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Nonclassical 21-Hydroxylase Deficiency

Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Maria I. New, Director, Adrenal Steroid Disorders Program, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1198, New York, New York 10029. E-mail: maria.new{at}mssm.edu.

	Abstract

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
Context: Nonclassical congenital adrenal hyperplasia (CAH) owing to steroid 21-hydroxylase deficiency (NC21OHD) is the most frequent of all autosomal recessive genetic diseases, occurring in one in 100 persons in the heterogeneous New York City population. NC21OHD occurs with increased frequency in certain ethnic groups, such as Ashkenazi Jews, in whom one in 27 express the disease. NC21OHD is underdiagnosed in both male and female patients with hyperandrogenic symptoms because hormonal abnormalities in NC21OHD are only mild to moderate, not severe as in the classical form of CAH. Unlike classical CAH, NC21OHD is not associated with ambiguous genitalia of the newborn female.

Main Outcome Measures: The hyperandrogenic symptoms include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males.

Conclusions: The signs and symptoms of hyperandrogenism are reversed with dexamethasone treatment.

	Introduction

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
IN 1979 A MILD FORM of adrenal steroid 21-hydroxylase deficiency (21OHD) called nonclassical steroid 21-hydroxylase deficiency (NC21OHD) was reported (1). Although a varying clinical severity of congenital adrenal hyperplasia (CAH) had always been observed, this report defined the mild form of 21OHD CAH using specific hormonal and genetic criteria. In 1986 the gene for 21OHD was published (2), and the molecular genetic mutations specific for the nonclassical form of 21OHD were published (3, 4, 5). Over the past 20 yr, our team in New York City has followed more than 400 patients, aged 8 months to 69 yr, who presented with NC21OHD. The genotypes for probands and family members of more than 400 affected individuals have been obtained. This is by far the largest group studied with molecular genetic techniques. In this paper, the diagnosis and treatment of NC21OHD will be reviewed, and the high prevalence of this disorder will be discussed. A widely underdiagnosed disorder in children and adults, NC21OHD is a cause of a variety of hyperandrogenic symptoms that are readily treatable in both males and females.

	Classical and Nonclassical 21-Hydroxylase Deficiency

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
CAH refers to a family of inherited disorders in which defects occur in one of five enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, ACTH levels rise via a negative feedback system and stimulate adrenal hormone secretion, resulting in hyperplasia of the adrenal cortex. In 21OHD, responsible for 90–95% of CAH cases, there is an accumulation of the precursors immediately proximal to the 21-hydroxylation step in the pathway of cortisol synthesis, and these precursors are shunted into the androgen pathway (Fig. 1).

View larger version (23K): [in this window] [in a new window]   FIG. 1. Scheme of adrenal steroid synthesis.

The nonclassical form of 21OHD was discovered during studies of the family members of classically affected patients; some completely asymptomatic family members were discovered to have human lymphocyte antigen (HLA) genetic linkage markers, indicating the presence of mutations at the 21-hydroxylase locus. On hormonal evaluation, diminished 21OH activity was confirmed. All of these individuals later became symptomatic (7). Subsequently, the molecular genetic basis of NC21OHD was described (5) (Table 1).

	Clinical Description of NC21OHD

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

View larger version (43K): [in this window] [in a new window]   FIG. 2. Clinical spectrum of classical and nonclassical 21OHD.

In children, the presenting signs of NC21OHD include premature pubarche (14, 15, 16, 17), cystic acne (Fig. 3) (18, 19), accelerated growth (20), and advanced bone age (21, 22, 23, 24). In males and females, premature development of pubic hair may occur as early as 6 months of age (25). In one study, NC21OHD was found in 30% of children with premature pubarche (14), whereas a lower prevalence was reported by another group (26). Of 48 patients with premature pubarche screened in another study, four were found to have NC21OHD (17). Severe cystic acne refractory to oral antibiotics and retinoic acid has been associated with NC21OHD (27). Although patients with NC21OHD demonstrate excessive somatic growth and tall stature in early childhood (20), this growth is arrested because of early epiphyseal fusion, which compromises final height (21, 28, 29). Thus, patients are tall children but short adults. In our cohort, 31 of 45 (69%) children with a genetic and hormonal diagnosis of NC21OHD and bone age recorded at or before age 12 had a bone age advancement of 2 yr or more. Treatment for this problem with human GH and LHRH analog has recently been reported by Lin-Su et al. (56). In this report, the children with NC21OHD treated for advanced bone age with human GH and LHRH analog achieved their target height when treatment began before the bone age was 12 yr.

