Congenital adrenal hyperplasia (CAH) results from a deficiency in one or another of the enzymes of cortisol biosynthesis. In about 95% of cases, 21-hydroxylation is impaired in the zona fasciculata of the adrenal cortex so that 17-hydroxyprogesterone (17-OHP) ... Congenital adrenal hyperplasia (CAH) results from a deficiency in one or another of the enzymes of cortisol biosynthesis. In about 95% of cases, 21-hydroxylation is impaired in the zona fasciculata of the adrenal cortex so that 17-hydroxyprogesterone (17-OHP) is not converted to 11-deoxycortisol. Because of defective cortisol synthesis, ACTH levels increase, resulting in overproduction and accumulation of cortisol precursors, particularly 17-OHP, proximal to the block. This causes excessive production of androgens, resulting in virilization. Slominski et al. (1996) presented evidence that the CYP21A2, CYP11A1 (118485), CYP17 (609300), and ACTHR (202200) genes are expressed in skin (see 202200). The authors suggested that expression of these genes may play a role in skin physiology and pathology and that cutaneous proopiomelanocortin activity may be autoregulated by a feedback mechanism involving glucocorticoids synthesized locally.
Merkatz et al. (1969) could not diagnose the disorder early in pregnancy by amniocentesis and hormone assay of the amniotic fluid.
Levine et al. (1980) expressed the opinion that experience is still so limited with HLA ... Merkatz et al. (1969) could not diagnose the disorder early in pregnancy by amniocentesis and hormone assay of the amniotic fluid. Levine et al. (1980) expressed the opinion that experience is still so limited with HLA typing of amniotic cells and with hormonal measurements of amniotic fluid that both approaches to prenatal diagnosis should be used. Gueux et al. (1988) found significant elevations of both 21-deoxycortisol and 17-hydroxyprogesterone in the amniotic fluids of affected pregnancies, as determined by HLA typing and linkage analysis to HLA probes. Hughes et al. (1987) determined the concentration of 17-OH-progesterone in the amniotic fluid collected from 55 pregnant women who had previously had a child with 21-hydroxylase deficiency. In 8 pregnancies the levels were raised. These parents elected to terminate in 4 cases, and examination of the fetus confirmed the diagnosis of CAH. In each case, the affected sib had been a salt-loser. The remaining 4 affected pregnancies proceeded to term, and each infant had salt-losing 21-hydroxylase deficiency. All 47 infants predicted to be unaffected were normal at birth; however, an increased plasma concentration of 17-OH-progesterone was documented in a male non-salt-loser at 3 months of age. Hughes et al. (1987) concluded that prenatal diagnosis of congenital adrenal hyperplasia by amniotic fluid steroid analysis is reliable only for the salt-losing form. They published a photograph of the external genitalia of a female fetus with 21-hydroxylase deficiency which showed clitoromegaly and fusion of the labia. Wudy et al. (1999) used routine stable isotope dilution/gas chromatography-mass spectrometry to profile 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, androstanediol, and 5-alpha-dihydrotestosterone in amniotic fluids of midgestation in 77 normal fetuses and 38 untreated or dexamethasone-treated fetuses at risk for 21-hydroxylase deficiency. Dexamethasone was suspended 5 to 7 days before amniocentesis. Regarding prenatal diagnosis of 21-hydroxylase deficiency, 17-hydroxyprogesterone and androstenedione presented the diagnostically most valuable steroids and were of equal diagnostic potential. They permitted successful diagnosis in 36 of 37 (97%) fetuses at risk; 12 were untreated and unaffected, 13 were treated and unaffected, 4 were untreated and affected (3 salt wasters and 1 simple virilizer), and 8 were treated and affected (5 salt wasters and 3 simple virilizers). In the latter group, 1 simple virilizer revealed normal steroid concentrations. The authors proposed that isotope dilution/gas chromatography-mass spectrometry, providing the highest specificity in steroid analysis, be routinely used in clinical steroid analysis whenever maximal reliability is requested. Definitive neonatal diagnosis of CAH is frequently complicated by normal 17-hydroxyprogesterone levels in 21-hydroxylase-deficient patients, residual maternal steroids, and other interfering substances in blood. In an effort to improve the diagnosis, Caulfield et al. (2002) developed a gas chromatography/mass spectrometry method for simultaneous measurement of 15 urinary steroid metabolites as early as the first day of life. Random urine samples from 31 neonatal 21-hydroxylase-deficient patients and 59 age-matched normal newborns were used in the development. Furthermore, the authors developed 11 precursor/product ratios that diagnosed and clearly differentiated the 4 enzymatic deficiencies that cause CAH. The throughput for one bench-top gas chromatography/mass spectrometry instrument was 20 samples per day. The authors concluded that this method afforded an accurate, rapid, noninvasive means for the differential diagnosis of CAH in the newborn period without the need for invasive testing and ACTH stimulation. New et al. (1983) published nomograms relating baseline and ACTH-stimulated levels of adrenal hormones. These nomograms distinguished the milder symptomatic and asymptomatic nonclassic forms of 21-hydroxylase deficiency (termed late-onset and cryptic forms, respectively), as well as heterozygotes for all of the forms, from normal subjects. The cutoff level for ACTH-stimulated 17OHP for the diagnosis of the nonclassic form of 21-hydroxylase deficiency (21OHD), established before molecular studies, is based on the mean +2 SD of 17OHP levels of obligate heterozygotes. However, carriers of CYP21 mutations present variable ACTH-stimulated 17OHP levels, ranging from normal values up to 30 nmol/liter. Bachega et al. (2002) sought to determine if ACTH-stimulated 17OHP levels in obligate carriers for 21OHD would be correlated with the impairment of the enzyme activity caused by these mutations, which would affect the 17OHP cutoff level for the diagnosis of the nonclassical form. Fifty-nine parents of patients with the classical and nonclassical forms of 21OHD had their DNA screened for the mutations found in the index case and were divided into 3 mutation groups according to the impairment of enzyme activity (A equal to 0%, B equal to 3%, and C greater than 20%). Blood samples were collected at baseline condition and 60 minutes after ACTH (250 microg intravenously) to measure 17OHP levels. The levels among groups A, B, and C were compared using the Kruskall Wallis test. ACTH-stimulated 17OHP levels identified 39% of the carriers (9 in group A, 2 in group B, and 12 in group C). The mean +/- SD basal 17OHP levels in groups A, B, and C were: 2.94 +/- 1.89, 1.77 +/- 0.81, and 3.90 +/- 2.43 nmol/liter, respectively (P greater than 0.05) and for ACTH-stimulated levels were 12.6 +/- 7.2, 13.2 +/- 12.9, and 16.8 +/- 7.8 nmol/liter, respectively (P greater than 0.05). Two carriers presented ACTH-stimulated 17OHP levels between 30 and 45 nmol/liter and their entire CYP21 sequencing revealed only 1 mutation in heterozygous state, indicating that the cutoff level might overestimate the diagnosis of the nonclassical form. The authors concluded that the variable ACTH-stimulated 17OHP levels in carriers are not related to CYP21 gene mutations with different impairment of enzyme activity. Mornet et al. (1986) demonstrated that one can use linkage of HLA-DNA probes in chorion villus samples in the first trimester diagnosis. They also used determination of 17-hydroxyprogesterone in the first trimester amniotic fluid in the diagnosis. Reindollar et al. (1988) described the use of a RFLP of the 21-hydroxylase gene for prenatal diagnosis. Lee et al. (1996) developed primers for differential PCR-amplification of the CYP21 gene and the nonfunctional CYP21P gene. Using the amplification created restriction site (ACRS) approach for direct mutation detection, a secondary PCR was then performed using a panel of primers specific for 11 mutations associated with CAH. Subsequent restriction analysis allowed not only the detection but also the determination of the zygosity of the mutations analyzed. In the analysis of 20 independent chromosomes in 11 families of CAH patients in Taiwan, Lee et al. (1996) detected 4 CYP21 mutation types besides deletion. In 5 different alleles, the CYP21P pseudogene contained some polymorphisms that the authors believed to be associated with the CYP21 gene. This finding suggested that gene conversion events are occurring in both CYP21P and CYP21. The combined differential PCR-ACRS protocol was described as simple, direct, and applicable to prenatal diagnosis of CAH using chorionic villi or amniotic cells. During the course of genetic analysis of CYP21 mutations in CAH families, Day et al. (1996) noticed a number of relatives genotyped as nucleotide 656G (613815.0006) homozygotes who showed no clinical signs of disease. They proposed that the putative asymptomatic nucleotide 656G/G individuals are incorrectly typed due to a dropout of 1 haplotype during PCR amplification of CYP21. They recommended that for prenatal diagnosis, microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nucleotide 656. Lako et al. (1999) reported the development of a linkage analysis approach using novel, highly informative microsatellite markers from the class III HLA region to allow highly accurate prenatal diagnosis in all families where samples are available from an affected child. To evaluate genotyping as a diagnostic complement to neonatal screening for CAH, Nordenstrom et al. (1999) analyzed DNA from 91 children who had been diagnosed with CAH between 1986 and 1997 for mutations in the CYP21 gene. Screening levels of 17-hydroxyprogesterone (17OHP) were compared in patients representing different genotypes. Genotyping was done by allele-specific PCR, the patients were divided into 4 groups by the severity of their mutations, and neonatal screening results were compared between these groups as well as with 141 values representing false positive samples. The screening levels of 17OHP were significantly different in the 5 groups of samples. Values above 500 nmol/L were clearly associated with the most severe genotypes, whereas conclusions concerning disease severity could not be drawn from individual samples representing lower levels. The authors concluded that genotyping is a valuable diagnostic tool and a good complement to neonatal screening, especially in confirming or discarding the diagnosis in cases with slightly elevated 17OHP levels. Koppens et al. (2002) noted that duplication of the CYP21A2 gene complicates mutation analysis. They recommended that whenever CYP21A2 mutation analysis is performed in an individual who is not a known carrier of the deficiency, the overall structure of the CYP21/C4 region (the RCCX area) should be determined by haplotyping to avoid erroneous assignment of carrier status. To improve the specificity of newborn screening for CAH, Minutti et al. (2004) developed a method using liquid chromatography-tandem mass spectrometry to measure 17-hydroxyprogesterone, androstenedione, and cortisol simultaneously in blood spots. The authors recommended the assay as a second-tier test of blood spots with positive results for CAH screening by conventional methods. Homma et al. (2004) studied the diagnostic value of the metabolite of 21-deoxycortisol, also known as pregnanetriolone (Ptl), and the metabolite of 17OHP, or pregnanetriol (PT), in identifying 21OHD in term and preterm neonates with elevated blood 17OHP on the newborn screening. They found spot urine Ptl to be a highly specific marker of 21OHD with a cutoff value of 0.1 mg/g creatinine, yielding an unambiguous separation between 21OHD and non-21OHD in term and preterm neonates. They recommended that spot urine Ptl measurement by gas chromatography/mass spectrometry in selected ion monitoring (GC/MS-SIM) be routinely performed in neonates with elevated blood 17OHP detected by newborn screening, if the diagnosis of 21OHD is uncertain. Van der Kamp et al. (2005) determined that gestational age rather than birth weight provides a better basis for cutoff levels of 17OHP in newborn blood screening tests for CAH. Janzen et al. (2007) reported a second-tier liquid chromatography-tandem mass spectrometry procedure that could be used to reduce false-positive results of standard 21-CAH newborn screening.
