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Original Studies |
University Children’s Hospital, Ludwig Maximilians University, D-80337 Munich, Germany
Address all correspondence and requests for reprints to: Dr. Hans Peter Schwarz, University Children’s Hospital, Ludwig Maximilians University, Lindwurmstrasse 4, D-80337 Munich, Germany. E-mail: hp.schwarz{at}kk-i.med.uni-muenchen.de
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 21-hydroxylase gene (CYP21) is located in the human leukocyte antigen (HLA) gene cluster region on the short arm of chromosome 6 (6p21.3). The functional gene (CYP21) and a nonfunctional pseudogene (CYP21P) are located closely adjacent in tandem arrangement with the C4A and C4B genes encoding for the fourth component of the serum complement (1, 2, 4). The CYP21 and CYP21P genes consist of 10 exons and show a high homology, with a nucleotide identity of 98% in their exon and 96% in their intron sequences (5, 6).
In most cases, the 21OHD-causing mutations are generated by unequal crossing over or gene conversion events (7, 8). Complete gene deletions, large gene conversions, single point mutations, and an 8-bp deletion have been described (reviewed in Refs. 2, 9). Commonly, the CYP21-inactivating point mutations are transferred by microconversions from the CYP21P to the CYP21 gene (8). In only a few cases have unique point mutations or novel mutations been identified, which are not present in the pseudogene (2, 9, 10, 11, 12, 13).
About 65–75% of the CAH patients are compound heterozygous for disease-causing mutations. The clinical expression of CAH is reported to correlate with the less severely mutated allele and, consequently, with the residual activity of 21-hydroxylase (14, 15, 16, 17, 18). Some studies have already addressed the correlation between CYP21 genotype and clinical phenotype (14, 15, 17). In general, this correlation appears to be rather high, although divergence between genotype and phenotype occurs (16). No data are available from Germany, although a high frequency of CAH is likely to exist (1 in 8000; Roscher, A. A., unpublished data from recent newborn screening efforts). To understand the variance, it is of importance to define the exceptions to the rule. Theoretically this can best be achieved by a genotyping approach capable of detecting close to 100% of the mutations in a defined cohort. As we have recently devised such a strategy for CAH genotyping (10) and due to the availability of a clinically very well defined large patient cohort, we therefore set out to readdress the issue of genotype-phenotype correlation.
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Subjects and Methods |
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A total of 172 CAH patients from 155 families (310 unrelated alleles) were studied. Informed consent for mutation analysis was obtained from all patients or the parents. The CAH cohort of unrelated patients consisted of 142 German patients and 13 patients of other ethnic origin: 4 Serbian, 3 Turkish, 1 Roma, 1 Arab, 1 Italian, 1 Greek patient, 1 patient with a Chinese father and a German mother, and 1 with a Syrian father and a German mother. Ninety-two patients suffered from the salt-wasting (SW) form, 52 from simple virilizing (SV) CAH, and 11 from the nonclassical (NC) form.
The phenotype classification of CAH due to 21OHD was based on clinical and hormonal criteria. Those for the SW form were failure to thrive, vomiting, dehydration, hyponatremia, hyperkalemia, and ambiguous genitalia in females according to Prader genital stage (PGS). All patients had extremely elevated levels of 17-hydroxyprogesterone (17OHP) and PRA, pathognomonic for CAH due to 21OHD. Criteria for the SV form included ambiguous genitalia in females, sexual precocity, acceleration of height and bone age development, and elevated basal and stimulated 17OHP levels. NC CAH was defined as girls with normal genitalia or mild virilization, in both sexes diagnosed by precocious pubarche and adrenarche. All of these groups showed clearly elevated 17OHP levels 1 h after ACTH stimulation (0.25 mg/m2 Synacthen) (19). Serum androgen levels, PRA, and urinary pregnanetriol, pregnanetriolone, THE, and THS were used to control adequacy of glucocorticoid and mineralocorticoid substitution therapy and as an adjunct in initial diagnosis.
