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Pediatric Endocrinology |
Departments of Obstetrics and Gynecology (E.S.K., B.A.C.-M., R.A.), Medicine (R.A.), and Pediatrics (R.D.C.), University of Alabama, Birmingham, Alabama 35233; and the Department d’Endocrinologie, Metabolismes, Nutrition, et Reproduction, Centre Hospitalier Regional et Universitaire de Lille (C.C.-R., D.D., R.A.), Lille, France
Address all correspondence and requests for reprints to: Ricardo Azziz, M.D., M.P.H., University of Alabama, 618 South 20th Street, OHB 549, Birmingham, Alabama 35233-7333.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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In conclusion, 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 our heterozygote population, we were unable to correlate the severity of the CYP21 mutation and/or the 17-OHP response to ACTH stimulation with the presence of the phenotype.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As expected from the prevalence of CAH and NCAH, the frequency of carriers (heterozygotes) in the population for 21-OH deficiency is quite common. Heterozygosity for 21-OH deficiency has been estimated to affect approximately 1 in 60 of the general non-Jewish Caucasian population (1), although it may affect as many as 1 in 3 of Askenazi Jews (10). Compared to normal individuals, carriers for 21-OH deficiency frequently demonstrate an exaggerated secretion of the 21-OH precursors 17-hydroxyprogesterone (17-OHP) and progesterone (P4) (11, 12, 13, 14, 15, 16, 17, 18) and 21-deoxycortisol (19), and lower levels of 11-deoxycorticosterone (11, 20) and aldosterone (20) after ACTH administration. In fact, between 50–80% of carriers demonstrate a 17-OHP level after ACTH stimulation that is above the 95th percentile of the control value (11, 12, 13, 14, 15, 16, 17, 18). These data suggest that adrenocortical dysfunction may be present in at least half of these individuals. Nonetheless, it is not known whether carriers for CYP21 mutations also demonstrate excess adrenal androgen secretion and, consequently, clinical hyperandrogenism. We now hypothesize that heterozygosity for CYP21 mutations in women increases the risk of developing hyperandrogenism, and that this risk is related to the severity of the mutation of CYP21 and/or the 17-OHP response to ACTH stimulation. To test these hypothesis we studied 38 obligate carriers for 21-OH deficiency for physical and historical signs and symptoms of hyperandrogenism (including 27 women hormonally) and compared them to 27 weight-, parity-, and age-matched controls.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Obligate carriers. Subjects were recruited from the patient populations of the University of Alabama at Birmingham (UAB; R. Azziz), the Children’s Hospital of Alabama (CHA; R. Cunningham), or the Centre Hospitalier Regional et Universitaire de Lille (CHRUL; C. Cortet-Rudelli and D. Dewailly). All were mothers of children with either CAH or NCAH and were presumed to be obligate carriers for CYP21 mutations. All women were premenopausal and had not taken hormonal medications for at least 3 months, excluding thyroid replacement (n = 1). Identification of these women was initially accomplished by a retrospective chart review of all children (i.e. probands) admitted to UAB, CHA, or CHRUL with the diagnosis of CAH or NCAH between 1967–1996.
The medical chart of all suspected probands was inspected, and only the mothers of children confirmed to be affected with 21-OH deficiency according to the following criteria were considered for further study: a) SW-CAH, mothers of children born with salt wasting, with or without virilization, and elevated levels of urinary pregnanetriol; b) SV-CAH, mothers of female children born with virilization or male infants with isosexual precocious puberty, no clinical evidence of salt-wasting, and elevated levels of urinary pregnanetriol and/or 17-OHP after acute iv ACTH stimulation (21); and 3) NCAH, mothers of children without virilization and 17-OHP levels above 45 nmol/L (15 ng/mL) after acute iv ACTH stimulation (3).
Sixty-six probands (i.e. children with 21-OH-deficient CAH or NCAH) were originally identified. Of these, the following mothers were excluded: 26 (39%) were not able to be located, declined to participate, or had expired (13 CAH and 11 NCAH), and 2 (3%) were adoptive mothers (1 CAH and 1 NCAH). The remaining 38 patients (carriers) were included in this study after giving written consent. None of the mothers had been previously diagnosed as suffering from CAH or NCAH themselves, and none of the obligate carriers studied was familiarly related. The study was approved by the institutional review boards of UAB, CHA, and CHRUL.