View larger version (125K): [in this window] [in a new window]   FIG. 3. Before and after treatment with dexamethasone (0.25 mg at the hour of sleep) for 3 months.

Women with NC21OHD can suffer from gonadal dysfunction and menstrual disorders including amenorrhea, anovulation, oligomenorrhea (7, 25, 36), and infertility (10, 37). Previous studies suggest that these irregularities may be due to the conversion of excess adrenal androgens to estrogens, which then disrupt gonadotropin secretion (38, 39). In one multicenter study by Speiser et al. (40), 26 women carrying one severe and one mild CYP21A2 mutation were said to be infertile. However, some of the women did not attempt to conceive and some may have conceived after treatment. In a recent study of 18 Croatian patients (10 males, eight females) with NC21OHD, all four women of reproductive age were fertile and all had conceived before treatment (41). Molecular genetic analysis of these women did not show correlation of fertility with genotype, although 50% were homozygous for the mild exon 7 mutation. Another study by Rumsby et al. (10) found that of six genetically characterized NC21OHD women, two had primary infertility, and four eventually succeeded in giving birth after experiences of miscarriage and other complications. In this small sample of six women, individuals with the exon 7 mutation in conjunction with a severe mutation presented with oligomenorrhea, whereas those homozygous for the exon 7 mutation had regular cycles and one was fertile. Thus, data from studies of small groups of patients with NC21OHD have been variable.

Some women with NC21OHD present with polycystic ovary syndrome (PCOS) (43, 44, 45). In these cases, adrenal sex steroid excess disrupts the cyclicity of gonadotropin release or directly affects the ovary, leading to the formation of ovarian cysts. These cysts may then autonomously produce androgens to compromise fertility. A 2003 consensus statement defined the diagnostic criteria of PCOS as the presence of two of the following three findings: 1) polycystic ovaries by sonography, 2) clinical or biochemical evidence of androgen excess, and 3) chronic menstrual abnormalities or anovulation, in addition to exclusion of other known disorders (46). NC21OHD also presents with hyperandrogenemia and anovulation, and thus should be ruled out in patients with PCOS. The frequency of NC21OHD in PCOS has not been determined in a large series. A study by Stikkelbroeck et al. (47) of 13 patients with CAH found that polycystic ovaries were no more frequent in female CAH patients than the general population; however, all patients had been treated since the diagnosis of CAH was made (11 of 13 had DNA confirmation of the diagnosis). The treatment may have resulted in a reversal of signs of PCOS. On the other hand, several studies have shown that CAH patients may exhibit ovarian adrenal rest tumors (48, 49) which, on ultrasound, may be difficult to differentiate from cystic ovarian tissue (50). A recent report from Montréal, Canada, by Dr. Geoffrey Hendy indicated that 10% of PCOS patients were proven to have NC21OHD (Hendy, G., personal communication).

It has been recognized that infertility of undetermined cause in women may be reversed with glucocorticoid therapy. In one report, five females with irregular menses and high 17-keto(oxo)steroids resumed regular menses and demonstrated adequate suppression of 17-ketosteroids and pregnanetriol within 2 months of beginning glucocorticoid therapy (51). This suggests the presence of an adrenal 21-hydroxylating defect, although no molecular genetic diagnosis was carried out (51). In another report of 18 infertile women with acne and/or facial hirsutism and hormonal criteria consistent with 21OHD (without molecular genetic confirmation of the disease), seven conceived shortly after initiating prednisone treatment alone; an additional four women conceived within 2 months of the addition of clomiphene to the therapeutic regimen (52). Hormonal profiles after initiation of therapy were not reported in this study.

Females with NC21OHD may present with hirsutism. In one study of 20 females with NC21OHD, 39% had isolated hirsutism (53). These studies did not include genetic analysis because they were published before the technique was available for diagnosis. Additionally, male-pattern baldness, classified by Ludwig scores (54), can be the sole presenting symptom of NC21OHD (Fig. 4).