There are 4 recognized clinical forms of congenital adrenal hyperplasia, the majority of cases being associated with 21-hydroxylase deficiency: salt-wasting (SW), simple virilizing (SV), nonclassic (NC) late-onset (also called attenuated and acquired), and cryptic. All 4 forms are ... There are 4 recognized clinical forms of congenital adrenal hyperplasia, the majority of cases being associated with 21-hydroxylase deficiency: salt-wasting (SW), simple virilizing (SV), nonclassic (NC) late-onset (also called attenuated and acquired), and cryptic. All 4 forms are closely linked to HLA and represent the effects of various combinations of alleles. In female newborns, the external genitalia are masculinized; gonads and internal genitalia are normal. Postnatally, untreated males as well as females may manifest rapid growth, penile or clitoral enlargement, precocious adrenarche, and ultimately early epiphyseal closure and short stature. A mild form of late-onset adrenal hyperplasia due to 21-hydroxylase deficiency can occur in adults and has hirsutism as the only manifestation in the most attenuated form. All types of adrenal hyperplasia were reviewed exhaustively by Bongiovanni and Root (1963). Prader et al. (1962) reported an enormous interlocking Swiss kindred. (See precocious puberty (176400) for a simulating condition.) Galal et al. (1968) concluded that the 2 clinical forms of 21-hydroxylase deficiency (with and without salt loss) correlate with the extent of the defect in the cortisol pathway. Some had suggested the existence of 2 different 21-hydroxylating systems, one specific for progesterone and concerned with aldosterone synthesis and the other specific for 17-alpha-hydroxyprogesterone involved in cortisol synthesis. However, Orta-Flores et al. (1976) presented evidence that there is only one 21-hydroxylation system with 2 active sites: one active on progesterone only and a second active on either substrate indiscriminately. The authors suggested that both sites are defective in the salt-losing variety and only the second in the non-salt-losing form. Presentation with gynecomastia and bilateral testicular masses was reported by Kadair et al. (1977) in a case of 21-hydroxylase deficiency. Others have reported bilateral testicular tumors. Lewis et al. (1968) found that intelligence is increased in the adrenogenital syndrome, a remarkable and possibly significant feature from the point of view of selection and gene frequency. However, McGuire and Omenn (1975) presented data indicating that patients with congenital adrenal hyperplasia do not have higher IQs than expected from the family background. Wenzel et al. (1978) found similar results. Blankstein et al. (1980) reported a possible allelic form of 21-hydroxylase deficiency in 2 sisters, aged 28 and 30 years, who had primary infertility and mild hirsutism but normal puberty, regular menses, and normal female sexual characteristics. Two sibs were normal. The affected sibs were HLA-identical; their healthy sibs were of different HLA type. Levine et al. (1980) studied serum androgen and 17-hydroxyprogesterone levels as well as HLA genotypes in 124 families of patients with classic 21-hydroxylase deficiency. In 8 kindreds, 16 pubertal or postpubertal persons of either sex were found to have biochemical evidence of 21-hydroxylase deficiency without clinical symptoms of excess virilism, amenorrhea, or infertility. They designated the disorder 'cryptic 21-hydroxylase deficiency.' Within each generation, the family members with the cryptic form were HLA identical. They suggested that these persons were compound heterozygotes for the classic gene and a cryptogenic gene. Of 42 pediatric patients with 21-hydroxylase deficiency (from 36 families) treated in Milwaukee between 1965 and 1981, 4 developed a malignant tumor: sarcoma or astrocytoma (Duck, 1981). Kuttenn et al. (1985) found that 21-hydroxylase deficiency was the basis of hirsutism in 24 of 400 women (6%). The diagnosis was made by a high plasma level of 17-hydroxyprogesterone and its marked increase after ACTH stimulation. From genotyping of the 24 families, a high correlation with HLA-B14 and Aw33 was found. Nine HLA-identical sibs showed similar biologic profiles but had no hirsutism; skin sensitivity to androgens may be important in determining clinical expression of the disorder. (It was previously known that unusual sensitivity to androgens can lead to hirsutism despite normal plasma levels of androgen (Kuttenn et al., 1977).) The patients were not distinguishable from women with idiopathic hirsutism or polycystic ovarian disease (184700), either clinically or in plasma androgen levels. Knochenhauer et al. (1997) hypothesized that heterozygosity for CYP21 mutations in women increases their risk of developing clinically evident hyperandrogenism, and that this risk is related to the severity of the mutation of CYP21 and/or the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation. To test these hypotheses, they studied 38 obligate carriers for 21-hydroxylase deficiency (i.e., mothers of children with CAH1 or nonclassic CAH), comparing them to 27 controls. Their data indicate that heterozygosity for CYP21 mutations does not appear to increase the risk of clinically evident hyperandrogenism, although carrying the defect was associated with higher mean and free T levels. Finally, due to the low frequency of androgen excess in their heterozygote population, they were unable to correlate the severity of CYP21 mutations and/or 17-OHP responses to ACTH stimulation with the presence of the phenotype. Sinnott et al. (1989) presented analyses of families that showed profound discordance between the clinical features of sibs with 21-hydroxylase deficiency who appeared to be HLA identical, both in terms of serologically defined HLA polymorphism and in gene organization at the 21-hydroxylase and C4 loci (C4A, 120810; C4B, 120820). For example, in 1 family a boy had the simple virilizing form while his 2 younger sisters, who were both HLA-identical to their brother, had additional salt-wasting features. In 1 family they made the unusual observation of HLA-Bw47-bearing haplotypes that appeared to carry a functional 21-hydroxylase gene. Jaresch et al. (1992) found a high frequency of asymptomatic adrenal tumors in association with homozygosity (82%) and heterozygosity (45%) for 21-hydroxylase deficiency. Jaresch et al. (1992) suggested that CAH should always be ruled out in the case of incidentally detected adrenal masses. Since CAH is a relatively frequent disorder and adrenal carcinoma belongs to the rarest malignant tumors, they concluded that malignant transformation of these tumors is unlikely. Ravichandran et al. (1996) pointed out that both homozygous and heterozygous patients with congenital adrenal hyperplasia have an increased cross-sectional area of their adrenal glands as well as an increased prevalence of adrenal incidentalomas, i.e., adrenal tumors discovered incidentally in the course of imaging studies performed for unrelated reasons (Jaresch et al., 1992). The prevalence of adrenal tumors may be more than 70% in nonclassic CAH and 'unmasked heterozygotes.' Ravichandran et al. (1996) presented 2 patients, female pseudohermaphrodites with the simple virilizing form of CAH and 21-hydroxylase deficiency, who functioned successfully as married phenotypic males. Both came to medical attention in their sixth decade by virtue of massive adrenal incidentalomas encountered in the evaluation of recurrent urinary tract infections. Each had a 46,XX karyotype, no palpable testes, and markedly elevated baseline levels of 17-hydroxyprogesterone. Both responded appropriately to dexamethasone suppression. Histologic and autopsy examination of the first patient's tumor and computed tomographic characteristics of the second patient revealed benign adenoma and mild lipoma, respectively. Ravichandran et al. (1996) concluded that these observations extended and confirmed previous recommendations that CAH be included in the differential diagnosis of adrenal incidentaloma and that baseline 17-hydroxyprogesterone levels be obtained, with ACTH stimulation if necessary, to diagnose the presence of nonclassic CAH. Beuschlein et al. (1998) noted that 21-hydroxylase deficiency had been implicated in the pathogenesis of adrenocortical tumors. They investigated the mutation spectrum of the CYP21B gene and the mRNA expression of P450c21 in 6 aldosterone-producing adenomas, 7 cortisol-producing adenomas, 2 nonfunctional incidentally detected adenomas, and 4 adrenal carcinomas. The 10 exons, intron 2, intron 7, all other exon/intron junctions, and 380 bp of the promoter region of CYP21B were sequenced. In samples from 2 patients (1 with a cortisol-producing adenoma and 1 with an androgen-secreting adrenocortical carcinoma), they detected the heterozygous germline mutation val281 to leu in exon 7 (V281L; 613815.0002). A somatic, heterozygous microdeletion was found in exon 3 of 1 aldosterone-producing adenoma. The P450c21 gene expression correlated with the clinical phenotype of the tumor, with low P450c21 mRNA expression in nonfunctional adenomas (18.8%, 1.5%) compared with high P450c21 expression in aldosterone- and cortisol-producing adenomas (84 +/- 8% and 101 +/- 4%, respectively, vs normal adrenals, 100 +/- 10%). They concluded that the pathophysiologic significance of this finding in the presence of 1 normal CYP21B gene seems to be low, suggesting that 21-hydroxylase deficiency is not a major predisposing factor for adrenal tumor formation. Stikkelbroeck et al. (2001) investigated the prevalence of testicular tumors in 17 adolescent and adult male patients with CAH aged 16 to 40 years. In 16 of 17 patients, one or more testicular tumors ranging in maximal length from 0.2 to 4.0 cm were found on ultrasonography. In 6 patients, the testicular tumors were palpable. Undertreatment, defined as the presence of a salivary androstenedione level above the upper reference morning level, was found in 5 of 17 patients at the time of investigation. The other 12 patients were treated adequately or even overtreated at the time of investigation. Nevertheless, 11 of these 12 patients showed testicular tumors on ultrasonography. Tumor size was significantly larger in patients who were heterozygous or homozygous for deletion or conversion of the CYP21 gene than in patients who did not have this genotype. Impairment of Leydig cell function as manifested by decreased plasma levels of testosterone was found in 6 of 17 patients. Semen analysis in 11 patients revealed azoospermia in 3 patients and poor semen quality in 4 patients. The authors concluded that, when carefully sought for, testicular adrenal rest tumors are frequently present in adolescent and adult males with CAH and are often accompanied by impaired spermatogenesis and Leydig cell failure. In a follow-up study of 52 males with congenital virilizing adrenal hyperplasia seen at Johns Hopkins between 1950 and 1978, 51 had 21-hydroxylase deficiency and 1 had 11-hydroxylase deficiency (Urban et al., 1978). Because little is known about the relation between endogenous TSH and cortisol secretion under physiologic or slightly disturbed conditions, Ghizzoni et al. (1997) evaluated the pulsatility, circadian rhythmicity, and 24-hour secretory patterns of cortisol and TSH in 8 prepubertal children with nonclassic CAH and 8 age-matched short normal children. In both groups, TSH and cortisol were secreted in a pulsatile and circadian fashion, with a clear nocturnal TSH surge. Although no difference in mean 24-hour TSH levels was observed between the 2 groups, daytime TSH levels were lower in the nonclassic CAH group than in controls (P less than 0.05). Cross-correlation analysis showed that TSH and cortisol were negatively correlated, possibly reflecting a negative glucocorticoid effect on TSH under physiologic conditions. The authors concluded that the hypothalamic-pituitary-adrenal axis has a primarily negative influence on endogenous TSH secretion and that even mild disturbances in cortisol biosynthesis can be associated with slight alterations in TSH secretion. Meyer-Bahlburg (1999) noted that women with classic CAH have relatively low fertility rates. The author stated that the largest clinic population was studied by Mulaikal et al. (1987), who studied 80 women with classic 21-hydroxylase deficiency who were evenly split into the SV and SW forms. Half of the women were not heterosexually active. Those who were heterosexually active nevertheless appeared to have low fertility. Among the 25 SV women who reported both adequate vaginal reconstruction and heterosexual activity, the fertility rate was 60%. Among the 15 SW women with both adequate introitus and heterosexual activity, the fertility rate was only 7%; a single pregnancy was reported and that ended in an elective termination. Meyer-Bahlburg (1999) reviewed the various physical and behavioral factors that could account for the observed low rates of child bearing. Merke et al. (2000) studied a group of patients with congenital adrenal hyperplasia in whom plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50% lower in those who had been hospitalized for adrenal crises than in those who had not. In 3 patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopic studies revealed a depletion of secretory vesicles in chromaffin cells. Thus, the authors concluded that congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system. Green-Golan et al. (2007) compared 6 adolescents with classic CAH with 7 age-, sex-, and body mass index group-matched controls to assess hormonal, metabolic, and cardiovascular response to prolonged moderate-intensity exercise comparable to brisk walking. The CAH patients showed defective glycemic control and altered metabolic and hormonal responses. Studies had shown that girls with CAH, a syndrome resulting in overproduction of adrenal androgens from early fetal life, are behaviorally masculinized. Nordenstrom et al. (2002) studied play with toys in a structured play situation and correlated the results with disease severity, assessed by CYP21 genotyping, and age at diagnosis. Girls with CAH played more with masculine toys than did controls when playing alone. In addition, the authors demonstrated a dose-response relationship between disease severity (i.e. degree of fetal androgen exposure) and degree of masculinization of behavior. They concluded that prenatal androgen exposure has a direct organizational effect on the human brain to determine certain aspects of sex-typed behavior. Hormones of the hypothalamic-pituitary-adrenal axis and sex hormones interact with extrahypothalamic regulatory centers of the brain, including the amygdala and hippocampus. The amygdala is important in the processing of emotion and generation of fear, whereas the hippocampus plays an important role in memory. Chronic hypercortisolemia is associated with hippocampal damage, while glucocorticoids and corticotropin-releasing factor play a major role in the regulation of amygdala function. Merke et al. (2003) performed MRI of the brain on 27 children with classic CAH and 47 sex- and age-matched controls. Volumes of the cerebrum, ventricles, temporal lobe, amygdala, and hippocampus were quantified. Females with CAH did not have brains with male-specific characteristics. In contrast, a significant decrease in amygdala volume was observed in both males and females with CAH (males, P = 0.01; females, P = 0.002). Iatrogenic effects on the hippocampus due to glucocorticoid therapy were not observed in children with CAH. The authors concluded that prenatal glucocorticoid deficiency with resulting alterations in hypothalamic-pituitary-adrenal axis regulation, sex steroid excess, or some combination of these preferentially affect the growth and development of the amygdala, a structure with major functional implications that warrant further exploration. Berenbaum and Bailey (2003) studied gender identity in girls with CAH in relation to characteristics of the disease and treatment, particularly genital appearance and surgery. Gender identity in girls with CAH was not related to degree of genital virilization or age at which genital reconstructive surgery was done. The authors concluded that moderate androgen excess early in development appears to produce a small increase in the risk of atypical gender identity, but this risk cannot be predicted from genital virilization. Gidlof et al. (2007) found that female patients with severe CYP21 deficiency had longer gestational age than did patients with a milder form of the disease, indicating that androgen excess, increased 17-hydroxyprogesterone levels, or cortisol deficiency, or a combination of these factors, may be of importance for prolongation of pregnancy. The same correlation was not seen for male patients. The authors concluded that steroid hormones may affect the prolongation of pregnancy or onset of labor or both. Moran et al. (2006) studied the frequency of CAH and nonclassic CAH (NCAH) infants born to mothers with 21-OH-deficient NCAH. The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The risk of a mother with 21-OH-deficient NCAH giving birth to a child affected with CAH was found to be 2.5%; at least 14.8% of children born to these mothers had NCAH.