Controls. Twenty-seven healthy females volunteers were recruited as controls (controls) for the biochemical analysis portion of this study after giving informed consent. All were physically normal without evidence of hirsutism or acne and without a family history of endocrinopathy or genetic disorder. None was taking hormonal medications for at least 3 months before the study. All had regular menstrual cycles (every 26–32 days), and all were parous. Seven of these women had served as controls in another study (22).
Study protocol
All carriers and controls underwent a physical exam. Hirsutism scoring was performed, using a modification of the method of Ferriman-Gallwey (23), by two of the investigators (R.A. or D.D.). Height, weight, and hip and waist circumference measurements were obtained.
An acute ACTH stimulation was performed in all subjects, except those who were postmenopausal (n = 3) or receiving hormonal therapy (n = 8). The acute ACTH-(1–24) stimulation was begun between 0700–0900 h, after an overnight fast, in the supine position and in the early follicular phase of the menstrual cycle (cycle days 2–8). In the event the patient had undergone a hysterectomy but not an oophorectomy (n = 2), they were instructed to maintain a basal body temperature chart for 6 weeks to best predict the time of the follicular phase of the cycle. Furthermore, serum P4 was measured to confirm the absence of ovulation at the time of the test. The test was performed as described previously (24). In brief, an iv catheter was placed in the forearm, and the patient was allowed to rest for 30–45 min. Three blood samples for serum and plasma were obtained 15 min apart (-35, -20, and -5 min), after which 0.25 mg ACTH-(1–24) (Cortrosyn, Organon, West Orange, NJ) was administered iv over 60 s. A final blood sample was obtained 60 min later. The serum was separated and stored at -70 C until assayed. Before freezing, the three basal samples were mixed to form the 0 min sample. In addition, 40 cc of blood were obtained in ethylenediamine tetraacetate-containing tubes for DNA isolation (see below).
Hormonal analysis
Baseline samples (0 min) were assayed for total testosterone (T), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and P4 (when necessary). Androstenedione (A4) and 17-OHP were measured in both the 0 and 60 min samples, using methods previously described (25). To decrease the interassay variance, serum samples were batched for analysis.
DNA isolation and molecular analysis
DNA from each carrier was to be tested for the nine most common known mutations affecting the CYP21 gene, including exon 1 (P30L), intron 2 (A/C656G), exon 3 (8-bp deletion), exon 4 (I172N), exon 6 (3-bp change), exon 7 (V281L), exon 8318 (Q318X), and exon 8356 (R356W), using allele-specific PCR as previously described (26). Furthermore, the presence of large deletions was sought using restriction endonuclease analysis, Southern blotting, and laser densitometry (27). High mol wt DNA was first prepared from peripheral leukocytes using phenol and chloroform, as previously described (28). The DNA was then placed in 0.01 mol/L Tris and 0.001 mol/L ethylenediamine tetraacetate (Sigma Chemical Co., St. Louis, MO) and stored at 4 C until required.
For allele-specific PCR, each reaction contained either the normal or mutant-type primer used in conjunction with a common primer. The common primer (either exon 3 or 6) is specific to the CYP21 gene and not the pseudogene CYP21P (26). Homozygosity or heterozygosity for a mutation can be determined by amplification in either the normal or mutant (or both) reaction vials for that defect. Positive controls for all mutations were obtained from patients previously determined to be homozygous or heterozygous for the specific mutations by either allele-specific dot blot hybridization (26, 29) or allele-specific PCR (26). In brief, 200 ng genomic DNA were denatured for 10 min at 98 C. The master mix consisted of 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgCl2 (PCR buffer II), 200 µmol/L deoxy-NTPs, 2.5 U/100 µL AmpliTaq (Perkin-Elmer, Branchburg, NJ), and 0.3 µmol/L of the respective primers. The reaction mix was covered with mineral oil (Sigma Chemical Co.).
PCR protocols were previously described for all mutations (24), except exon 10 (P453S). As the detection of P453S using allele-specific PCR has not been previously described, it should be noted that we used the following primers (sequence from 5'-3'): 1) Ex10-normal, AGG-GCA-GGG-CGT-CCC-CGG-AGG-G; and 2) Ex10-mutant, AGG-GCA-GGG-CGT-CCC-CGG-AGG-A, both paired with normal exon 6 sense primer (generously provided by Dr. Robert Wilson of New York Hospital-Cornell Medical Center). The exon 10 amplification protocol consisted of 4 cycles of 94 C for 1 min, 60 C for 1.5 min, and 72 C for 10 min; followed by 30 cycles of 94 C for 1 min, 60 C for 1.5 min, and 72 C for 4 min; and a final cycle of 94 C for 1 min, 60 C for 1.5 min, and 72 C for 10 min. The amplified products were analyzed by electrophoresis (Bio-Rad, Hercules, CA) through a 0.8% agarose gel (Bethesda Research Laboratories, Gaithersburg, MD) with ethidium bromide.