View larger version (82K): [in this window] [in a new window]   FIG. 4. Male-pattern baldness typical of females affected with NC21OHD.

	Hormonal Features

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
The most definitive hormonal diagnostic test for 21OHD is an ACTH (Cortrosyn 0.25 mg) stimulation test, which measures the serum concentrations of 17-hydroxyprogesterone (17-OHP) at 0 and 60 min after ACTH administration. Test values may be plotted in a nomogram (Fig. 5), which reflects the different degrees of hormonal compromise in patients with classical and nonclassical 21OHD, and heterozygous carriers of a CYP21A2 mutation (57). As indicated by the nomogram, patients with NC21OHD typically aggregate midway down the regression line with 60-min stimulated 17-OHP values between 1,000 and 10,000 ng/dl.

View larger version (30K): [in this window] [in a new window]   FIG. 5. Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-OHP. The scales are logarithmic. A regression line for all data points is shown.

	Psychobiology of NC21OHD

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

	Molecular Genetics

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
Hormonally and clinically defined nonclassical and classical forms of CAH are associated with distinct genotypes (Table 1). These genotypes are characterized by varying levels of enzyme activity, as defined by in vitro expression studies (61, 62, 63).

The gene encoding 21-hydroxylase is a microsomal cytochrome P450 termed CYP21A2 (64) (Fig. 6) (previously P450c21) mapped to the short arm of chromosome 6 within the HLA complex (65).

View larger version (9K): [in this window] [in a new window]   FIG. 6. HLA region of chromosome 6p. 21B is the active gene, whereas 21A is the pseudogene. I, II, III, Major Histocompatibility Complex I, II, and III; DP, DP-antigen gene; DR, DR-antigen gene; DQ, DQ-antigen gene; C4, C4 complement genes; Bf, complement factor B gene; C2, C2 complement genes; B, B-antigen gene; C, C-antigen gene; A, A-antigen gene.

The CYP21A2 and CYP21A1P genes, which each contain 10 exons, share 98% sequence homology in exons and approximately 96% sequence homology in introns (Fig. 7). In a large percentage of the patients with NC21OHD, the exon 7 (V281L) mutation has been associated with a duplication of the pseudogene and the C4B gene (73, 74). This is especially common in patients with the HLA haplotype B14DR1.

View larger version (13K): [in this window] [in a new window]   FIG. 7. The two homologs: CYP21A2 (the active gene) and CYP21A1P (the pseudogene). Noncorrespondent bases number less than 90 over a distance of 5.1 kb of DNA. Numbered are the pseudogene base changes that are frequently identified on mutant CYP21A2 genes responsible for 21OHD. Mutations associated with NC21OHD are indicated with black squares (exons 1, 7, 8, and 10).

The genotype for the classical form of 21OHD is predicted to be a severe mutation on both alleles at the 21-hydroxylase locus, with markedly reduced enzymatic activity generally associated with salt wasting. The point mutation A (or C) to G near the end of intron 2, which is the single most frequent mutation in classical 21OHD, causes premature splicing of the intron and a shift in the translational reading frame (63, 76). Most patients who are homozygous for this mutation have low or absent serum aldosterone levels and the severe salt-wasting form of the disorder (77, 78). One mutation in exon 4 (I172N), specifically associated with simple-virilizing 21OHD (79), has been shown by in vitro expression studies to result in 1% of normal enzyme activity (79). Adrenal production of aldosterone is normally in the range of 1:100 to 1:1000 that of cortisol. The very low residual activity of the I172N mutation apparently is still able to allow aldosterone synthesis and thus prevent significant salt wasting in most cases of the simple-virilizing form of 21OHD.

In contrast to the classical form, patients with NC21OHD are predicted to have mild mutations on both alleles or one severe and one mild mutation of CYP21A2 (compound heterozygote). Missense mutations in exon 7 (V281L) and exon 1 (P30L), which are predominantly associated with nonclassical disease, reduce enzymatic activity in cultured cells to 20–50% of normal (80). Nonclassical patients have normal aldosterone secretion and therefore do not experience salt wasting. A recent report found that missense mutations in exon 8 (R339H) and exon 10 (P453S) are associated with the nonclassical phenotype as well (84) (Table 1).

