SW, New MI. Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Arch Sex Behav 2008; 37:85.
  69. Berenbaum SA, Resnick SM. Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia. Psychoneuroendocrinology 1997; 22:505.
  70. Mathews GA, Fane BA, Conway GS, et al. Personality and congenital adrenal hyperplasia: possible effects of prenatal androgen exposure. Horm Behav 2009; 55:285.
  71. Engberg H, Butwicka A, Nordenström A, et al. Congenital adrenal hyperplasia and risk for psychiatric disorders in girls and women born between 1915 and 2010: A total population study. Psychoneuroendocrinology 2015; 60:195.
  72. Falhammar H, Butwicka A, Landén M, et al. Increased psychiatric morbidity in men with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2014; 99:E554.
  73. Jenkins-Jones S, Parviainen L, Porter J, et al. Poor compliance and increased mortality, depression and healthcare costs in patients with congenital adrenal hyperplasia. Eur J Endocrinol 2018; 178:309.
  74. Berenbaum SA. Cognitive function in congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30:173.
  75. Johannsen TH, Ripa CP, Reinisch JM, et al. Impaired cognitive function in women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2006; 91:1376.
  76. Nass R, Baker S. Androgen effects on cognition: congenital adrenal hyperplasia. Psychoneuroendocrinology 1991; 16:189.
  77. Helleday J, Bartfai A, Ritzén EM, Forsman M. General intelligence and cognitive profile in women with congenital adrenal hyperplasia (CAH). Psychoneuroendocrinology 1994; 19:343.
  78. Kelso WM, Nicholls ME, Warne GL, Zacharin M. Cerebral lateralization and cognitive functioning in patients with congenital adrenal hyperplasia. Neuropsychology 2000; 14:370.
  79. Mueller SC, Temple V, Oh E, et al. Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH). Psychoneuroendocrinology 2008; 33:973.
  80. Malouf MA, Migeon CJ, Carson KA, et al. Cognitive outcome in adult women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res 2006; 65:142.
  81. Mulaikal RM, Migeon CJ, Rock JA. Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 1987; 316:178.
  82. Meyer-Bahlburg HF. What causes low rates of child-bearing in congenital adrenal hyperplasia? J Clin Endocrinol Metab 1999; 84:1844.
  83. Stikkelbroeck NM, Hermus AR, Braat DD, Otten BJ. Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Obstet Gynecol Surv 2003; 58:275.
  84. Hagenfeldt K, Janson PO, Holmdahl G, et al. Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod 2008; 23:1607.
  85. Nordenskjöld A, Holmdahl G, Frisén L, et al. Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2008; 93:380.
  86. Stikkelbroeck NM, Hermus AR, Schouten D, et al. Prevalence of ovarian adrenal rest tumours and polycystic ovaries in females with congenital adrenal hyperplasia: results of ultrasonography and MR imaging. Eur Radiol 2004; 14:1802.
  87. Cabrera MS, Vogiatzi MG, New MI. Long term outcome in adult males with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86:3070.
  88. Stikkelbroeck NM, Otten BJ, Pasic A, et al. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86:5721.
  89. Stikkelbroeck NM, Suliman HM, Otten BJ, et al. Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features. Eur Radiol 2003; 13:1597.
  90. Claahsen-van der Grinten HL, Otten BJ, Sweep FC, et al. Testicular tumors in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency show functional features of adrenocortical tissue. J Clin Endocrinol Metab 2007; 92:3674.
  91. Vanzulli A, DelMaschio A, Paesano P, et al. Testicular masses in association with adrenogenital syndrome: US findings. Radiology 1992; 183:425.
  92. Avila NA, Shawker TS, Jones JV, et al. Testicular adrenal rest tissue in congenital adrenal hyperplasia: serial sonographic and clinical findings. AJR Am J Roentgenol 1999; 172:1235.
  93. Claahsen-van der Grinten HL, Sweep FC, Blickman JG, et al. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 2007; 157:339.
  94. Martinez-Aguayo A, Rocha A, Rojas N, et al. Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 2007; 92:4583.
  95. Falhammar H, Nyström HF, Ekström U, et al. Fertility, sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia. Eur J Endocrinol 2012; 166:441.
  96. Stikkelbroeck NM, Hermus AR, Suliman HM, et al. Asymptomatic testicular adrenal rest tumours in adolescent and adult males with congenital adrenal hyperplasia: basal and follow-up investigation after 2.6 years. J Pediatr Endocrinol Metab 2004; 17:645.
  97. Claahsen-van der Grinten HL, Stikkelbroeck N, Falhammar H, Reisch N. MANAGEMENT OF ENDOCRINE DISEASE: Gonadal dysfunction in congenital adrenal hyperplasia. Eur J Endocrinol 2021; 184:R85.
  98. Newfield RS, New MI. 21-hydroxylase deficiency. Ann N Y Acad Sci 1997; 816:219.
  99. Merke DP, Chrousos GP, Eisenhofer G, et al. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 2000; 343:1362.
  100. Weise M, Mehlinger SL, Drinkard B, et al. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high-intensity exercise. J Clin Endocrinol Metab 2004; 89:591.
  101. Weise M, Drinkard B, Mehlinger SL, et al. Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise. J Clin Endocrinol Metab 2004; 89:3679.
  102. El-Maouche D, Hargreaves CJ, Sinaii N, et al. Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab 2018; 103:2336.
  103. Ritchie LD, Harrington LT, MacGregor AR, Vandenburg MJ. Nifedipine as low-dose monotherapy for essential hypertension: a primary care study. Cardiovasc Drugs Ther 1989; 3 Suppl 1:341.
  104. Verma S, Green-Golan L, VanRyzin C, et al. Adrenomedullary function in patients with nonclassic congenital adrenal hyperplasia. Horm Metab Res 2010; 42:607.
  105. Jaresch S, Kornely E, Kley HK, Schlaghecke R. Adrenal incidentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia. J Clin Endocrinol Metab 1992; 74:685.
  106. Charmandari E, Chrousos GP, Merke DP. Adrenocorticotropin hypersecretion and pituitary microadenoma following bilateral adrenalectomy in a patient with classic 21-hydroxylase deficiency. J Pediatr Endocrinol Metab 2005; 18:97.
  107. Charmandari E, Weise M, Bornstein SR, et al. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab 2002; 87:2114.
  108. Speiser PW, Serrat J, New MI, Gertner JM. Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1992; 75:1421.
  109. Riepe FG, Krone N, Krüger SN, et al. Absence of exercise-induced leptin suppression associated with insufficient epinephrine reserve in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes 2006; 114:105.
Topic 149 Version 21.0

References

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