Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 315306, 315311, 418, 90794; DO: 0050811;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency | 201910 | Autosomal recessive | 3 | CYP21A2 | 613815 |
| 6p21.33 | Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency | 201910 | Autosomal recessive | 3 | CYP21A2 | 613815 |
A number sign (#) is used with this entry because this form of congenital adrenal hyperplasia is caused by homozygous or compound heterozygous mutation in the CYP21A2 gene (613815), encoding steroid 21-hydroxylase, on chromosome 6p21.
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.
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.
Reviews
Merke and Auchus (2020) reviewed the genetic and pathophysiologic features of CAH, as well as the current views regarding the diagnosis, treatment, and management of severe and mild forms of the disease.
Winqvist et al. (1992) demonstrated that 21-hydroxylase, which is prominent in the zona glomerulosa of the adrenal cortex, is a major autoantigen in idiopathic Addison disease (240200). This is another example of the way in which genetic disease can be mimicked by the development of autoantibodies against the gene product that is genetically deficient in the inherited disorder. Other examples are hemophilia A (306700), dystrophic epidermolysis bullosa (131750), hereditary angioedema (106100), and perhaps congenital myasthenia gravis (254210). All of these hereditary disorders appear to have an acquired mimic which is an autoimmune disorder.
Congenital adrenal hyperplasia-1 is an autosomal recessive disorder.
Spiro et al. (1999) reported the first case of maternal uniparental disomy for chromosome 6 ascertained through congenital adrenal hyperplasia, which arose because of reduction to homozygosity (or hemizygosity) of an autosomal recessive mutation. The mother was heterozygous for the I172N mutation (613815.0001); the father had no detectable mutations. DNA microsatellite analysis with polymorphic markers spanning the entire chromosome 6 indicated inheritance of a single maternal allele and absence of paternal alleles in the proband. The patient was born with intrauterine growth retardation, followed by catch-up growth.
Patients with 21-hydroxylase deficiency also show genetic linkage disequilibrium with complement allotypes. Different forms of 21-hydroxylase deficiency are associated with characteristic HLA haplotypes. Holler et al. (1985) studied HLA types and plasma 17-hydroxyprogesterone levels after ACTH stimulation in 134 German families of patients with salt-wasting (SW), simple virilizing (SV), or nonclassic (NC) late-onset CAH. Hormone evidence for CAH was found in 6 otherwise healthy relatives who, therefore, were thought to be NC cryptic cases. The SW form was strongly associated with HLA Bw47, whereas the SV form was associated with B5(w51). The almost complete association of the NC form with HLA B14 was confirmed. These alleles, especially Bw47 and B14, are components of normally rare haplotypes. Thus, all or almost all persons in the general population with 1 of these haplotypes will be heterozygotes.
Dupont et al. (1977) demonstrated close linkage of 21-hydroxylase deficiency and the HLA complex (lod score = 3.394 at a recombination fraction of 0.00). One patient had inherited a maternal recombinant between HLA-A and HLA-B. Studies in this family indicated that the abnormal gene is close to the HLA-B locus. Both the salt-losing and non-salt-losing forms of 21-hydroxylase deficiency show linkage to HLA, suggesting allelism. Murtaza et al. (1978) identified possible genetic compounds.
Levine et al. (1978) obtained a lod score of 9.5 with a 0.00 recombination fraction. In a study of 48 patients, 48 sibs and their parents, all patients were HLA-different from their unaffected sibs. When 2 or more children were affected in a sibship they were always HLA-B identical. In 34 unrelated patients no selective increase of a particular haplotype was observed, thus excluding association or linkage disequilibrium. Klouda et al. (1980) found a lod score of almost 9.0 for the linkage of HLA-B and 21-hydroxylase deficiency at a recombination fraction of 0.03. They pointed to the association of an excess of HLA-Bw47 with a deficiency of HLA-B8 persons. The workers concluded that the 21-hydroxylase locus 'lies outside the HLA system and is closely linked to the HLA-DR locus.' Fleischnick et al. (1983) demonstrated that extended MHC haplotypes are markers for different mutations causing 21-hydroxylase deficiency, just as the extended restriction nonalpha-globin haplotypes are markers for different beta-thalassemia mutations. In studying 29 families, more than 20% were found to have a very rare extended haplotype (taking into consideration complement loci and glyoxalase I as well). Furthermore, 3 other haplotypes were each found twice in unrelated patients concordant for their disease phenotype and ethnic background. Previously, striking linkage disequilibrium was noted; e.g., in Sheffield, England, the frequency of Bw47 was 27.3% in the patient population and 0.4% in the general European population. They commented on the fact that Klouda et al. (1980) as well as at least 1 other group placed CAH between D/DR and GLO1, whereas others place it between HLA-A and HLA-D/DR (Pucholt et al., 1980; Bias et al., 1981). Sobel et al. (1980) pointed out that heterozygotes can be detected by the linkage principle. They also reported the first instance of presumed recombination between AH3 and the HLA-B locus.