Hormone assays
Serum steroid hormones (17-OHP, cortisol, dehydroepiandrosterone sulfate, androstenedione, and testosterone) were determined by standard commercial RIA. Hormonal reference data were used according to the procedure described by New et al. (19) and Schnakenburg et al. (20). PRA was measured using an angiotensin I RIA kit from DiaSorin, Inc. (Saluggia, Italy).
Mutation analysis of the CYP21 gene
Comprehensive genotyping was performed as previously described by Krone et al. (10). In brief, gene deletions and large gene conversions were detected by nonradioactive Southern blotting of TaqI-, BglII-, and EcoRI/BglII-digested DNA hybridized with probes specific for the CYP21 and C4 genes. The CYP21 gene was amplified from TaqI-digested DNA resulting in a 3.5-kb PCR product. TaqI restriction digestion was performed before PCR to amplify exclusively the functional CYP21 gene. CYP21-inactivating point mutations and small deletions were detected by DNA sequencing with overlapping sequencing reactions covering all exons, introns, and the promoter region using the PE Applied Biosystems dye terminator cycle sequencing technique (Foster City, CA) with nested primers. The samples were separated on ABI PRISM 377 DNA sequencer and analyzed using ABI PRISM Sequence Navigator.
Categorization in mutation groups
The disease-causing mutations were divided into four mutation groups as previously described by Speiser et al. (14) and Wedell et al. (15).
The null group contained alleles with mutations resulting in an enzyme
with no activity (classical known mutations: gene deletion, large gene
conversion, 
8bp, E6 cluster, F306+t, Q318X, R356W). Group A
contained patients who were homozygous for the intron 2 splice site
mutation or were compound heterozygous with I2G and a null mutation
(I2G/I2G or I2G/null). The intron 2 splice site mutation is also known
to result in an enzyme with minimal residual activity. Patients
homozygous for a less severe I172N mutation or compound heterozygous
with mutations from null or I2G, respectively, were placed in group B
(I172N/I172N, I172N/I2G, I172N/null). The I172N mutation results in
about 2% of residual enzyme activity in in vitro expression
experiments. Group C contained patients who were homozygous for P30L,
V281L, and P453S or were compound heterozygous with more severe
mutations from other groups. These mutations result in a partial
decrease in enzyme activity. A fifth group included patients with
unique or novel mutations not yet tested for their influence on
in vitro enzyme activity. Furthermore, this group included
the only three patients in whom we have been unable to detect a
mutation in one or both CYP21 genes.
Genotypes categorized in groups null and A were predicted to result in SW CAH. Those in group B were expected to manifest as a SV phenotype, and those in group C as NC CAH. These assumptions were evaluated in the phenotypically categorized cohort with respect to their positive predictive value (ppv): ppvnull equals the number of SW patients in group null divided by the total number of patients with null genotype multiplied by 100. The positive predictive value for group A was: ppvA equals the number of SW patients in group A divided by the total number of patients with A genotype multiplied by 100. The ppv for group B was calculated as follows: ppvB equals the number of SV patients in group B divided by the total number of patients with the B genotype multiplied by 100. The ppv for group C was: ppvC equals the number of NC patients in group C divided by the total number of patients with the C genotype multiplied by 100.
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Results |
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Our cohort contained the full spectrum of known mutations generated by
the mechanism of unequal crossing over and apparent gene conversion
(Table 1
). Altogether gene deletions,
large gene conversions, the frequent intron 2 splice site mutation (I2
G), and the I172N mutation occurred in 77.4% of the mutated alleles.
Gene deletions were present in 63 alleles (20.3%), and large gene
conversions were present in 22 alleles (7.1%). Point mutations were
detected in 221 alleles (71.3%). The most frequent point mutation was
the intron 2 splice site mutation, which was found in a total of 94
alleles (30.3%). Other mutations frequently detected were the I172N
mutation (which was present in 61 alleles, 19.7%), the Q318X mutation
(4.8%), and the R356W mutation (4.5%).
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and 2 group D).
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In 27.75% of the cases a homozygous genotype was detected; 72.25% of
the patients were compound heterozygous. In Table 2 genotypes are
categorized according to their predicted functional consequence and
compared to the clinical phenotype. All 32 patients in the null
mutation group suffered from the SW form as predicted. In group A, 45
of 50 patients were congruent with the expected SW phenotype.