The detection of large deletions of CYP21 was performed as follows. Ten micrograms of DNA were digested with the restriction endonuclease TaqI, which separates CYP21 and CYP21P into fragments of 3.2 and 3.7 kilobases (kb), respectively (27). The restriction endonuclease products were analyzed by electrophoresis on 1% agarose gels followed by Southern transfer to a positively charged nylon membrane (Boehringer Mannheim, Indianapolis, IN). Membranes were baked, prehybridized, and hybridized with labeled probe as previously described (30). Plasmid pC21/3c from the 10th International Histocompatibility Workshop was used as a hybridization probe. This plasmid had been isolated from a human fetal adrenal complementary DNA library, as previously reported (31). The probe was digoxin-labeled by random prime labeling (Genius System, Boehringer Mannheim, Indianapolis, IN) (30). Filters were washed, and the products were detected using the Genius System (Boehringer Mannheim). The filters were exposed for autoradiography, and the relative intensities of the 3.7- and 3.2-kb TaqI fragments were compared by laser densitometry.
Statistical analysis
A statistical software package was used to perform Student’s
t test on the continuous data and 
2 on the
discontinuous variables (Kiwkstat, TexasSoft, Cedar Hill, TX). Power
analysis was performed using PASS software (Jerry Hintze, Kayville,
UT).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the 38 carriers studied, 28 were mothers of SW-CAH, 5 were mothers of SV-CAH, and 5 were mothers of NCAH children. Thirty-four were Caucasian, 3 were African-American, and 1 patient was of Asian-Indian descent. Three carriers were postmenopausal (all CAH), and 8 were receiving hormonal therapy (5 CAH and 3 NCAH). Of the controls, 22 were Caucasian, 4 were African-American, and 1 was Asian.
Biochemical data
Only the 27 carriers who were premenopausal and not receiving
hormonal therapy underwent biochemical and acute ACTH testing and were
compared to controls. There was no significant difference in age,
gravidity, parity, body mass index, or waist/hip ratio between the 27
untreated premenopausal carriers and the controls (Table 1
). Carriers demonstrated higher mean baseline total and
free T levels and lower SHBG levels (Fig. 1) than
controls. Of the carriers, 14.8% (4 of 27) and 3% (1 of 27) had total
and free T levels above the 95th percentile of control values (2.5 and
0.03 nmol/L, respectively). There was no statistical difference between
the group means for DHEAS (Fig. 1), although 11.1% (3 of 27) of
carriers had DHEAS levels greater than 95% of controls (7.67
µmol/L). Of the carriers, 11.1% (3 of 27) and 3% (1 of 27) had
basal or post-ACTH stimulation levels greater than 95% of controls
(78.8 and 155.0 nmol/L, respectively). There was no difference in the
mean level of A4 at baseline or after ACTH stimulation or in the
incremental change between carriers and controls (Fig. 2).
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). As
expected, carriers had a higher mean 17-OHP-stimulated level and
increment than controls (Fig. 3). Studying the distribution of the
stimulated 17-OHP values at 60 min (Fig. 4), 7.4% (2 of
27), 48.1% (13 of 27), and 48.1% (13 of 27) of carriers had a basal,
stimulated, or net increment level, respectively, above the 95th
percentile of control values (3.62, 14.0, and 11.79 nmol/L,
respectively). In addition, three carriers (11.1%) had levels above
30.3 nmol/L (10 ng/mL), and one had a value exceeding 60.6 nmol/L (20
ng/mL). These levels are consistent with the diagnosis of NCAH (3). The
characteristics of these patients are listed in Table 2.
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DNA was available for 36 of 38 carriers for CYP21 genotyping
(Table 3). Of the carriers studied, 50.0% (18 of 36)
had a single mutation, 33% (12 of 36) had 2 mutations, and 16.7% (6
of 36) had three or more mutations. In 27.8% (10 of 36) of carriers,
the mutations were contiguous, consistent with a large gene conversion.