Speiser et al. (1992) correlated genotype and phenotype in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A-to-G change in the second ... Speiser et al. (1992) correlated genotype and phenotype in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A-to-G change in the second intron affecting pre-mRNA splicing in 26% (613815.0006), large deletions in 21%, the ile172-to-asn mutation (613815.0001) in 16%, and the val281-to-leu mutation (613815.0002) in 11%. Patients were classified into 3 mutation groups based on the degree of predicted enzymatic compromise. Mutation group A with no enzymatic activity consisted principally of severely affected salt-wasting patients, group B with 2% activity of simple virilizing patients, and group C with 10 to 20% activity of nonclassic mildly affected patients, but each group contained patients with phenotypes either more or less severe than predicted. The data suggested that most of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. They postulated that phenotypic severity might be influenced by parental imprinting or by negative allelic complementation giving an exaggerated gene dosage effect. However, there was no evidence of either of these phenomena in the group of families studied. Nikoshkov et al. (1997) studied a rare allele in 2 sibs with late-onset CAH1. This allele contained 3 sequence alterations: a C-to-T transition located 4 bases upstream of translation initiation, a pro105-to-leu substitution, and a pro453-to-ser substitution (see 613815.0009). The last mutation has been found in other ethnic groups, whereas pro105 to leu seems to be unique to this family. They tested the function of the -4, pro105-to-leu, and pro453-to-ser mutations by in vitro translation after expression of the mutant enzymes in cultured cells. While the -4 substitution had no measurable effect, the pro105-to-leu and pro453-to-ser mutations reduced enzyme activity to 62 and 68% for 17-hydroxyprogesterone and 64 and 46% for progesterone, respectively. When present in combination, these 2 mutations caused a reduction of enzyme activity to 10% for 17-hydroxyprogesterone and 7% for progesterone. These results indicate that pro105-to-leu and pro453-to-ser alleles should only cause very subtle disease when not in combination but may be considered when genotyping patients with the mildest forms of CAH1. Using allele-specific oligonucleotide hybridization, SSCP, and heteroduplex analyses, Witchel et al. (1996) identified 38 subjects from 21 different families who had 2 deleterious CYP21 mutations. All 38 were homozygous or compound heterozygotes for the intron 2 splicing mutation, which as mentioned earlier, is often identified in 21-hydroxylase deficiency. Comparison of their phenotypic CAH features with their CYP21 genotypes showed phenotypic heterogeneity extending from classic salt-losing 21-hydroxylase deficiency to asymptomatic phenotypes. Witchel et al. (1996) suggested 3 possibilities for this phenotypic heterogeneity: the presence of other (compensating splice) mutations; the presence of additional functional copies of the CYP21 gene; or leakiness of the splice mutation. Miller (1997) noted a fourth possibility, i.e., the activity of other genes encoding proteins other than P450C21 that have steroid 21-hydroxylase activity. Cytochrome P450 enzymes tend to be 'promiscuous' enzymes that bind many different substrates and catalyze a wide variety of hydroxylations. The author hypothesized that adrenal expression of such an enzyme could account for the cryptic 21-hydroxylase activity seen in patients with known CYP21 deletions who experience apparent recovery of their ability to synthesize mineralocorticoids. According to Miller (1997), the identification of such enzymes may constitute the next major advance in the clinical biology of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. As indicated earlier, the majority of mutations causing steroid 21-hydroxylase deficiency result from recombinations between the functional gene and the closely related, highly homologous pseudogene. Levo and Partanen (1997) analyzed mutations and recombination breakpoints in the CYP21 gene and determined the associated haplotypes in 51 unrelated Finnish families with CAH. These represented at least half of all CYP21 deficiency patients in Finland. The results indicated multiple founder mutation-haplotype combinations in this population. The 3 most common haplotypes constituted half of all affected chromosomes; only one-sixth of the haplotypes represented single cases. Several of the frequent mutation-haplotype combinations in Finland had been found in other populations of patients of European origin, thus suggesting that these haplotypes were of ancient origin. Jaaskelainen et al. (1997) reported a population-wide analysis of 120 patients with 21-hydroxylase deficiency found in Finland. Blood samples for CYP21 genotyping were obtained from 78 patients (65%), and their phenotypes were compared with their genotypes. In general, the severity of gene defects correlated well with clinical expression. All patients carrying mutations with severe effects on enzymatic activity had the salt-wasting form of 21-hydroxylase deficiency. Those with the I2 splice mutation (613815.0006), which in some reports has a variable phenotype, had severe mineralocorticoid deficiency. In contrast, patients with the I172N mutation (613815.0001) expressed a wide spectrum of phenotypes that could not be attributed to additional mutations. Wedell (1998) reported that in Sweden direct mutation detection had been used for diagnosis of 21-hydroxylase deficiency since 1990. Approximately 400 affected 21-hydroxylase genes had been analyzed. Approximately 95% of alleles were accounted for by mutations that had arisen by interaction with the adjacent pseudogene, including gene deletion and 9 smaller sequence aberrations. A total of 13 rare, mostly population-specific mutations had been characterized among the remaining 5%. Some of these rare mutations were present in the pseudogene at a low frequency, indicating that they had started to spread at a low rate in the population. The mutations could be divided into different groups according to severity. This made it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt-wasting and prenatal virilization could be estimated, and overtreatment avoided in mildly affected cases. Wedell (1998) stated she had seen no exception to the rule that patients who are homozygous for null mutations develop salt-wasting (unless treated early) and are severely virilized, if female. She classified the frequent mutations into 3 classes: nonclassic (NC), the least severe; simple virilizing (SV), with intermediate severity; and salt-wasting (SW), the most severe. Prenatal virilization occurred with the SV and SW groups. Dacou-Voutetakis and Dracopoulou (1999) analyzed the CYP21 genes of children with premature adrenarche (PA) to detect possible correlations with hormonal and clinical data. Abnormal genotypes were detected in 45.8% of the subjects studied; 8.3% were homozygotes, with genotypes concordant with the nonclassic phenotype of 21-hydroxylase deficiency, and 37.5% were heterozygous for 9 different molecular defects of the CYP21 gene. The authors noted that CYP21 heterozygosity was clinically expressed in some subjects prepubertally, and in a significant number of cases, the genotype could not be predicted by the age of onset of PA, the mean difference between bone age and chronologic age, or the results of a Synachten test. They suggested that follow-up of these children through puberty is imperative and may reveal the clinical significance of the molecular defect, namely more hypertrichosis, intense acne, early puberty, possible abnormal menses, and/or fertility problems in the affected individuals. By allele-specific PCR, Bachega et al. (1998) determined the frequency of point mutations in 130 Brazilian patients with the classic and nonclassic forms of CAH1 and correlated genotypes with phenotypes. The most frequent mutations were I2 splice (613815.0006), 42% in salt wasting; I172N (613815.0001), 33% in simple virilizing; and V281L (613815.0002), 40% in late-onset form. The frequency of the 9 most common point mutations was similar to that reported for other countries, except for the 8-nucleotide deletion (613815.0015) and the exon 6 cluster (613815.0016), which were less frequent in the classic form. The 93 fully genotyped patients were classified into 3 mutation groups based on the degree of enzymatic activity (group A, less than 2%; group B, approximately 2%, and group C, greater than 18%). In group A, 62% of the cases presented the salt-wasting form; in group B, 96% the simple virilizing form; and in group C, 88% the late-onset form. Screening for large rearrangements and 15 point mutations detected 80% of the affected alleles. The authors concluded that the absence of previously described mutations in 20% of the affected alleles suggested the presence of new mutations in their population. Nimkarn et al. (1999) analyzed the CYP21 gene in a patient with CAH1 and her family. The entire exon coding and intron regions, as well as the -1 kb 5-prime promoter region, were sequenced and analyzed. No mutation was found in this 3.7-kb sequence. A potential CYP11B1 defect, which could closely mimic the clinical and biochemical phenotype of CAH1, was excluded by sequencing a 2.6-kb segment that spanned the entire coding region of the CYP11B1 gene. Krone et al. (2000) determined the frequency of CYP21-inactivating mutations and the genotype-phenotype relationship in 155 well-defined unrelated CAH patients. They identified 306 of 310 (99%) disease-causing alleles. The most frequent mutation was the intron 2 splice site mutation (613815.0006; 30%), followed by gene deletions (20%), the I172N mutation (613815.0001; 20%) and large gene conversions (7%). Five new point mutations were detected. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppvnull) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppvA to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppvB was 74%. In group C, categorized as P30L (613815.0004), V281L (613815.0002), or P453S (613815.0010) in homozygous or compound heterozygous form with a more severe mutation, ppvC was 65% to exhibit the nonclassic form of CAH, but 90% when excluding the P30L mutation. Thus, Krone et al. (2000) concluded that in general, a good genotype-phenotype relationship was shown in patients with either the severest or the mildest mutations. A considerable degree of divergence was observed within the mutation groups of intermediate severity. Dracopoulou-Vabouli et al. (2001) examined the types and relative frequencies of molecular defects and genotype/phenotype correlations in the Hellenic population. They searched for deletions, conversions, and 11 of the most frequent mutations of the CYP21 gene in 222 chromosomes from 111 unrelated subjects and their parents. The most frequent mutations were the I2 splice (613815.0006) (42.9%), deletions and conversions (24.5%), and Q318X (613815.0020) (14.3%) in the salt-wasting form; I172N (613815.0001) (35.3%), the I2 splice (29.4%), and P30L (613815.0004) (19.1%) in the simple virilizing form; and V281L (613815.0002) (41.1%), P30L (21.4%), and P453S (613815.0010) (14.3%) in the nonclassic form. Compared with other populations, Greek patients had a higher frequency of Q318X in the salt-wasting form, of P30L in both simple virilizing and nonclassic forms, and of P453S in the nonclassic form. The concordance of genotype to phenotype in the total sample was 87%. However, the concordance rate was different in the 3 forms of the disease. Thus, complete concordance was detected in the genotypes predicting the salt-wasting phenotype, a slightly lower concordance (95.2%) was detected in the genotypes predicting the simple virilizing phenotype, and the lowest concordance (67.6%) was observed in genotypes predicting the nonclassic phenotype. The authors concluded that the concordance between genotype and phenotype decreases as the severity of the disease diminishes. Deneux et al. (2001) analyzed CYP21 in 56 unrelated French women with symptomatic nonclassic CAH. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was val281 to leu (613815.0002), which was present on 51% of alleles and in 80% of women. Three novel mutations were found. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risked giving birth to children with a classic form of the disease. Potential genotype/phenotype correlations were examined by classifying the patients into 3 groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher, in compound heterozygotes for mild and severe mutations (group B) compared with women with 2 mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in 2 women, a severe mutation was found on both alleles (group C). The authors concluded that the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus. L'Allemand et al. (2000) reported a case of nonclassic 21-hydroxylase deficiency, with a moderately elevated 17-hydroxyprogesterone level (145 nmol/L in filter paper blood spot), who was detected in newborn screening. The phenotype was female, with no sign of virilization. Confirmatory diagnosis revealed elevated serum levels of 17-hydroxyprogesterone and of 21-desoxycortisol, whereas cortisol, PRA, and electrolytes were normal. Hydrocortisone substitution was considered at the age of 6 months, when virilization became obvious. For clinical reasons, this case was classified as late-onset CAH with unusually early manifestation. However, the diagnosis of classic 21-hydroxylase deficiency was obtained by Southern blotting studies, suggesting that the patient was homozygous for the 30-kb deletion (613815.0011), including the 3-prime end of the CYP21P pseudogene, the C4B gene, and the 5-prime end of the functional CYP21 gene. Typically, patients homozygous for the 30-kb deletion encoding classic CAH possess a unique CY21P/21 hybrid gene with the junction site located after the third exon, yielding a nonfunctional pseudogene. The girl in question, however, was heterozygous for the 8-bp deletion (613815.0015), suggesting that the chimeric pseudogene on one allele had a junction site before the third exon. The patient was a compound heterozygote for a 30-kb deletion encoding classic CAH on the paternal allele, and a 30-kb deletion encoding nonclassic CAH on the maternal allele. This novel maternal CYP21P/21 hybrid gene is characterized by a junction site before intron 2 and differs from the normal CYP21 gene only by the P30L mutation in exon 1 (613815.0004) and by containing the promoter region of the CYP21P pseudogene. Because the P30L mutation results in an enzyme with 30 to 60% activity of the normal P450c21 enzyme, and the CYP21P promoter reduced the transcription to 20% of normal, this puzzling phenotype of a nonclassic CAH with early onset may be fully explained by the genotype of the patient and considered as an intermediate form between the simple virilizing and nonclassic form. A chimeric CYP21P/CYP21 gene with its 5-prime end corresponding to CYP21P and 3-prime end corresponding to CYP21 has been identified (Tusie-Luna and White, 1995) and found to be nonfunctional because of a deleterious mutation that results in a frameshift and a truncated protein. Lee et al. (2002) reported 2 chimeric CYP21P/CYP21 genes in CAH patients. Both genes had a sequence with -300 nucleotides of the 5-prime head as the CYP21P gene. The coding region consisted of a fusion molecule with the CYP21P gene in 2 different regions. The junction in 1 patient was located in the chi-like sequence in the third intron and in the other patient was located in the minisatellite consensus of exon 5 of the CYP21P gene. Analysis of restriction fragment length polymorphisms in these two 3.3-kb chimeric molecules showed that these sequences arose as a consequence of unequal crossover between CYP21P and CYP21. Although genotype can usually predict phenotype, genotype-phenotype discordance had been described in CAH. Charmandari et al. (2002) investigated the association between adrenomedullary function, disease severity, and genotype in 37 children, 28 with salt-wasting and with 9 simple virilizing CAH. Patients carrying disease-causing mutations were divided into 4 groups: null, 9 patients homozygous for mutations shown to confer no 21-hydroxylase activity; A, 15 patients homozygous for the intron 2 mutation (613815.0006) or compound heterozygous for the intron 2 mutation and a null allele; B, 8 patients homozygous for the I172N mutation (613815.0001) or compound heterozygous for I172N and a more severe mutation; and C, 1 patient homozygous for the P30L (613815.0004) mutation. Genotype groups null and A were predicted to have salt-wasting CAH, group B was predicted to have the simple virilizing phenotype, and group C was predicted to have nonclassic CAH. A fifth group, D, included 4 patients in whom mutations were detected in only 1 allele. Plasma total metanephrine and free metanephrine concentrations were significantly lower in children with salt-wasting CAH than in those with the simple virilizing form of the disease. Plasma free metanephrine concentrations best predicted phenotype, with accuracy similar to that of genotype. Concordance rates between genotype and phenotype were higher in the most severely affected patients. Patients with free metanephrine value equal to or less than 8.5 pg/ml were likely to manifest the salt-wasting phenotype. The plasma free metanephrine concentration correlated with the expected 21-hydroxylase activity based on genotype, and there was a significant trend for free metanephrine concentrations across the null, A, and B genotype groups (P less than 0.0001). The authors concluded that measurement of adrenomedullary function, best assessed by the free metanephrine concentration, is a useful biomarker of disease severity in 21-hydroxylase deficiency. Molecular genotype and plasma free metanephrine concentration predict phenotype with similar accuracy. Both methods are more accurate in the most severe forms of the disease. Speiser and White (2003) provided a comprehensive review of congenital adrenal hyperplasia. In a discussion of correlations between phenotype and genotype, they pointed out that CYP21 mutations can be grouped into 3 categories according to the level of enzymatic activity predicted from in vitro mutagenesis and expression studies. The first group consists of mutations such as deletions or nonsense mutations that totally ablate enzyme activity; these are most often associated with salt-wasting disease. The second group of mutations, consisting mainly of the I172N mutation (613815.0001), yields enzymes with 1 to 2% of normal activity. These mutations permit adequate aldosterone synthesis and thus are characteristically found in patients with simple virilizing disease. The third group includes mutations, such as V281L (613815.0002) and P30L (613815.0004), that produce enzymes retaining 20 to 60% of normal activity; these mutations are associated with the nonclassic disorder. Compound heterozygotes for 2 different CYP21 mutations usually have a phenotype compatible with the presence of the milder of the gene defects. A source of phenotype-genotype variability is the leakiness of splice mutations. An A-to-G transition in the splice acceptor site at the 3-prime end of intron 2 at nucleotide 656 (613815.0006) comprises 25% of all classic 21-hydroxylase deficiency alleles and usually results in abnormally spliced mRNA transcripts. Experimental and clinical observations suggested, however, that a small amount of the mRNA is normally spliced. A mere 1 or 2% of normal functional enzyme activity can change the patient's phenotype from salt-wasting to simple virilizing disease. Pinto et al. (2003) sought to optimize diagnosis and follow-up by comparing phenotype with genotype. Sixty-eight patients with CAH due to 21-hydroxylase deficiency were studied by clinical, hormonal, and molecular genetic methods. Patients were classified according to predicted mutation severity: group 0, null mutation (17.6%); group A, homozygous for IVS2 splice mutation or compound heterozygous for IVS2 and null mutations (33.8%); group B, homozygous or compound heterozygous for I172N mutation (14.7%); group C, homozygous or compound heterozygous for V281L or P30L mutations (26.5%); and group D, mutations with unknown enzyme activity (7.4%). All group 0 and A patients had the salt-wasting form, and group C had nonclassical forms. Group B included 5 salt-wasting and 5 simple virilizing forms. Groups 0 and A were younger at diagnosis, and females were more virilized than those in group B. Group B had higher basal plasma 17-hydroxyprogesterone and testosterone levels than group C. Hydrocortisone doses given to groups 0, A, and B were similar at all ages, but lower in group C (P less than 0.01). Final height was below target height in classical and nonclassical forms. The authors concluded that the severity of the genetic defects and the clinical-laboratory features are well correlated. They stated that genotyping, combined with neonatal screening and optimal medical and surgical treatment, can help in the management of CAH. Stikkelbroeck et al. (2003) assessed the frequencies of CYP21 mutations and studied genotype-phenotype correlation in a large population of Dutch 21-hydroxylase deficient patients. From 198 patients with 21-hydroxylase deficiency, 370 unrelated alleles were studied. Gene deletion/conversion was present in 118 of 370 alleles (31.9%). The most frequent point mutations were I2G (613815.0006) (28.1%) and I172N (613815.0001) (12.4%). Clustering of pseudogene-derived mutations in exons 7 and 8 on a single allele (V281L-F306+1nt-Q318X-R356W; 613815.0033) was found in 7 unrelated alleles (1.9%). Six novel mutations were found. Genotype-phenotype correlation in 87 well documented patients showed that 28 of 29 (97%) patients with 2 null mutations and 23 of 24 (96%) patients with mutation I2G (homozygous or heterozygous with a null mutation) had classic salt wasting. Patients with mutation I172N (homozygous or heterozygous with a null or I2G mutation) had salt wasting (2 of 17, 12%), simple virilizing (10 of 17, 59%), or nonclassic CAH (5 of 17, 29%). All 6 patients with mutation P30L (613815.0004), V281L (613815.0002), or P453S (613815.0010) in homozygosity or compound heterozygosity had nonclassic CAH. The authors concluded that the frequency of CYP21 mutations and the genotype-phenotype correlation in 21-hydroxylase deficient patients in the Netherlands showed general high concordance with previous reports from other Western European countries. However, a cluster of 4 pseudogene-derived point mutations on exons 7 and 8 on a single allele, observed in almost 2% of the unrelated alleles, seems to be particular for the Dutch population, and 6 novel CYP21 gene mutations were found. Soardi et al. (2008) studied the functional effects of 3 novel and 1 recurrent (R408C; 613815.0030) CYP21A2 mutations in 10 Brazilian and 2 Scandinavian patients. They also analyzed the degree of enzyme impairment caused by H62L (613815.0034) alone or combined with P453S (613815.0010). Low levels of residual activities obtained for the novel mutations and R408C classified them as classical CAH mutations, whereas H62L showed an activity within the range of nonclassical mutations.
Congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency is caused by mutation in the CYP21A2 gene; for a complete discussion of the molecular genetics of this disorder, see 613815.
Congenital adrenal hyperplasia affects about 1 in 5,000 births.