	21OHD Genotype-Phenotype Correlations

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
In 98% of 21OHD patients, genotype corresponds with hormonal phenotype; however, rare cases of nonconcordance have important implications in prenatal diagnosis of 21OHD and genetic counseling (78). In our large cohort of 1502 patients with the genetically confirmed diagnosis of CAH, 440 patients have been assigned the clinical diagnosis of NC21OHD. In 438 of the 440 patients with NC21OHD, clinical phenotype correlated with nonclassical genotypes (homozygous mild/mild or heterozygous mild/severe), demonstrating a 99% concordance of hormonal phenotype with genotype. Of the 440 NC21OHD patients, 1% demonstrated genotype-phenotype nonconcordance. Nine individuals had a genotype indicative of classical 21OHD but did not have a classical phenotype: females did not have ambiguous genitalia and fell within the nonclassical range of stimulated 17-OHP values. However, the concordance of genotype with specific clinical signs of hyperandrogenism such as hirsutism, acne, or short stature has yet to be studied.

	Frequency of NC21OHD

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
Through studies of kindreds including a proband with classical or NC21OHD (82) and molecular screening of the 21-hydroxylase alleles of the heterogeneous population of New York City (83), the frequency of NC21OHD has been estimated to be 1:100, making it the most common of all autosomal recessive diseases, even more common than sickle cell anemia, Tay-Sachs, cystic fibrosis, and phenylketonuria (a disease for which newborn screening is mandated in every state in the United States) (Fig. 8). Screening for classical CAH is conducted in 48 states in the United States. The nonclassical form of CAH is not detected by hormonal screening. This would require DNA screening, which is not yet available.

View larger version (23K): [in this window] [in a new window]   FIG. 8. Disease frequencies in different ethnic groups.

A higher frequency of NC21OHD was reported in certain ethnic groups (82). The results of this study were supported by a subsequent study of a random population of 100 people (83), which confirmed the highest ethnic-specific frequency to occur in the Ashkenazi Jews at 1:27 (82). Interestingly, whereas the prevalence of NC21OHD in Ashkenazi Jews is high, there is no increased prevalence of the severe classical form of 21OHD in this population (82). Other ethnic groups with high disease frequency included Hispanics (1:40), Slavs (1:50), and Italo-Americans (1:300) (Table 3) (82, 83, 84, 85, 86). These data were based on small groups that have recently been studied in larger groups (Wilson, R., S. Nimkarn, M. Dumic, J. Obeid, M. Azar, H. Najmabadi, F. Saffari, M. New, unpublished data).

	Prenatal Diagnosis and Treatment of NC21OHD

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
We have made the prenatal diagnosis of NC21OHD in both males and females (Tables 5 and 6). The diagnosis was made by molecular genetic techniques, except for one female patient in which the diagnosis was made by HLA genotyping, as the patient was born in 1991 before routine molecular genetic testing was available. The genetic diagnosis was made on cells from amniocentesis and tissue from chorionic villus sampling (Fig. 9). In the newborn females, the genitalia were normal female whether or not dexamethasone treatment was administered to the mother according to the algorithm in Fig. 10. The treatment with dexamethasone was administered to the mother from the fourth to 10th week of gestation until term to four female fetuses. The male fetuses were partially treated from the first to 18th week of gestation. One male fetus was treated until term (Table 6) because the karyotype was initially reported erroneously as 46,XX and the genitalia on sonography showed a large phallic structure. The exon 7, 1, and 10 mutations have been associated with the nonclassical phenotype. The genotypes of the patients included an exon 7 (V281L) mutation in all female fetuses and in nine of the 10 male fetuses. The remaining male fetus had an exon 1 mutation. Two male fetuses were homozygous for the exon 7 mutation, whereas five female fetuses were homozygous for the exon 7 mutation. No fetuses carried the exon 10 mutation. The diagnosis was confirmed postnatally by hormonal tests.

View larger version (30K): [in this window] [in a new window]   FIG. 9. Prenatal genetic diagnosis and treatment of pregnancies for classical 21OHD. Diagnosis was made by cells from amniocentesis and tissue from chorionic villus sampling. DEX, Dexamethasone; CVS, chorionic villus sampling; Nl F, normal female. [From New et al. (92 ) with permission.]