In group B (predicted as SV) a mixed distribution of phenotypes was found (37 with SV and 13 with SW CAH). A mixed result was also observed in group C (predicted as NC), in which 11 patients suffered from the NC CAH and 6 patients suffered from SV CAH. This diverse phenotypic expression in group C patients may be explained by the fact that all but 1 of the SV patients in this group were compound heterozygous for the P30L mutation and another more severe mutation (gene deletion, large gene conversion, intron 2 splice site mutation). The calculated ppv for the mutation groups were: ppvnull, 100%; ppvA, 90%; ppvB, 74%; and ppvC, 64.7%. However, when the ppv for group C was calculated after excluding the patients with the P30L mutation, the ppvC(V281L, P453S) was 90%. This finding would imply that prediction from in vitro expression experiments cannot always predict the clinical consequences in vivo.
The clinical characterization of female patients showed that, except
for group C and a tendency in group B, the various genotypes types had
little influence on the degree of virilization of the external
genitalia, as assessed by Prader genital stage (Table 3). The degree of virilization of the
external genitalia ranged in group null from PGS III–V (modal IV), in
group A from PGS II–V (modal IV), in group B from PGS II–V
(modal III), and in group C from PGS 0–IV (modal 0).
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). The 17OHP levels between groups null
and A were indistinguishable and reflected the severe 21OHD. In group
B, there was a tendency for lower 17OHP levels. However, there was
still marked overlap with the groups including the more severe
mutations. Patients with milder clinical symptoms included in group C
had the lowest basal and stimulated 17OHP levels.
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Discussion |
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The 10 previously described major mutations, which apparently are generated by recombination between the active CYP21 gene and the corresponding pseudogene (2, 8), were also found to dominate the mutation spectrum of our cohort. In addition, 5 unique or novel mutations that have not been reported in other populations to date were revealed. The diagnostic sensitivity of the method employed was 98.7%, as 306 of 310 alleles were found to carry disease-causing mutations. This figure is definitely higher than what has been reported in other large studies with sensitivities of CYP21 mutation detection of around 90–96% (14, 17, 21). The combination of methodological sensitivity (10) and homogeneity of the patient cohort may explain this finding.
Including gene deletions and large gene conversions, our finding attests to the fact that the overwhelming majority of mutations causing 21OHD are located within the CYP21 gene. Mutation frequencies of affected alleles were closely similar to those published in other large cohorts (9, 14, 15, 22). Most frequent was the intron 2 splice mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%), and large gene conversions (7.1%). As the NC form of CAH is underrepresented in retrospective studies, and most males may be missed, the V281L mutation was only detected in 2.9% of the total number of alleles, with a female preponderance.
Some alleles harbor more than 1 mutation. We found 5 such alleles, each with 2 disease-causing mutations, in 4 patients: I172N-F306+t (n = 3), I172N-R356W, and V281L-R356W. As these mutations are contiguous on the CYP21P gene, they must have been transferred to the CYP21 gene as a small conversion. No discontinuous, truly distinct, double mutation, such as mutations I2G and Q318X described by Wedell et al. (23), was detected in the present report. Two de novo mutations were found. One allele with a de novo mutation I172N was present on the maternal haplotype in a boy, but not in his mother; 1 de novo and at the same time unique mutation was on the paternal chromosome in a girl, but not in her father, with paternity assessed by HLA typing. De novo mutations have been supposed to arise from uniparental disomy (in the case of patient homozygosity), from germline mutation, or from mosaicism in the carrier gonad (24). De novo mutations are believed to account for about 1% of CYP21 mutations (14, 15). As not all parents of our CAH patients could be routinely phenotyped, we may not have identified all mutations that arose de novo. Five patients carried a novel or unique CYP21 mutation (not present in the pseudogene), which, except for L300F, was also present in 1 of the parents. Thus, novel mutations occurred in 3.2% of our patients, which is close to the frequency of 3.9% (5 of 127 patients) reported by Wedell et al. (15).