Presumably because of linkage disequilibrium, the common severe form of 21-hydroxylase deficiency is positively associated with Bw47 and negatively with B8, while the late-onset type is positively associated with B14 (reviewed by Petersen et al., 1982). HLA haplotyping was used to confirm the genetic compound nature of the cryptic form of 21-hydroxylase deficiency (Zachmann and Prader, 1979; Levine et al. (1980, 1981)).
Patients with the HLA-Bw47 antigen invariably show simultaneous deficiencies of 21-hydroxylase activity and the C4A (Rodgers) form of C4. The HLA-Bw47(w4) antigen is very similar serologically and otherwise to the more common antigen HLA-B13(w4). Therefore, it was proposed that a deletion or rearrangement simultaneously affected the B13 gene and the closely linked 21-hydroxylase locus. White et al. (1984) used a plasmid with bovine adrenal cDNA insert encoding part of the cytochrome P450 polypeptide to examine this hypothesis. The hybridization patterns of normal DNA and that from 21-hydroxylase-deficient persons were compared. One band from both EcoRI and TaqI digests was absent in DNA from a patient homozygous for HLA-Bw47. Of 6 unrelated patients homozygous for CAH and heterozygous for HLA-Bw47, 5 had a relative intensity of this band consistent with heterozygosity and one had complete absence. The deletion segregated with HLA-Bw47 in a large pedigree with 21-hydroxylase deficiency and HLA-Bw47. These authors referred to the structural gene for P450(C21). Close linkage of said gene and that for C4A is indicated by the occurrence of the null allele at that locus. Apparently only one of the two 21-hydroxylase genes is mutant. Several alternative explanations might be considered. The second gene may in fact be mutated also. The second gene may be regulated by the renin-angiotensin system and be involved in aldosterone synthesis in the zona glomerulosa. The second gene may be a pseudogene or may be expressed only at certain times in ontogeny or in other organs (the kidney and liver also contain 21-hydroxylase activity). In an addendum, White et al. (1984) stated that reexamination of the C4 allotypes associated with HLA-Bw47 led to the conclusion that the data are consistent with the P450(C21) gene being near the C4B (Chido) gene and both of those genes being deleted in the case of the HLA-Bw47 haplotype.
Speiser et al. (1985) studied the frequency of 21-hydroxylase deficiencies in several ethnic groups and showed that the gene for the nonclassic form is in linkage disequilibrium with HLA-B14. The classic form shows linkage disequilibrium with HLA-Bw47;DR7.
By analysis of data collected on 157 families ascertained through a proband with the classic form of 21-hydroxylase deficiency, Aston et al. (1988) could not arrive at a definitive conclusion as to whether the gene is closer to HLA-B or to HLA-DR. They pointed out the limitations of present methods of estimating genetic distance when recombination frequencies are of the order of 0.005.
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.
Jones (1978) found cases of mild 'adult' adrenal hyperplasia manifest by oligomenorrhea and treated like the usual form with adrenocorticosteroids.
Cutfield et al. (1983) described 2 male cousins with partial 21-hydroxylase deficiency presenting with bilateral testicular masses and infertility. In both cases, the testicular masses, consisting of adrenocorticotropic hormone-dependent pluripotential interstitial cells, were thought to play a major etiologic role in infertility. Nighttime (11 p.m.), low-dose dexamethasone therapy led to disappearance of the masses and restoration of fertility. Hydrocortisone, 10 mg 3 times daily, had failed to accomplish this reversal.