In the canton of Zurich, Switzerland, Prader (1958) estimated the frequency of the congenital adrenogenital syndrome to be 1 in 5,041 live births, giving a frequency of ... Congenital adrenal hyperplasia affects about 1 in 5,000 births. In the canton of Zurich, Switzerland, Prader (1958) estimated the frequency of the congenital adrenogenital syndrome to be 1 in 5,041 live births, giving a frequency of carriers of 1 in 35. Childs et al. (1956) had estimated the frequency in Maryland to be 1 in 67,000 births. In Toronto, Qazi and Thompson (1972) estimated the minimum frequency of salt-losing C-21 hydroxylase deficiency as 1 per 26,292. Presumably it is a salt-losing variety of 21-hydroxylase deficiency that is present in relatively high frequency in Eskimos of Alaska (Hirschfeld and Fleshman, 1969). Other recessive conditions of high frequency among the Alaskan Eskimos include Kuskokwim disease (208200), methemoglobinemia (250800), and pseudocholinesterase deficiency (see 177400). The forms of adrenal hyperplasia that may present in adulthood are 21- and 11-hydroxylase deficiencies. Speiser et al. (1985) concluded that nonclassic 21-hydroxylase deficiency is probably the most frequent autosomal recessive genetic disease. It is especially frequent in Ashkenazim (3.7%), Hispanics (1.9%), Yugoslavs (1.6%), and Italians (0.3%). With the exception of the Yugoslavs, the gene for the nonclassic form is in linkage disequilibrium with HLA-B14. The classic form shows linkage disequilibrium with HLA-Bw47;DR7. Sherman et al. (1988) estimated the frequency of the gene for the nonclassic form of 21-hydroxylase D to be as high as 0.223 among Ashkenazi Jews. Segregation analysis of families ascertained through a nonclassic proband and those ascertained through a classic proband showed essentially identical results. The authors concluded that the possibility that the gene is incompletely penetrant in a small number of homozygotes is likely for the nonclassic form and unlikely for the classic form. Layrisse et al. (1987) studied 19 Venezuelan families of mixed ethnic origin having 20 affected newborns with the salt-wasting form of 21-hydroxylase deficiency. HLA haplotypes and complotypes were determined. The results were markedly different from those reported in the literature which show an association at the population level with HLA-Bw47 and the extended haplotype HLA-Bw47,DR7,FC91,0. Four of the unrelated patients were homozygous for all MHC loci tested while 3 others were homozygous for at least 2 HLA loci. The findings were interpreted as indicating that among Venezuelan patients, salt-wasting 21-hydroxylase deficiency results in the main from founder effect of relatively few independent mutations. The mutation marked by HLA-Bw47 was not observed in this population. Thilen and Larsson (1990) performed a retrospective study of all Swedish patients with CAH born between 1969 and 1986, to determine possible benefits of neonatal screening. Information was obtained concerning 67 males and 83 females. Of these, 143 were regarded as classic and 7 as nonclassic (symptoms after 5 years of age or cryptic). All but 2 (a girl with 11-hydroxylase deficiency and a boy with beta-hydroxysteroid dehydrogenase deficiency) had 21-hydroxylase deficiency. The prevalence was 1 in 11,500. Salt loss was displayed by 93 patients (48 male, 45 female), all before the age of 3 months. The median age at diagnosis for boys in this group was 21 days. Gender assignment was a major problem in 38 of 57 girls, with ambiguous genitalia noticed at birth. Of these girls, 15 were considered to be male before the diagnosis of CAH was made. In a similar study in Kuwait, Lubani et al. (1990) found 60 children with CAH diagnosed between 1978 and 1988, giving an estimated prevalence of 1 in 9,000 live births. In addition, there was presumptive evidence of CAH resulting in the death of 20 other children, giving a prevalence figure of 1 in 7,000. In 54 patients (90%), 21-hydroxylase deficiency was diagnosed; in 3 patients each, the diagnosis was 3-beta-hydroxysteroid dehydrogenase deficiency and 11-beta-hydroxylase deficiency. Chrousos et al. (1982) estimated that 6 to 12% of hirsute women have 21-hydroxylase deficiency because of homozygosity for a mild allele of the 21-hydroxylase gene. They calculated that the frequency of the gene for the attenuated form of the disease is 0.015 to 0.057. From 1991 to 1994, approximately 4.5 million infants had newborn screening for CAH in Japan. In this cohort, Tajima et al. (1997) identified 2 sibs and 2 unrelated newborns who had mild elevations of serum 17-hydroxyprogesterone levels at 5 days of age but no symptoms of CAH. These 4 cases were diagnosed as having probable nonclassic steroid 21-hydroxylase deficiency. The 2 sibs had ile172-to-asn (613815.0001) and arg356-to-trp (613815.0003) mutations in 1 allele and a gene conversion that included the pro30-to-leu (613815.0004) mutation in the other allele. The first unrelated case had a gene conversion encoding the same pro30-to-leu mutation in 1 allele. The second allele had an intron 2 mutation (668-12 A-to-G), which perturbed splicing, and the arg356-to-trp mutation. The second unrelated case was a compound heterozygote for an arg356-to-trp and a 707del8 mutation. Since the estimated rate of detection of the nonclassic form by mass screening (1 in 1,000,000) seemed low compared to the established detection rate for the classic form (1 in 18,000), the authors concluded that detection by neonatal screening may be particularly difficult for nonclassic cases in which both alleles contain only nonclassic associated mutations. Witchel et al. (1997) hypothesized that those heterozygous for 21-hydroxylase deficiency have a survival advantage. They found significantly elevated cortisol responses in 28 proven carriers compared to 22 mutation-negative controls (30 min cortisol levels: normal, 24.2 micro g/dL; carrier, 28.1 microg/dL; P less than 0.005). The authors proposed that the higher cortisol response observed in carriers may enable a rapid return to homeostasis in response to infectious, inflammatory, or other environmental stresses and may protect from inappropriate immune responses, such as autoimmune diseases. Wedell (1998) reviewed the molecular genetics of CAH due to 21-hydroxylase deficiency. In Sweden, where approximately 400 affected 21-hydroxylase genes had been analyzed, 9 common pseudogene-derived mutations accounted for approximately 95% of alleles. A total of 13 rare, mostly population-specific mutations had been characterized among the remaining 5%. The mutations could be divided into different groups according to severity, making it possible to predict clinical outcome in affected subjects based on genotyping. The risk of salt wasting and prenatal virilization could be estimated, and overtreatment could be avoided in mildly affected cases. Lako et al. (1999) reported screening for 17 different CYP21 mutations in a total of 284 disease chromosomes in the British population. The most common mutations were large scale deletions or conversions (210910.0011; 210910.0012) in 45% of affected chromosomes, the intron 2 splice mutation (210910.0006) in 30.3%, R357W (210910.0003) in 9.8%, and I172N (210910.0001) in 7% of affected chromosomes. Mutations were detected in over 92% of the chromosomes examined. Ferenczi et al. (1999) screened 167 Hungarian CAH patients (representing 306 unrelated chromosomes and 56.2% of the total group of registered Hungarian patients). Eight of the most common mutations were screened using allele-specific amplification. The most frequent mutation in the Hungarian CAH population was the intron 2 splice mutation. The results showed a good genotype/phenotype correlation for most mutations. The intron 2 mutation was usually associated with the severe form of CAH, whereas I172N was associated with a wide spectrum of phenotypes. New and Wilson (1999) gave a comprehensive review of congenital adrenal hyperplasia. They stated that approximately 40 mutations in the CYP21 gene causing 21-OH deficiency had been identified. The most common mutations appeared to the result of either of 2 types of meiotic interaction between CYP21 and the pseudogene CYP21P: (i) misalignment and unequal crossing-over, resulting in large-scale DNA deletions, and (ii) apparent gene conversion events that result in the transfer to CYP21 of smaller-scale deleterious mutations in the CYP21P pseudogene. Fitness et al. (1999) investigated the utility of genotyping 9 CYP21 mutations, linked chromosome 6p markers, and a dimorphic X-Y marker from neonatal screening samples (Guthrie cards). DNA was extracted and CYP21 PCR products were subjected to ligase detection reactions, simultaneously analyzing 9 CYP21 mutations; PCR products of other genes were subjected to direct gel analysis. Rates for heterozygosity for classic and nonclassic CYP21 mutations (excluding CYP21 deletions) were 2.8% and 2.0%, respectively, in New Zealanders. Baumgartner-Parzer et al. (2005) used CYP21A2 genotyping (sequence/Southern blot analysis) to determine CAH carrier frequency in a middle European (Austrian) population. The study included 100 migrants from the former Yugoslavia and 100 individuals of non-Yugoslavian origin. None of these individuals showed clinical hyperandrogenism or had a family history of CAH. Genotyping 400 unrelated alleles from 200 clinically unaffected individuals, this study revealed a carrier frequency of 9.5%, including so-called 'classic' (5.5%) and 'nonclassic' (4%) CYP21A2 gene aberrations. The observed heterozygosity for CAH in Yugoslavs was not different (P = 0.8095) from that in non-Yugoslavs. The authors concluded that the observed CAH carrier frequency of 9.5% suggests a higher prevalence of CAH heterozygosity in a middle European population than hitherto estimated independently of the individuals' Yugoslav or non-Yugoslav origin. Wilson et al. (2007) studied the ethnic-specific distribution of mutations in 716 patients with 21-hydroxylase deficiency. Prevalent allelic mutations and genotypes were found to vary significantly among ethnic groups, and the predominance of the prevalent mutations and genotypes in several of these populations was significant. A large deletion (613815.0011) was prevalent in Anglo-Saxons; a V281L mutation (613815.0002) was prevalent in Ashkenazi Jews; a R356W mutation (613815.0003) was prevalent in Croatians; an IVS2AS-13 mutation (613815.0006) was prevalent in Iranians and Yupik-speaking Eskimos of Western Alaska; and a Q318X mutation (613815.0020) was prevalent in East Indians. Genotype/phenotype noncorrelation was seen when at least one IV2AS-13 mutation in the CYP21A2 gene was present.
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) is suspected in the following:...