View larger version (35K): [in this window] [in a new window]   FIG. 10. Algorithm for prenatal diagnosis and treatment of 21-OHD. The mother comes for prenatal diagnosis, and dexamethasone treatment is started blind to the sex or affection status of the fetus. Dexamethasone treatment would be terminated if the fetus has a male sex, is an unaffected female fetus, or is a nonclassical patient based on genotype. A female fetus with classical 21OHD is treated until term. hCG, Human chorionic gonadotropin; GA, gestational age.

	Treatment and Reversal of Signs

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

The preliminary results in 20 females (91) suggest that screening would be beneficial and cost-effective in infertility and dermatology clinics. Irregular menstruation and acne are reversed within 3 months of treatment with dexamethasone (0.25 mg at the hour of sleep each day) (Fig. 11), whereas hirsutism may be reversed within 30 months (91). More studies on the response of NC21OHD to treatment must be performed. Correlation of genotype with remission and/or recrudescence of signs in response to treatment also warrants further investigation.

View larger version (19K): [in this window] [in a new window]   FIG. 11. Reversibility of symptoms in patients with NC21OHD (n = 20). Preliminary data indicate that irregular menses and acne can be reversed with glucocorticoids within 3 months, whereas hirsutism requires nearly 30 months. [Adapted from Ref. 21 .]

Children with NC21OHD do not achieve a final height that is owed them by their parents because they frequently suffer an advanced bone age and arrest their growth early. Some are very short (24, 28). However, there is now treatment with human GH and/or LHRH analog to increase the final height so that children will achieve the target height predicted from the heights of the parents (56).

	Importance of Heightened Awareness of NC21OHD

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 
Signs of hyperandrogenemia are of great concern to the American population, as evidenced by the expenditures on acne, hirsutism, frontal balding, and infertility. Table 7 indicates the money spent annually on current treatments for various signs of hyperandrogenemia. NC21OHD could be more effectively and economically treated with low-cost glucocorticoid treatment. Recently, infertility has been treated by assisted reproductive techniques including in vitro fertilization and intracytoplasmic sperm injection. Generally, one cycle of in vitro fertilization costs $30,000 and patients often undergo more than one cycle, with the second cycle followed by intracytoplasmic sperm injection at $2,500 per injection. In properly diagnosed nonclassical patients, fertility could be restored through inexpensive oral treatment with glucocorticoids, rather than difficult and expensive interventions. NC21OHD should be suspected and diagnosed in patients with hyperandrogenism, especially patients in ethnic groups at high risk for NC21OHD.

In summary, NC21OHD is a widely underdiagnosed disease causing a variety of hyperandrogenic symptoms, which are easily treated with glucocorticoid therapy. The availability of DNA analysis may encourage populations at risk for NC21OHD to obtain diagnosis and treatment. In ethnic groups such as Ashkenazi Jews, in whom the disease has a high prevalence, the diagnosis of NC21OHD should be considered. Genotyping is currently available and facilitates the diagnosis of NC21OHD. Because this disease is frequent and treatment is easy and cost-effective, it behooves clinicians to suspect the diagnosis in patients with hyperandrogenic symptoms.

	Footnotes

 
This work was supported by National Institute of Child Health and Human Development Grant HD00072 and National Institutes of Health Grant RR19484.

Disclosure summary: the author has nothing to disclose.

First Published Online August 15, 2006

Abbreviations: C4, Fourth component; CAH, congenital adrenal hyperplasia; HLA, human lymphocyte antigen; NC21OHD, nonclassical steroid 21OHD; 21OHD, 21-hydroxylase deficiency; 17-OHP, 17-hydroxyprogesterone; PCOS, polycystic ovary syndrome.

Received July 28, 2006.

Accepted August 4, 2006.

	References

Top Abstract Introduction Classical and Nonclassical 21... Clinical Description of NC21OHD Hormonal Features Psychobiology of NC21OHD Molecular Genetics 21OHD Genotype-Phenotype... Frequency of NC21OHD Prenatal Diagnosis and Treatment... Treatment and Reversal of... Importance of Heightened... References

 

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