Cutler and Laue (1990) investigated the use of a new form of therapy which would combine hydrocortisone in strictly physiologic dosage with antiandrogen and aromatase-inhibitor therapy. By blocking androgen and the conversion of testosterone to estrogen, they hoped to achieve normal growth. The proposal, which remained to be tested, was suggested by the success of a similar program in the treatment of familial male precocious puberty (176410).
A multicentric study of prenatal treatment of 21-hydroxylase deficiency with dexamethasone administered by mouth to the mother was undertaken in France (Forest et al., 1989). Wudy et al. (1994) reported successful treatment of a single case with dexamethasone (0.5 mg, tid, p.o.) starting from the beginning of the eighth week of gestation.
Cornean et al. (1998) studied 22 prepubertal children with 21-hydroxylase deficiency whose steroid therapy was considered to be optimal in terms of linear growth and skeletal maturity. The authors reported a significant increase in body mass index (BMI) as a consequence of increased body fat. This was consistent with an early 'rebound' of BMI, which is associated with obesity in later childhood and an increased risk of long-term health problems related to adult obesity.
In children, CAH is often treated with cortisone acetate and fludrocortisone. Certain patients with CAH require very high substitution doses of cortisone acetate, and a few do not respond to cortisone acetate at all. Nordenstrom et al. (1999) reported a patient with 21-hydroxylase deficiency in whom elevated pregnanetriol levels in urine were not suppressed during treatment with cortisone acetate (65 mg per m2-day). The patient's lack of response to treatment with cortisone acetate was caused by a low conversion of cortisone to cortisol, assumed to be secondary to low 11-beta-hydroxysteroid dehydrogenase activity. These results supported the use of hydrocortisone, rather than cortisone acetate, for substitution therapy in adrenal insufficiency.
Travitz and Metzger (1999) discussed prenatal treatment of classic 21-OH forms of congenital adrenal hyperplasia. Dexamethasone (DEX) is a potent glucocorticoid that inhibits the adrenal cortex through feedback on the hypothalamus and pituitary. It is used for prenatal treatment because, compared with other glucocorticoids, it crosses the placenta more efficiently (approximately 50% reaches the fetal side), has a longer half-life (approximately 4 to 6 hours), and has a greater suppressive effect on ACTH. The arguments for and against prenatal DEX therapy were reviewed.
Lo et al. (1999) reported the pregnancy outcomes and serial measurements of maternal serum steroid levels in 4 women with classic 21OH deficiency, 3 of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to 4 healthy female newborns with normal female external genitalia, none of whom were affected with 21OH deficiency. In 3 women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (2 divided doses). The authors concluded that despite the high maternal serum concentration of androgens, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain.
Laue et al. (1996) reported better control of linear growth, weight gain, and bone maturation in a short-term crossover study of a 4-drug treatment regimen containing an antiandrogen (flutamide), an inhibitor of androgen-to-estrogen conversion (testolactone), reduced hydrocortisone dose, and fludrocortisone, compared to the effects of a control regimen of hydrocortisone and fludrocortisone. Merke et al. (2000) reported the results of a subsequent long-term randomized parallel study comparing these 2 treatment regimens. Twenty-eight children completed 2 years of follow-up. During 2 years of therapy, compared to children receiving hydrocortisone and fludrocortisone treatment, children receiving flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone had significantly higher plasma 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels. Despite elevated androgen levels, children receiving the new treatment regimen had normal linear growth rate and bone maturation. No significant adverse effects were observed after 2 years. The authors concluded that the regimen of flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone provides effective control of CAH with reduced risk of glucocorticoid excess.
In CAH due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. Charmandari et al. (2001) investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis. They found that the serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group compared with the prepubertal and postpubertal groups. The mean volume of distribution was also significantly higher in the pubertal than in the prepubertal patients but not in the postpubertal patients. In addition, the half-life of free cortisol was significantly shorter in females compared with males. Charmandari et al. (2001) concluded that puberty is associated with alteration in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. They also concluded that these alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.