DiagnosisClinical Diagnosis21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) is suspected in the following:Females who are virilized at birth, or who become virilized postnatally, or who have precocious puberty or adrenarche. Virilization affects maturation, growth (leading to tall stature), and sex hormone-sensitive areas (external genitalia, skin, and hair) (leading to secondary sexual characteristics).Males with virilization in childhood (i.e., pseudoprecocious puberty)Any infant with a salt-losing crisis in the first four weeks of lifeTestingAffected Untreated Individuals 17-hydroxyprogesterone (17-OHP). The diagnosis of 21-OHD CAH is confirmed by biochemical findings, such as an unequivocally elevated serum concentration of 17-OHP (see Figure 1):FigureFigure 1. 17-OHP nomogram for the diagnosis of steroid 21-hydroxylase deficiency (60-minute cotrosyn stimulation test). The data for this nomogram was collected between 1982 and 1991 at the Department of Pediatrics, the New York Hospital-Cornell Medical (more...)Classic 21-OHD CAH. >20,000 ng/dL Non-classic 21-OHD CAH. 2,000 to 15,000 ng/dLNote: Normal ranges for sex and pubertal status vary by laboratory reflecting the methods utilized. In adult females, the normal ranges depend on phase of the menstrual cycle. Plasma renin. Plasma renin activity (PRA):Is markedly elevated in individuals with the salt-wasting form of 21-OHD CAH; Can be elevated in some individuals with the simple virilizing form of 21-OHD CAH.Direct measurement of active renin can also be used. Note: PRA measures the enzyme activity of renin to generate angiotensin I; the active renin assay immunoradiometrically measures renin substrate (not activity) [Krüger et al 1996].Other adrenal steroids. Serum concentrations of:Δ4-androstenedione and progesterone are increased in males and females with 21-OHD CAH;Testosterone and adrenal androgen precursors are increased in affected females and prepubertal males.Note: In individuals with the salt-wasting form of 21-OHD CAH, the serum concentration of aldosterone is inappropriately low compared to the level of plasma renin activity (PRA) elevation.ACTH stimulation test. The serum concentration of 17-OHP and Δ4-androstenedione measured at baseline and at 60 minutes after intravenous injection of a standard 250-µg bolus of synthetic ACTH (CortrosynTM) are plotted on the nomogram in Figure 1. Although the ACTH stimulation test provides far more reliable diagnosis of 21-OHD CAH than a test of baseline values alone, the results should be confirmed with molecular genetic testing of CYP21A2. Note: Performing an ACTH stimulation test may not be feasible because of the relatively large volume of blood required for a newborn, lack of an appropriate setting in a neonatal intensive care unit, and clinical instability of a sick newborn. Molecular genetic testing is more appropriate for diagnosis.Electrolytes. Individuals with untreated or poorly controlled salt wasting may have a decreased serum concentration of sodium, chloride, and total carbon dioxide (CO2), an increased serum concentration of potassium, and inappropriately increased urine concentration of sodium.Karyotype. Females with 21-OHD CAH have a normal 46,XX karyotype; males with 21-OHD CAH have a normal 46,XY karyotype.CarriersIndividuals with one normal allele and one mutant allele are carriers (heterozygotes) and are asymptomatic. Following ACTH stimulation, however, carriers may have slightly higher serum concentrations of 17-OHP than individuals with two normal alleles (Figure 1). In addition, because overlap exists in serum concentration of 17-OHP between heterozygotes and non-carriers after ACTH stimulation, such testing is no longer the preferred method of carrier identification. Molecular genetic testing is recommended.Newborn ScreeningNewborn screening for 21-OHD CAH serves two purposes:To identify infants with the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crisesTo expedite the diagnosis of females with ambiguous genitaliaNote: Newborn screening can also detect some (though not all) individuals with the non-classic form of 21-OHD CAH [Votava et al 2005].States with mandated newborn screening for 21-OHD CAH are identified in the National Newborn Screening Status Report (pdf). The concentration of 17-OHP is measured on a filter paper blood spot sample obtained by the heel-stick technique as used for newborn screening for other disorders [Pang & Shook 1997].The majority of screening programs use a single screening test without retesting of samples with questionable 17-OHP concentrations (see Published Guidelines/Consensus Statements) [Clayton et al 2002, Joint LWPES/ESPE CAH Working Group 2002].To improve efficacy of screening, a small number of screening programs re-evaluate samples with borderline first-tier test results with a second tier test. For example, because of the high false-positive rate of immunoassay methods, some programs measure the concentration of different hormones (17-OHP, Δ4-androstenedione, and cortisol) by liquid-chromatography-tandem mass spectrometry as a second-tier test on samples with a positive first-tier test [Minutti et al 2004]. Note: (1) Results on blood samples taken in the first 24 hours of life are elevated in all infants and may give false-positive results [Allen et al 1997, Therrell et al 1998]. (2) False-positive results may also be observed in low birth-weight infants [Allen et al 1997] or premature infants [al Saedi et al 1996]. (3) False-negative results may be observed in neonates receiving dexamethasone for management of unrelated problems [Rohrer et al 2003]. Molecular Genetic TestingGene. CYP21A2 is the only gene in which mutation is known to cause 21-OHD CAH.Clinical testingTargeted mutation analysis. Molecular genetic testing of CYP21A2 for a panel of common mutations and gene deletions detects 80%-98% of disease-causing alleles in affected individuals. Many of these common mutations arise as a result of gene conversion (see Molecular Genetics). Note: The majority of individuals from heterogeneous populations with 21-OHD CAH are compound heterozygotes [Krone et al 2000].Deletion/duplication analysis. A variety of methods such as Southern blot analysis, homozygosity testing for single nucleotide polymorphisms, quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH can be used to detect this and other large (exonic, multiexonic, and whole-gene) deletions or duplications. Approximately 20% of mutant alleles are deleted for a 30-kb gene segment that encompasses the 3' end of the CYP21A1P pseudogene, all of the adjacent C4B complement gene, and the 5' end of CYP21A2 (see Molecular Genetics). In one recent study 7% of CYP21A2 alleles in the population studied were duplications [Parajes et al 2008].Sequence analysis of the coding region and flanking intronic regions detects the common mutations in addition to rarer alleles that are not identified by targeted mutation analysis. Note: Exonic and multiexonic deletions are often not detected by sequence analysis and require deletion/duplication analysis.Table 1. Summary of Molecular Genetic Testing Used in 21-OHD CAHView in own windowGene SymbolTest MethodMutations Detected 1Mutation Detection Frequency by Test Method 2Test AvailabilityCYP21A2Targeted mutation analysisSee footnote 3~80%-98%Clinical Deletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletionsSequence analysisSequence variants 5>80%-98%1. See Molecular Genetics.2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Mutation panels vary by laboratory. Common mutations often included: c.293-13A>G; c.293-13C>G, p.Pro31Leu, p.Ile173Asn, exon 6 mutation cluster p.(Ile237Asn, Va238Glu, Met240Lys), p.Val282Leu, p.Leu308Phefs*6, p.Gln319X, p.Arg357Trp, p.Pro454Ser, p.Gly111Valfs*21, and the 30-kb chimeric pseudogene3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Interpretation of test resultsSequence analysis. For issues to consider in interpretation of sequence analysis results, click here.Targeted mutation analysis. Issues to consider in interpretation of targeted mutation analysis:A large-scale gene conversion (see Molecular Genetics) can replace a large segment of functional CYP21A2 sequence with a segment of the CYP21A1P pseudogene that is nonfunctional as a result of more than one deleterious mutation [Mao et al 2002]. Thus, when targeted mutation analysis detects multiple mutations, it is possible that the mutations are either in trans configuration (i.e., are on separate chromosomes, one inherited from each parent) or in cis configuration (i.e., are on the same chromosome and thus represent only one mutant allele rather than two; most likely arising from gene conversion). To avoid diagnostic errors, studying both parents as well as the proband is recommended to confirm the mutations and to determine if they are in cis configuration or trans configuration.Another potential cause of misdiagnosis is CYP21A2 duplication [Koppens et al 2002]. This could result in false positives during carrier screening of individuals who are not obligate carriers. A person carrying a functional gene and a duplicated copy with a mutation on the same chromosome may be incorrectly labeled a carrier. Such individuals may be identified by deletion/duplication analysis or haplotype analysis (research testing only).Testing StrategyTo confirm the diagnosis in newborns (after the first day of life) (a) with elevated 17-OHP concentration detected as positive newborn screening, (b) at risk for classic 21-OHD CAH, or (c) with ambiguous genitalia, the following are indicated:Complete historyComplete physical examinationUltrasound examination of the pelvis and adrenal glandsKaryotype or FISH for X- and Y-chromosome detectionMeasurement of serum concentration of 17-OHP and adrenal androgensMolecular genetic testing of CYP21A2 to confirm or exclude the diagnosis of 21-OHD CAH Note: (1) Marked elevation of 17-OHP concentration is usually adequate to confirm diagnosis of classic 21-OHD CAH presenting in the newborn period. (2) An ACTH stimulation test can also be performed to confirm the diagnosis; however, the relatively large volume of blood required often precludes use of this test. Measurement of plasma renin activity (PRA) and serum electrolyte concentrations while monitoring for signs and symptoms of adrenal crisisTo confirm the diagnosis in a proband with non-classic 21-OHD CAHA 60-minute ACTH stimulation test orA single early-morning (before 8 AM) measurement of plasma 17-OHP concentration (baseline values in affected individuals are not always elevated) andMolecular genetic testing of CYP21A2Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prognostication for an affected individual relies on genotype/phenotype correlation. If a genotype associated with salt wasting is identified, administration of salt-retaining hormone (9α-fludrohydrocortisone) and salt supplementation may avert a salt-wasting crisis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in CYP21A2.A contiguous gene syndrome involving CYP21A2 and TNX led to a combination of Ehler-Danlos syndrome, hypermobility type and 21-OHD CAH [Burch et al 1997, Schalkwijk et al 2001].
21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) occurs in a classic form and a non-classic form (Table 2)....
Natural History21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) occurs in a classic form and a non-classic form (Table 2).In classic 21-OHD CAH prenatal exposure to potent androgens such as testosterone and Δ4-androstenedione at critical stages of sexual development virilizes the external genitalia of genetic females, often resulting in genital ambiguity at birth. The classic form is further divided into the simple virilizing form (~25% of individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting CAH caused by 21-OHD CAH are at risk for life-threatening salt-wasting crises.Individuals with the non-classic form of 21-OHD CAH have only moderate enzyme deficiency and present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.Table 2. Clinical Features in Individuals with Classic and Non-Classic 21-OHD CAHView in own windowFeature21-OHD CAHClassicNon-ClassicPrenatal virilizationPresent in femalesAbsent Postnatal virilizationMales and femalesVariableSalt wasting~75% of all individualsAbsentCortisol deficiency ~100% RareClassic Simple Virilizing 21-OHD CAHExcess adrenal androgen production in utero results in genital virilization at birth in 46,XX females. In affected females, the excess androgens result in varying degrees of enlargement of the clitoris, fusion of the labioscrotal folds, and formation of a urogenital sinus. Because anti-müllerian hormone (AMH) is not secreted, the müllerian ducts develop normally into a uterus and fallopian tubes in affected females. It is not possible to distinguish between simple virilizing classic 21-OHD CAH and salt-wasting classic 21-OHD CAH based solely on the degree of virilization of an affected female at birth.After birth, both females and males with classic simple virilizing 21-OHD CAH who do not receive glucocorticoid replacement therapy develop signs of androgen excess including precocious development of pubic and axillary hair, acne, rapid linear growth, and advanced bone age. Untreated males have progressive penile enlargement and small testes. Untreated females have clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, and reduced fertility.The initial growth in the young child with untreated 21-OHD CAH is rapid; however, potential height is reduced and short adult stature results from premature epiphyseal fusion. Even if treatment with cortisol replacement therapy begins at an early age and secretion of excess adrenal androgens is controlled, individuals with 21-OHD CAH do not generally achieve the expected adult height. Bone age remains advanced compared to chronologic age.Pubertal development. In boys and girls with proper glucocorticoid therapy and suppression of excessive adrenal androgen production, onset of puberty usually occurs at the appropriate chronologic age. However, exceptions occur even among individuals in whom the disease is well controlled [Trinh et al 2007]. It should be noted that in some previously untreated children, the start of glucocorticoid replacement therapy triggers true precocious puberty. This central precocious puberty may occur when glucocorticoid treatment releases the hypothalamic pituitary axis from inhibition by estrogens derived from excess adrenal androgen secretion.Fertility. For most females who are adequately treated, menses are normal after menarche and pregnancy is possible [Lo et al 1999]. Overall fertility rates, however, are reported to be low. Reported reasons include inadequate vaginal introitus leading to unsatisfactory intercourse, pain with vaginal penetration [Gastaud et al 2007], elevated androgens leading to ovarian dysfunction, and psychosexual behaviors around gender identity and selection of sexual partner(s). Males. In males, the main cause of subfertility is the presence of testicular adrenal rest tumors (TART), which are thought to originate from aberrant adrenal tissue. In addition, hypogonadotrophic hypogonadism may result from suppression of LH secretion by the pituitary by excessive adrenal androgens and their aromatization products [Ogilvie et al 2006a].Adrenal medulla. In individuals with classic 21-OHD CAH, deficiency of cortisol also affects the development and functioning of the adrenal medulla, resulting in lower epinephrine and metanephrine concentrations than those found in unaffected individuals [Merke et al 2000].Classic salt-wasting 21-OHD CAH. When the loss of 21-hydroxylase function is severe, adrenal aldosterone secretion is insufficient for sodium reabsorption by the distal renal tubules, resulting in salt wasting as well as cortisol deficiency and androgen excess. Infants with renal salt wasting have poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatremia, and hyperkalemic metabolic acidosis progressing to adrenal crisis (azotemia, vascular collapse, shock, and death). Adrenal crisis can occur as early as age one to four weeks.Affected males who are not detected in a newborn screening program are at high risk for a salt-wasting adrenal crisis because their normal male genitalia do not alert medical professionals to their condition; they are often discharged from the hospital after birth without diagnosis and experience a salt-wasting crisis at home. Conversely, the ambiguous genitalia of females with the salt-wasting form usually prompts early diagnosis and treatment.Although an overt salt-wasting crisis classifies the child as a salt waster, some degree of aldosterone deficiency, determined by the adrenal capacity to produce aldosterone in response to renin stimulation, was found in all forms of 21-OHD CAH [Nimkarn et al 2007].Non-Classic 21-OHD CAHNon-classic 21-OHD CAH may present at any time postnatally, with symptoms of androgen excess including acne, premature development of pubic hair, accelerated growth, advanced bone age, and as in classic 21-OHD CAH, reduced adult stature as a result of premature epiphyseal fusion [New 2006]. The mildly reduced synthesis of cortisol observed in individuals with non-classic 21-OHD CAH is not clinically significant.Females with non-classic 21-OHD CAH. It is difficult to predict which affected women will show signs of virilization [Kashimada et al 2008].Females with non-classic 21-OHD CAH are born with normal genitalia; postnatal symptoms may include hirsutism, temporal baldness, delayed menarche, menstrual irregularities, and infertility. Approximately 60% of adult women with non-classic 21-OHD CAH have hirsutism only; approximately 10% have hirsutism and a menstrual disorder; and approximately 10% have a menstrual disorder only. Many women with non-classic 21-OHD CAH develop polycystic ovaries. The fertility rate among untreated women is reported to be 50% [Pang 1997]. Non-classic 21-OHD CAH was identified in 2.2% to 10% of women with hyper-androgenism [New 2006, Escobar-Morreale et al 2008, Fanta et al 2008]. Males with non-classic 21-OHD CAH. Little has been published about males with non-classic 21-OHD CAH. They may have early beard growth and an enlarged phallus with relatively small testes. Typically, they do not have impaired gonadal function; they tend to have normal sperm counts [New 2006]. Bilateral adrenocortical incidentoma was reported as the sole finding in an adult male with non-classic CAH [Nigawara et al 2008].Gender role behavior. Prenatal androgen exposure in females with classic forms of 21-OHD CAH has a virilizing effect on the external genitalia and childhood behavior. Changes in childhood play behavior correlated with reduced female gender satisfaction and reduced heterosexual interest in adulthood. Affected adult females are more likely to have gender dysphoria, and experience less heterosexual interest and reduced satisfaction with the assignment to the female sex. Prenatal androgen exposure correlates with a decrease in self-reported femininity by adult females, but not an increase in self-reported masculinity by adult females [Long et al 2004]. The rates of bisexual and homosexual orientation, which were increased in women with all forms of 21-OHD CAH, were found to correlate with the degree of prenatal androgenization. Bisexual/homosexual orientation was correlated with global measures of masculinization of nonsexual behavior and predicted independently by the degree of both prenatal androgenization and masculinization of childhood behavior [Meyer-Bahlburg et al 2008].In contrast, males with 21-OHD CAH do not show a general alteration in childhood play behavior, core gender identity, or sexual orientation [Hines et al 2004]. Pathogenesis. When the function of 21-hydroxylating cytochrome 450 is inadequate, the cortisol production pathway is blocked, leading to the accumulation of 17-hydroxyprogesterone (17-OHP). The excess 17-OHP is shunted into the intact androgen pathway where the 17,20-lyase enzyme converts the 17-OHP to Δ4-androstenedione, which is converted into androgens. Since the mineralocorticoid pathway requires minimal 21-hydroxylase activity, mineralocorticoid deficiency (salt wasting) is a feature of the most severe form of the disease.The lack of steroid product impairs the negative feedback control of adrenocorticotropin (ACTH) secretion from the pituitary, leading to chronic stimulation of the adrenal cortex by ACTH, resulting in adrenal hyperplasia.