The frequency of mutations is as follows: exon 1, 16.7% (6 of 36);
intron 2, 44.4% (16 of 36); exon 3, 8.3% (3 of 36); exon 4, 16.7% (6
of 36); exon 6, 2.8% (1 of 36); exon 7, 8.3% (3 of 36); exon
8318, 36.1% (13 of 36); exon 8356, 27.8% (10
of 36); and exon 10, 2.8% (1 of 36). Sufficient DNA was available for
restriction analysis and Southern blotting in 26 of the carriers. All
demonstrated a normal CYP21/CYP21P ratio, indicating that none had a
large gene deletion. The extended family of 3 carriers (no. 2, 12, and
19) with 3 or more mutations was examined, and the defects were not
found in the mother (father deceased) of carrier 2 and were present in
the father, but not the mother of carrier 12. In carrier 19, we were
able to study her child and spouse. Her child had inherited all 3 of
the mother’s (carrier 19) mutations in addition to a gene deletion
from the father.
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). In this patient, her mother was
found to be genotypically normal, whereas her father was heterozygous
for the same mutations, confirming the heterozygous status of this
patient. The parents of another patient (no. 13) were both deceased,
and the parents of carrier 24 were not available. Clinical features of hyperandrogenism and prevalence of androgen excess among carriers
All carriers were examined for historical and physical features of hyperandrogenism. Hirsutism was defined as a Ferriman-Gallwey score of 6 or more, menstrual/ovulatory dysfunction was defined as a history of menstrual cycles of more than 35 days, and hyperandrogenemia was defined as a total or free T, A4, and/or DHEAS levels above the upper 95th percentile of control values (2.5 nmol/L, 0.03 nmol/L, 78.8 nmol/L, and 7.67 µmol/L, respectively). A total of eight carriers appeared to be clinically affected. One carrier had both oligomenorrhea and hyperandrogenemia, two had hirsutism and hyperandrogenemia, and one had hirsutism and oligomenorrhea. Three women demonstrated only oligomenorrhea, and one demonstrated only hirsutism (Ferriman-Gallwey score = 6), all with normal androgen levels.
Defining functional androgen excess (FAE) as the presence of at least
two of three hyperandrogenic features (i.e. hirsutism,
oligomenorrhea, and/or hyperandrogenemia), four (10.5%) of the
carriers appeared to be affected (95% confidence interval,
2.9–24.8%). Based on this confidence interval, if we assume that the
rate of FAE in the general population is 5%, 10%, or 20%, than the
prevalence of FAE among our carriers was not significantly higher than
expected (P > 0.05). As the exact rate of FAE in the
general population is not known, we used power analysis to determine
the number of obligate heterozygotes required to determine statistical
difference between the carrier group (FAE = 10.5%) and the
general population. Furthermore, if the true FAE rate in the general
population is 5%, 10%, or 20%, then approximately 160, 26,200, and
160 carriers, respectively, would be required to establish a
significant difference in the prevalence rate, at a ß of 0.20 and an
of 0.05, where represents a type 1 error (probability of
rejecting null hypothesis when it is true) and ß represents a type 2
error (probability of accepting the null hypothesis when it is not
true).
A brief discussion of power analysis is warranted. The power of the
statistical test is equal to 1 - ß. Variables that influence power
are sample size, sample variance, choice of hypothesis, and . The
actual size difference between the sample value (i.e.
carrier FAE = 10.5%) and the presumed general population value
(i.e. FAE = 5%, 10%, or 20%) has a bigger impact on
the power then all of the above. However, as sample and general
population values are fixed, the sample size must be increased to
determine significance. By increasing the number of carriers from 38 to
X (i.e. 160, 26,200, and 160 as described above
for 5%, 10%, and 20% FAE, respectively), the ß value is decreased
because the sample variance is decreased, and hence, the power is
increased. The sample size required to achieve statistical significance
is calculated by setting the selected (i.e. 0.05) and
ß (i.e. 0.20) and calculating the number required to
decrease the population variance until the and ß values are
met.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Nonetheless, our current data do not support the hypothesis that heterozygosity for CYP21 mutations is a risk factor for androgen excess. Defining FAE as the presence of at least two of three hyperandrogenic features (i.e. hirsutism, oligomenorrhea, and/or hyperandrogenemia), only 10.5% of carriers appeared to be affected. This criteria for FAE is consistent with those drawn up for the diagnosis of polycystic ovary syndrome at a recent NIH consensus conference (33). The frequency of FAE among our heterozygotes was compared to a range of expected prevalences for the disorder in the general Caucasian population. These prevalences (5–20%) are consistent with published reports denoting the frequency of hirsutism (34, 35, 36) or sonographically (37, 38, 39) or histopathologically (40) diagnosed polycystic ovaries in unselected populations. No statistical difference could be demonstrated between the observed and the expected frequency. Nonetheless, it should be noted that almost one third of carriers were either postmenopausal and/or receiving hormonal therapy, which could have resulted in an underestimation of the disease frequency. Nonetheless, an attempt was made to minimize the impact of this bias by using a history of menstrual cycles before menopause for possible inclusion. In addition, the obligate heterozygotic population examined consisted of parous women who may be less affected then nulliparous carriers of CYP21 mutations.