In a multicenter retrospective chart review of 54 patients with salt-wasting 21-OHD CAH who were diagnosed in the first 6 months of life and had reached adult height, Muirhead et al. (2002) found that adult height was negatively correlated with androstenedione in infancy (p = 0.03) and childhood (p less than 0.01) and with testosterone in childhood (p = 0.01). They recommended that androgen levels be used in conjunction with growth velocity measurements to optimize glucocorticoid dosing in persons with 21-OHD CAH.
Bonfig et al. (2007) studied final height outcome and influences of steroid treatment in 125 patients (77 females) with CAH. They concluded that patients with CAH are able to achieve adequate FH with conventional therapy. Total pubertal growth is significantly decreased, and treatment with prednisone results in decreased FH.
The Joint LWPES/ESPE CAH Working Group (2002) published a consensus to address the best practice, management guidelines, and innovative therapies for CAH caused by 21-hydroxylase deficiency, including guidelines for neonatal diagnosis and treatment, clinical evaluation in term and premature neonates, newborn screening for CAH, prenatal diagnosis, and treatment and management in adolescence and adulthood.
Creighton et al. (2003) objected to the surgical management guidelines of the consensus statement of the Joint LWPES/ESPE CAH Working Group (2002) and stated that the only consensus attainable at that time would be that of a dedicated multidisciplinary team addressing an individual case including the full participation of the affected family.
Van Wyk and Ritzen (2003) summarized follow-up studies in 18 patients who underwent bilateral adrenalectomy for CAH, 3 of whom were young children with double null CYP21 mutations adrenalectomized prophylactically. Adrenal crises associated with severe illnesses occurred in 5 patients at times when their glucocorticoid substitution was suboptimal. All were responsive to appropriate therapy. Significant elevations of adrenal steroid precursors, presumably from ectopic adrenal rests, were observed postoperatively in 8 of the patients. In most patients, signs of androgen excess had decreased, and obesity became less of a problem with lowering the dose of glucocorticoid. The authors concluded that adrenalectomy is a safe and efficacious method of managing congenital adrenal hyperplasia in selected patients.
Dexamethasone administration to the pregnant woman is used for the prevention of genital masculinization in female fetuses with CAH. Although no somatic teratologic side effects had been found, animal research showed the adverse effects of glucocorticoids on brain structures such as the hippocampus, raising concerns about possible functional side effects of dexamethasone on human development. Meyer-Bahlburg et al. (2004) completed a survey of 487 children, 1 month to 12 years of age, focused on cognitive and motor development. The mothers of 174 prenatally dexamethasone-exposed children (including 48 with CAH) and 313 unexposed children (including 195 with CAH) completed 4 standardized developmental questionnaires about their children. None of the comparisons of prenatally dexamethasone-exposed children and unexposed controls was significant. With the methods used, the authors were unable to document any adverse effects of early-prenatal dexamethasone treatment, in the doses recommended for the treatment of pregnancies at risk for CAH, on motor and cognitive development.
Hirvikoski et al. (2007) studied the long-term effects on neuropsychologic functions and scholastic performance of dexamethasone (DEX) treatment in utero to prevent virilization of affected females. Prenatally treated children, 7 to 17 years old, were assessed with standardized neuropsychologic tests (A Developmental Neuropsychological Assessment and Wechsler Intelligence Scales for Children) and child-completed questionnaires measuring self-perceived scholastic competence. Short-term treated, CAH-unaffected children performed poorer than the control group on a test assessing verbal working memory (P = 0.003), and they rated lower on a questionnaire assessing self-perception of scholastic competence (P = 0.003). Hirvikoski et al. (2007) concluded that prenatal DEX treatment is associated with previously undescribed long-term effects on verbal working memory and on certain aspects of self-perception that could be related to poorer verbal working memory and that these findings may thus question future DEX treatment of congenital adrenal hyperplasia.
In an evaluation of bone mineral density (BMD) and bone metabolism in CAH patients, Sciannamblo et al. (2006) observed that CAH patients were shorter than controls and had whole-body BMD measurements that were significantly lower than those of controls after controlling for height. Serum concentrations of bone-specific alkaline phosphatase (see 171760) and C-terminal telopeptide of type I collagen (see 120150), indices of bone metabolism, were higher in CAH patients than in control subjects. Sciannamblo et al. (2006) concluded that young adult patients with the classical form of CAH have decreased bone density values compared with healthy controls and that this may put them at risk of developing osteoporosis early in life.