In more than 95% of individuals with 21-OHD CAH, genotype can be used to predict disease severity. Salt-wasting, simple virilizing, or non-classical phenotypes can be predicted in an individual who undergoes molecular genetic testing. In general, an individual's phenotype correlates with the greatest degree of residual enzyme activity from a mutant allele (i.e., the expressed phenotype reflects the mutation with the less severe phenotypic effect of two alleles). ...
Genotype-Phenotype CorrelationsIn more than 95% of individuals with 21-OHD CAH, genotype can be used to predict disease severity. Salt-wasting, simple virilizing, or non-classical phenotypes can be predicted in an individual who undergoes molecular genetic testing. In general, an individual's phenotype correlates with the greatest degree of residual enzyme activity from a mutant allele (i.e., the expressed phenotype reflects the mutation with the less severe phenotypic effect of two alleles). However, for reasons that are not understood, genotype does not always predict phenotype either within mutation-identical groups [Krone et al 2000] or within the same family (i.e., sibs with 21-OHD CAH who have the same mutations can have different phenotypes). Alleles can be grouped as severe or mild, based on residual enzyme activity (Table 3). Salt-wasting 21-OHD CAH usually has the most severe mutations (e.g., homozygous deletions). Phenotypes with intermediate severity group are more variable within mutation groups than the phenotypes within severe or mild mutation groups [Krone et al 2000]. Non-classic 21-OHD CAH usually has one mild allele or both mild alleles [Wilson et al 1995]. In the context of prenatal diagnosis, it is important to distinguish classic and non-classic genotypes in order to determine the need to offer prenatal treatment. In families in which the proband is a virilized female, predicting the risk of genital virilization in subsequent affected female fetuses is feasible. In families in which the proband is a male, predicting the risk of genital virilization in subsequent affected female fetuses based on genotype is not possible. Classic 21-OHD CAH. The genotype for the classic form of 21-OHD CAH is predicted to be a severe mutation on both CYP21A2 alleles, with completely abolished enzyme activity determined by in vitro expression studies. Note: The point mutation c.293-13A>G or c.293-13C>G, one of the most frequent mutations in classic 21-OHD CAH, causes premature splicing of the intron and a shift in the translational reading frame. Although most individuals who are homozygous for this mutation have salt-wasting 21-OHD CAH, variation in severity of salt wasting is observed. This genotype-phenotype non-concordance can be explained by increased alternate splicing that can occur when the normal splicing is abolished by the splice site mutation, allowing some protein production but with variable activity [Higashi et al 1988].Non-classic 21-OHD CAH. Individuals with non-classic CAH are predicted to have two mild mutations or one mild and one severe mutation (i.e., to be compound heterozygotes). Approximately two-thirds of individuals with non-classic 21-OHD CAH are compound heterozygotes. Missense mutations p.Pro31Leu in exon 1 and p.Val282Leu in exon 7 reduce enzyme activity and are generally associated with this form of the disease. However, variation in the phenotype associated with one mild mutation can be observed: In a small number (<3%) of affected individuals with the p.Val282Leu or p.Pro31Leu mutation and a severe mutation, the classic phenotype was observed when a non-classic phenotype was expected. In a very small percent of affected individuals with the p.Ile173Asn mutation and a severe mutation, the non-classic phenotype (rather than the expected classic phenotype) was observed [Stikkelbroeck et al 2003].Table 3. Grouping of Common CYP21A2 Mutations by Residual Enzyme ActivityView in own windowEnzyme ActivityPhenotype CYP21A2 Mutation0%Severe (classic)Whole-gene deletion (null mutation) Large-gene conversion p.Gly111Valfs*21 p.[Ile237Asn; Val238Glu; Met240Lys] p.Leu308Phefs*6 p.Gln319X p.Arg357TrpMinimal residual activity (<1%)c.293-13A>G or c.293C>G2%-11%p.Ile173Asn~20%-50%Mild (non-classic)p.Pro31Leu p.Val282Leu p.Pro454SerFrom Krone et al [2000]
The production of cortisol in the zona fasciculata of the adrenal cortex occurs in five major enzyme-mediated steps. Congenital adrenal hyperplasia (CAH) results from deficiency in any one of these enzymes; impaired cortisol synthesis leads to chronic elevations of ACTH and overstimulation of the adrenal cortex resulting in hyperplasia. The five forms of CAH are summarized in Table 4. Impaired enzyme function at each step of adrenal cortisol biosynthesis leads to a unique combination of retained precursors and deficient products. The most common enzyme deficiency, accounting for more than 90% of all CAH, is 21-hydroxylase deficiency (21-OHD)....
Differential DiagnosisThe production of cortisol in the zona fasciculata of the adrenal cortex occurs in five major enzyme-mediated steps. Congenital adrenal hyperplasia (CAH) results from deficiency in any one of these enzymes; impaired cortisol synthesis leads to chronic elevations of ACTH and overstimulation of the adrenal cortex resulting in hyperplasia. The five forms of CAH are summarized in Table 4. Impaired enzyme function at each step of adrenal cortisol biosynthesis leads to a unique combination of retained precursors and deficient products. The most common enzyme deficiency, accounting for more than 90% of all CAH, is 21-hydroxylase deficiency (21-OHD).Table 4. Enzyme Deficiencies Resulting in CAHView in own window% of CAH Deficient Enzyme SubstrateProductAndrogenMineralo-corticoidUnknown 1Steroidogenic acute regulatory protein (STAR)--Mediates cholesterol transport across mitochondrial membrane Deficiency 2 Deficiency 3 Unknown 13β-hydroxysteroid dehydrogenase (3β-HSD) Pregnenolone, 17-OH pregnenolone, DHEAProgesterone, 17-OHP, Δ 4-androstenedioneDeficiency 2 Deficiency 3 Unknown 117α-hydroxylasePregnenolone17-OH pregnenoloneDeficiency 2Excess 4Progesterone17-OH (17-OHP)>90%21-hydroxylaseProgesteroneDeoxycorticosterone (DOC)Excess 5Deficiency 317-hydroxy progesterone11-deoxycortisol5%11β-hydroxylaseDeoxycorticosteroneCorticosteroneExcess 5Excess 41. Unknown because of rarity of disease 2. Males undervirilized at birth3. Associated with salt wasting4. Associated with hypertension5. Females virilized at birth or laterNon-classic 21-OHD CAH should be considered in females who present with any of the variable hyperandrogenic symptoms. A general occurrence rate of 1%-3% is reported in females with hyperandrogenism, but in certain populations the prevalence is much higher.Cytochrome P450 oxidoreductase deficiency. A rare form of CAH not included in Table 4 is cytochrome P450 oxidoreductase deficiency, caused by mutations in POR. Urinary steroid excretion indicates an apparent combined partial deficiency of the two steroidogenic enzymes P450C17 (17-hydroxylase) and P450C21 (21-hydroxylase). Of note, cytochrome P450 oxidoreductase is important in the electron transfer from NADPH to both enzymes.The phenotypic spectrum of cytochrome P450 oxidoreductase deficiency ranges from isolated steroid abnormalities to classic Antley-Bixler syndrome (ABS). Individuals with POR deficiency have cortisol deficiency, ranging from clinically insignificant to life threatening. Newborn males have ambiguous genitalia, including small penis and undescended testes; newborn females have vaginal atresia, fused labia minora, hypoplastic labia majora, and/or large clitoris. Craniofacial features of ABS, at the most severe end of the POR spectrum, can include craniosynostosis, choanal stenosis or atresia, stenotic external auditory canals, and hydrocephalus. Skeletal anomalies can include radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, camptodactyly, joint contractures, arachnodactyly, and clubfeet.Inheritance is autosomal recessive.