Interestingly, in two CAH patients, only one affected allele was identified, whereas the other allele did not carry a known or novel mutation. In the third patient, both alleles were unaffected (wild type). In all three patients hormonal parameters were concordant with 21OHD, and 11ß-hydroxylase deficiency was ruled out by undetectable urinary THS. Even direct DNA sequencing of the whole exon, intron, and the promoter region up to bp -450 of the CYP21 gene did not give any explanation for the lack of mutation detection in our patients. All three patients have CAH by clinical and hormonal definition. Wilson et al. (16) reports a family in which only one allele was found to have a mutation, and sequencing up to the -400 nucleotide CYP21 gene did not demonstrate an abnormality. Nimkarn et al. (25) reports a patient with phenotypical CAH but no disease-causing mutation in either the CYP21 or CYP11B1 allele. Mutations in the CYP21 promoter region have been identified (26). It has been suggested that in case of suspicion, CYP21 sequencing should extend to -2000 bases to detect any other mutations in the transcriptional regulatory region (16).
Generally, the allele harboring the less severe mutation determines the phenotype in CAH. There is a good relation in null mutations and in nonclassical mutations with the V281L haplotype. This is in concordance with previous studies (9, 14, 15). All of our patients with null mutations suffered from the SW form of CAH as predicted. All but one patient with the V281L mutation in group C had NC or late-onset CAH. The probability for patients in group A with the intron 2 splice site mutation to have the SW form was 90%. Expression studies of the intron 2 splice mutation did not reveal any clue to explain the 10% divergence in such phenotypic expression (27). Marked divergence between observed and predicted clinical phenotypes was observed in group B with the I172N mutation; 26% of patients had a SW phenotype, and 74% had a SV phenotype. Similar observations have been reported by others (14, 18). There is much more concordance between genotype and phenotype in group C as long as mutation P30L is excluded. Although in in vitro expression systems residual 21-hydroxylase activity in the P30L enzyme is as high as that in the V281L and P453S variants, this does not translate into a corresponding in vivo activity. Five of the six patients with the P30L mutation in group C clinically had SV, but not NC, CAH. To some extent, Prader genital stages in girls and, more typically, serum 17-OHP levels mirrored the severity of the genotype. Significantly different 17-OHP levels, depending on the genotype, have recently been reported from the Swedish CAH-screening program (28). The overall analysis of our data shows that the best relationship between genotype and phenotype occurs in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. In particular, a phenotype prediction is difficult in patients within group B, although 74% of the patients suffer from the predicted SV form. Furthermore, the P30L mutation has a special status in the group of mild mutation, resulting in a mild SV phenotype. We therefore propose that for prediction purposes group C should be divided into two subgroups: one including the P30L mutation, and the other containing the V281L and P453S mutations.
Divergence in phenotypes and a significant number of unrevealed alleles in 21OHD has been observed in all studies worldwide. Phenotypic variance may even be present in siblings (29), which suggests a role for modifiers of 21-hydroxylase transcription, translation, and action. As cases have been described with spontaneous partial recovery from CAH (30), factors apart from the CYP21 gene effect must play a role. The observed discordance between genotype and phenotype may be the result of either postulated extraadrenal hydroxylase activity or other factors that modify steroid synthesis or steroid action. Although some promoter elements important for CYP21 gene transcription are known, and regulatory proteins affecting 21-hydroxylase expression have been proposed (31, 32), much remains unexplained. Moreover, different receptor numbers or binding affinity for androgens, cortisol, or aldosterone may contribute to the phenotypic variability. Furthermore, the activity of transcription factors and the expression of transport proteins may be individually regulated.
In our opinion, phenotype prediction should be made with caution when prenatal diagnosis is concerned. Genotyping seems to be a useful complementary tool in newborn screening, especially in confirming or excluding the diagnosis of CAH in patients with slight to moderate elevations of 17-OHP levels (9).
In the present study with a large number of CAH patients, a good relationship between genotype and phenotype is shown in the groups of the severest and the mildest mutations. Mutations with intermediate severity resulted in phenotypes, with some overlap in the expressed clinical manifestation. Although the overall ppv is 83.9%, a strict and long term clinical observation is still mandatory in all patients with CAH even after hormonal and molecular diagnoses.
Received October 7, 1999.
Revised November 19, 1999.
Accepted November 19, 1999.
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