Falhammar et al. (2007) studied BMD, fracture prevalence, and markers of bone metabolism in adult females with CAH. Patients had lower BMD than controls at all measured sites. In patients less than 30 years old, 48% were osteopenic versus 12% in controls (p = 0.009). In patients 30 years or older, 73% were osteopenic or osteoporotic versus 21% in controls (p less than 0.001). BMD was similar in the 2 classical forms and had no obvious relationship to genotypes. More fractures were reported in patients than in controls (p less than 0.001). The number of vertebral and wrist fractures almost reached significance (p = 0.058). Falhammar et al. (2007) concluded that women with CAH have low BMD and increased fracture risk, and suggested that BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.
Nordenskjold et al. (2008) studied the outcome of feminizing surgery on 62 CAH women aged 18 to 63 years and 62 age-matched controls to correlate operative method and mutation status. Half of the CAH women claimed that the disease affected their sex life. They were less satisfied with their genitals, whether operated or not. Clitoris size and function were affected by the surgical method. Five women had a clinically evident vaginal stenosis on examination, and almost half of patients experienced a narrow vagina. The overall psychosexual aspects of life were affected in these patients with later sexual debut, fewer pregnancies and children, and an increased incidence of homosexuality, and these quality of life factors were correlated to the severity of the mutations. The authors concluded that the overall quality of life in adult women with CAH is affected both by the type of mutation and operative procedure; they suggested that indications for clitoroplasty should be restrictive, and medical, surgical, and psychological treatment should be centralized.
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 (259450), 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 (201910.0011; 201910.0012) in 45% of affected chromosomes, the intron 2 splice mutation (201910.0006) in 30.3%, R357W (201910.0003) in 9.8%, and I172N (201910.0001) 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.
Hannah-Shmouni et al. (2017) performed CYP21A2 genotyping in 200 unrelated healthy Ashkenazi Jewish subjects and 200 random US Caucasians who did not self-identify as a specific ethnicity. Nonclassic CAH carriership was found similarly in 15% (95% confidence interval (CI): 10.4-20.7) of Ashkenazi Jews and 9.5% (95% CI, 5.8-14.4) of Caucasians (p = 0.13). The proportion of Ashkenazi Jewish nonclassic CAH carriers (0.15 vs 0.309, p less than 0.0001) and disease-affected (0.005 vs 0.037, p = 0.009) was not as high as previously reported by Speiser et al. (1985). The estimated prevalence of nonclassic CAH in Caucasians was 1 in 200 (0.5%, 95% CI: 0.01-2.8). Hannah-Shmouni et al. (2017) concluded that a nonclassic CAH is a common condition, regardless of ethnicity, and should be considered with preconception and infertility counseling.
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.
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.
In the mouse, Chaplin et al. (1986) showed that only one of the two 21-hydroxylase genes is expressed. The authors presented the complete primary structure of both 21-hydroxylase encoding genes. The active gene in the mouse is referred to as A, whereas in man it is referred to as B. In the mouse, Chaplin et al. (1986) found a deletion of 215 nucleotides spanning the second exon in the 21-hydroxylase B gene; other nucleotide changes introduced frameshifts and premature termination codons. A hybrid gene composed of the 21-hydroxylase B promoter placed 5-prime of the 21-hydroxylase A structural sequences was efficiently transcribed following transfection into adrenocortical tumor cells. These findings demonstrated that the lack of expression was due to mutations within the 21-hydroxylase B structural gene and not due to a defect of the promoter. In the human, the CA21HA gene is a pseudogene and the nature of the gene deletions that prevent expression is different from that in the mouse. Specifically, the 21-hydroxylase A gene has an 8-base deletion within the third exon, introducing a premature termination codon (White et al., 1986; Higashi et al., 1986). See review by White et al. (1987) and White et al. (1987).
Gotoh et al. (1988) described deletion of the 21-hydroxylase gene in mice of a particular H-2 recombinant haplotype. They found, furthermore, that newborn homozygous mice are deficient in 21-hydroxylase activity and that homozygosity results in death at an early postnatal stage. Morphologic changes in the adrenal glands of newborn homozygotes were observed.
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