To establish the extent of disease in an individual diagnosed with 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH), the following evaluations are recommended:To assess for salt wastingPlasma renin activity (PRA) or direct renin assaySerum electrolytesTo distinguish classic and non-classic forms of 21-OHD CAHBaseline 17-OHP, Δ4-androstenedione, cortisol, and aldosteroneACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline levelTo assess the degree of prenatal virilization in femalesCareful physical examination of the external genitalia and its orificesVaginogram to assess the anatomy of urethra and vaginaTo assess the degree of postnatal virilization in both males and femalesBone maturation assessment by bone ageSerum concentration of adrenal androgens (unconjugated dehydroepiandrosterone [DHEA], Δ4-androstenedione, and testosterone)Treatment of ManifestationsIt is imperative to make the diagnosis of 21-OHD CAH as quickly as possible in order to initiate therapy and arrest the effects of cortisol deficiency and mineralocorticoid deficiency, if present.A multidisciplinary team of specialists in pediatric endocrinology, pediatric urology/surgery, medical genetics, and psychology is essential for the diagnosis and management of the individual with ambiguous genitalia [Hughes et al 2006].Classic 21-OHD CAH Glucocorticoid replacement therapy. The goal of glucocorticoid replacement therapy is to replace deficient steroids, minimize adrenal sex hormone and glucocorticoid excess, prevent virilization, optimize growth, and promote fertility [Clayton et al 2002].Treatment for CAH principally involves glucocorticoid replacement therapy, usually in the form of hydrocortisone (10-20 mg/m2 per 24 hours) given orally in two or three daily divided doses. Glucocorticoid therapy for children involves balancing suppression of adrenal androgen secretion against iatrogenic Cushing's syndrome in order to maintain a normal linear growth rate and normal bone maturation.Overtreatment with glucocorticosteroids can result in Cushingoid features and should be avoided. It often occurs when serum concentration of 17-OHP is reduced to the physiologic range for age. An acceptable range for serum concentration of 17-OHP in the treated individual is higher (100-1,000 ng/dL) than normal, providing androgens are maintained in an appropriate range for gender and pubertal status.During periods of stress (e.g., surgery, febrile illness, shock), all individuals with classic 21-OHD CAH require increased amounts of glucocorticoid. Typically, two to three times the normal dose is administered orally or by intramuscular injection when oral intake is not tolerated.Affected individuals should carry medical information regarding emergency steroid dosing.Individuals with classic 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (such as prednisone and dexamethasone) that tend to suppress growth in childhood can be used.Mineralocorticoid replacement therapy. Treatment with 9α-fludrohydrocortisone (Florinef®) (0.05-0.3 mg/day orally) and sodium chloride (1-3 g/day added to formula or foods) is necessary in individuals with the salt-wasting form of 21-OHD CAH.Sodium chloride supplementation may not be necessary after infancy; the amount of mineralocorticoid required daily may likewise decrease with age.Feminizing genitoplasty. Per the 2006 joint LWPES/ESPE (Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology) consensus statement [Lee et al 2006]: “Surgery should only be considered in cases of severe virilization (Prader III-V) and be performed in conjunction, when appropriate, with repair of the common urogenital sinus. Because orgasmic function and erectile sensation may be disturbed by clitoral surgery, the surgical procedure should be anatomically based to preserve erectile function and the innervation of the clitoris. Emphasis is on functional outcome rather than a strictly cosmetic appearance. It is generally felt that surgery that is performed for cosmetic reasons in the first year of life relieves parental distress and improves attachment between the child and the parents; the systematic evidence for this belief is lacking.”When necessary, vaginoplasty is usually performed in late adolescence because routine vaginal dilation is required to maintain a patent vagina.Precocious puberty. The true precocious puberty that may occur in 21-OHD CAH can be treated with analogs of luteinizing hormone-releasing hormone (LHRH).Testicular adrenal rest tumors. Response of testicular adrenal rest tumors to intensified glucocorticoid treatment may decrease the tumor size and improve testicular function [Bachelot et al 2008]. Testis-sparing surgery is considered in males who fail medical treatment, but the outcome has not been favorable, perhaps because of long-standing obstruction of the tubules [Claahsen-van der Grinten et al 2008]. Assistive reproductive technologies (ART) may also be considered to achieve fertility [Sugino et al 2006].Transition from adolescence to adulthood. Improved care for individuals with 21-OHD CAH has resulted in a good prognosis and normal life expectancy. In adults the goals of treatment shift away from preservation of normal growth, the main concern in children, to the preservation of fertility, healthy sexual function, and maintenance of general well being including bone health and the assessment of and management for risk of cardiovascular diseases. Optimal treatment of adults with CAH requires a multidisciplinary approach, including psychological support by specialists [Ogilvie et al 2006a]. The lack of evidence-based treatment protocols for adults [Kruse et al 2004] underscores the need for prospective studies to understand the natural history of 21-OHD CAH in adults [Bachelot et al 2008].Adrenalectomy. Bilateral adrenalectomy has been reported as a treatment of individuals with severe 21-OHD CAH who are homozygous for a null mutation and who have a history of poor control with hormone replacement therapy [Van Wyk et al 1996, Meyers & Grua 2000]. It is thought that these individuals may be more successfully treated as individuals with Addison disease; however, compliance with the medication regimen post-operatively is exceedingly important. Only small series of adults undergoing adrenalectomy have been reported (see review in Bachelot et al [2008]), the largest of which included five persons [Ogilvie et al 2006b]. The three main indications for adrenalectomy were: infertility, virilization, and obesity. Improvements in all three areas were noted in all reported cases. More long-term data are needed to determine the outcome of those undergoing adrenalectomy, since the potential increase in ACTH postoperatively can worsen adrenal rest tissues.Non-Classic 21-OHD CAHIndividuals with non-classic 21-OHD CAH do not always require treatment. Many are asymptomatic throughout their lives, or symptoms may develop during puberty, after puberty, or post partum.Traditionally, individuals with non-classic 21-OHD CAH have been treated with lower amounts of glucocorticoid than those required for individuals with classic 21-OHD CAH. Indications for treatment include bone age advancement, severe acne [Degitz et al 2003], hirsutism, menstrual irregularity, testicular masses, and infertility.Prevention of Primary ManifestationsSalt-wasting crisis. Newborn screening programs aim to identify infants with classic 21-OHD CAH and to initiate treatment prior to a potentially life-threatening salt-wasting crisis.See Treatment of Manifestations, Glucocorticoid replacement therapy and Mineralocorticoid replacement therapy.Prevention of Secondary ComplicationsShort stature. Short stature may result from glucocorticoid-induced growth suppression caused by over-treatment with glucocorticoids or from advanced skeletal maturation caused by inadequate glucocorticoid treatment. Injections of human growth hormone alone or in combination with gonadotropin-releasing hormone (GnRH) may be used both to improve linear growth in individuals with 21-OHD CAH who have significant growth failure [Quintos et al 2001] and to improve final height [Lin-Su et al 2005].SurveillanceThe following evaluations should be performed every three to four months when children are actively growing. Evaluation may be less often thereafter. The frequency of evaluation should vary depending on individual needs.Efficacy of glucocorticoid replacement therapy is monitored by measurement of the following:Early-morning serum concentrations of 17-OHP, Δ4-androstenedione, and testosterone approximately every three months during infancy and every three to six months thereafter. (In some instances, measurement of urinary pregnantriols and 17 ketosteroids in a 24-hour urine sample may help assess hormonal control. However, the process of urine collection makes it less practical than a simple blood draw.)Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excessBone age to assess osseous maturation (at 6- to 12-month intervals)Efficacy mineralocorticoid replacement therapy is monitored by measurement of the following:Blood pressureEarly morning plasma renin activity or direct renin assay in a controlled position (usually upright)Monitoring for testicular abnormalities in males. Periodic imaging of the testes either by ultrasonography or MRI should begin after puberty and be repeated every three to five years.Evaluation of Relatives at RiskIf prenatal testing for 21-OHD CAH has not been performed, it is appropriate to measure 17-OHP from newborn screening blood samples of at-risk sibs to facilitate early diagnosis and treatment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationFemale genital ambiguity. Through molecular genetic testing of fetal DNA, defects in 21-OHD CAH synthesis can be diagnosed in utero. Genital ambiguity in female fetuses may be reduced or eliminated by suppressing fetal androgen production through administration of dexamethasone to the mother beginning early in gestation and continuing until delivery. Prenatal treatment should continue to be considered experimental and should only be used within the context of a formal IRB-approved clinical trial. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherPregnant females with classic 21-OHD CAH. Pregnant females who have classic salt-wasting 21-OHD CAH need to be monitored closely by an endocrinologist. Maintenance doses of glucocorticoid and mineralocorticoid usually need to be increased because adrenal androgens tend to increase during pregnancy. Despite excess production of maternal adrenal androgens, the genitalia of their female fetuses may not be virilized [Lo et al 1999].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCYP21A26p21.33Steroid 21-hydroxylaseCYP21A2 @ Human Cytochrome P450 (CYP) Allele Nomenclature Committee CYP21A2 homepage - Mendelian genesCYP21A2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia (View All in OMIM) View in own window 201910ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCYNormal allelic variants. The functional gene for adrenal 21-hydroxylase, CYP21A2, is located approximately 30 kb from a nonfunctional pseudogene, CYP21A2P, on chromosome 6p in the human leukocyte antigen (HLA) gene cluster. CYP21A2 and CYP21A2P, the latter of which is inactive because of the presence of multiple deleterious mutations, share a high level of nucleotide sequence identity (98% between exons and 96% between introns). Both the functional gene and the pseudogene comprise ten exons. Five normal allelic variants of the functional gene CYP21A2 are given in Table 5.Pathologic allelic variants. CYP21A2 and CYP21A2P occur in a region of other repeated (duplicated) genes arranged in tandem. This arrangement facilitates recombination events between repeated sequences. Such recombination events are a major cause of CYP21A2 mutations that result in 21-OHD CAH. Recombination resulting from unequal crossing over during meiosis between the functional CYP21A2 homologs can result in gross CYP21A2 deletion or duplication. The high degree of sequence similarity between CYP21A2 and CYP21A2P facilitates gene conversion [Higashi et al 1988, Tusié-Luna & White 1995, Wedell 1998], a phenomenon whereby a segment of functional CYP21A2 is replaced by a segment copied from the CYP21A2P pseudogene. Therefore, the segment of the converted CYP21A2 has sequence variants typical of the pseudogene. These variants are pathologic and inactivate normal CYP21A2 expression and/or translation of normal protein. Small-scale gene conversions account for some of the common mutations, such as a combination of p.Pro31Leu, c.293-13A or C>G, and p.Gly111Valfs*21 on the same allele, detected by allele specific polymerase chain reaction method. Large-scale gene conversions also occur, some of which may require additional testing (see Molecular Genetic Testing, Interpretation of test results). Approximately 20% of mutant alleles are the result of meiotic recombination between repeated sequences that result in a 30-kb deletion that encompasses the 3' end of the CYP21A1P pseudogene, all of the adjacent C4B complement gene, and the 5' end of CYP21A2, thereby producing a nonfunctional chimeric pseudogene [White et al 1988].Another common mutation is c.293-13A>G or c.293-13C>G, occurring with a frequency of 20%-30%, leading to aberrant splicing and truncated small or unusual protein. Nine disease-causing mutations in the nonfunctional pseudogene inactivate the functional gene when transferred from CYP21A2P to CYP21A2 by gene conversion [Wedell 1998]. These nine mutations, together with CYP21A2 deletion and apparent large gene conversions, account for approximately 95% of all disease-causing CYP21 alleles [Wedell 1998].More than 100 mutations, including point mutations, small deletions, small insertions, and complex rearrangements of the gene, have been described to date. (For more information, see Table A.)Table 5. Selected CYP21A2 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference SequencesNormalc.25_27dupCTGp.Leu9dup 2NM_000500.5 NP_000491.2c.308G>Ap.Arg103Lys (p.Lys102Arg)c.552C>Gp.Asp184Glu (p.Asp183Glu)c.806G>Cp.Ser269Thr (p.Ser268Thr)c.1482C>Tp.Asn494Ser (p.Asn493Ser)Pathologicc.92C>Tp.Pro31Leu (p.Pro30Leu)c.293-13A>G (659A>G)--c.293-13C>G (659C>G)--c.332_339del (8-bp deletion in exon 3 or 707_714del)p.Gly111Valfs*21 (G110_Y112delfs)c.518T>Ap.Ile173Asn (p.Ile172Asn)c.[701T>A;713T>A;719T>A]p.[Ile237Asn; Val238Glu; Met240Lys] (I236N, V237E, M239K) (exon 6 mutation cluster)c.844G>Tp.Val282Leu (p.Val281Leu)c.844G>Cp.Val282Leu (p.Val281Leu)c.923dupT (Leu307insT)p.Leu308Phefs*6 (F306+T)c.955C>Tp.Gln319X (p.Gln318X)c.1069C>Tp.Arg357Trp (p.Arg356Trp)c.1360C>Tp.Pro454Ser (p.Pro453Ser) Entire gene deletion--Entire gene duplication--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions 2. White et al [1986], Higashi et al [1986]Normal gene product. The encoded protein is predicted to contain 494 amino acids with a molecular weight of 55 kd. The enzyme is at most 28% homologous to other cytochrome P450 enzymes.Abnormal gene product. Aberration of the gene product depends on the specific mutation. Approximately 20% of the mutations are meiotic recombinations deleting a 30-kb gene segment that encompasses the 3' end of the CYP21A1P pseudogene, all of the adjacent C4B complement gene, and the 5' end of CYP21A2, producing a nonfunctional chimeric pseudogene.