A closer review of our previous data also supports our present finding that CYP21 mutations do not increase the risk of hyperandrogenism (25). Firstly, although we did not genotype all hyperandrogenic patients, the frequency of CYP21 mutations encountered in our original study (i.e. 1 in 75) (25) was not significantly greater than that expected in the general population (1 in 60) (1). Secondly, the majority of our hyperandrogenic patients with CYP21 mutations in this study also demonstrated multiple and varied steroidogenic abnormalities, more consistent with a generalized adrenocortical hyperfunction than with a deficiency in 21-OH activity.
Although the prevalence of FAE among carriers did not appear to be higher than expected, there was some evidence to indicate that heterozygosity for CYP21 mutations does result in mild abnormalities of androgen biosynthesis. For example, carriers had higher mean total and free T levels than controls, consistent with the findings of other studies (24). Furthermore, mean circulating SHBG levels were lower among heterozygotes. Whether this is related to mild hyperinsulinism, as noted for NCAH patients (41), or to primary hyperandrogenism is presently not known. Although we did not detect a significant difference in the mean DHEAS levels between carriers and controls, others have noted such a finding (2). Consistent with previous reports (2), the mean pre- and poststimulation A4 levels were not different between the groups. Finally, and as expected, stimulated 17-OHP values were higher among carriers than controls, although 52% of both stimulated and net increment 17-OHP levels were within the normal range. These data confirm the insensitivity of a simple ACTH stimulation test for the detection of heterozygosity for 21-OH deficiency, as noted by others (11, 15).
All carriers had identifiable defects in the nine mutations examined, and no subject was homozygous for any single defect. Ten of 36 carriers (27.7%) probably had inherited a gene conversion based upon the finding of 2 or more sequential mutations, whereas another 50% had single mutations. Half of the carriers demonstrated two or more mutations. Examination of the extended family of three mothers (no. 2, 12, and 19) with 3 or more mutations confirmed that the mutations were all carried on 1 chromosome and that they were, in fact, carriers. Mutations of CYP21 in our obligate heterozygotes were most frequent in intron 2 (44.4%), exon 8318 (36.1%), exon 8356 (27.8%), exon 1 (16.7%), and exon 4 (16.7%). All others mutations occurred in less than 10% of patients. Although CYP21 mutation frequency rates have been reported for CAH and NCAH patients (3, 6, 8, 42), none of the previous reports have documented the frequency of defects among carriers. Nonetheless, our population has a higher rate of exon 8318 and exon 8356 mutations than a CAH population (6) studied. The incidence of intron 2 defects was similar to the frequency observed in a study of CAH patients (6) (44.4% and 41.6%, respectively), but higher than the findings of others in CAH (6, 8). Among our mothers of children with CAH or NCAH, 3 demonstrated 17-OHP simulated values suggestive of NCAH (i.e. >30.3 nmol/L). However, genotypic analysis of the parents of 1 of these women (no. 12) indicated that she actually was a carrier and not homozygous, at least for the 9 studied mutations. The parents of the other 2 individuals were not available for study. Nonetheless, our population of obligate heterozygotes may not be representative of the larger population, because all were parous and were obtained from centers in northeastern France and southeastern U.S.
In conclusion, it does not appear that heterozygosity for CYP21 mutations increases the risk of clinical androgen excess above that expected in the general population. Several reports have attempted to correlate genotype to phenotype in NCAH and CAH individuals (6, 8, 42). However, we were unable to correlate the severity of the CYP21 mutation and/or the 17-OHP response to ACTH stimulation with the presence of FAE in our heterozygote population because of their low frequency of clinically evident androgen excess.
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Acknowledgments |
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Footnotes |
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Received July 30, 1996.
Revised September 24, 1996.
Revised October 3, 1996.
Accepted October 8, 1996.
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