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Original Studies |
Department of Pediatrics, Kuopio University Hospital (J.J., R.V.), FIN-70211 Kuopio; and the Finnish Red Cross Blood Transfusion Service, Tissue Typing Laboratory (A.L., J.P.), FIN-00310 Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. J. Jääskeläinen, Department of Pediatrics, Kuopio University Hospital (J.J., R.V.), P.O. Box 1777, FIN-70211 Kuopio, Finland.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The most severe, salt-wasting (SW), form of 21-OHD results from total or near-total absence of functional 21-hydroxylase enzyme and is attributable to the most drastic mutations (deletions, conversions, and stop codons) in the CYP21 gene (7). Affected females with SW 21-OHD are born with ambiguous genitalia and are diagnosed mostly as newborns, whereas in boys, a SW crisis (hypovolemia, acidosis, hyponatremia, and hyperpotassemia) may be the first sign of the disease. This is not always detected, and a preponderance of affected females over affected males has been shown in virtually all prevalence studies (4). However, this has been reported to be a bias of ascertainment; the real ratio is about 1:1 (8). The simple virilizing (SV) form of the disease results from milder mutations (mainly substitutions) that leave residual enzyme activity, typically 1–2% of the normal (7). Females with SV 21-OHD present with virilization of external genitalia, but do not develop a SW crisis. Boys with this form are typically diagnosed later in childhood, when signs caused by excessive androgen secretion become prominent. Some of these patients also have deficient aldosterone synthesis, as evidenced by elevated PRA (4). The mild NC form of 21-OHD is associated with mutations resulting in 20–50% of the enzymatic activity (7). Females with NC 21-OHD are generally diagnosed at or after adolescence, when they present with hirsutism, acne, irregular menses, and infertility, whereas in genetically affected males this form is usually not recognized.
Although the overall correlation between the genotype and the clinical outcome appears to be rather good (9, 10, 11), some reports have indicated unexpected discrepancies, even in patients with apparently identical CYP21 genes (11, 12, 13, 14, 15, 16). To study this correlation further, we here describe the clinical expression of all 120 patients found to have 21-OHD in Finland in a genetically well defined and homogeneous population of about 5 million (17, 18). Due to a clear founder effect, only a limited number of different CYP21 mutation-haplotype combinations have been demonstrated in this population (19, 20). Consequently, additional genetic and environmental variation, which may have been one of the contributory causes of the discrepancies between genotype and phenotype in earlier reports, can be expected to be low.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients with 21-OHD were sought in all 5 university hospitals and 16 central hospitals that exist in Finland. Diagnosis registers and personal contacts were used to locate the patients. As the public health service in Finland is responsible for the diagnostics and initial treatment of such patients, we believe that our population sample corresponds well to all Finnish patients with 21-OHD. A total of 120 patients were found, and blood samples for the genotype determination could be obtained from 78 (65%) of these patients. As the sex ratio and clinical spectrum of 21-OHD in the genotyped group were analogous to those in the whole patient group, the genotyped patients well represented the total patient population.
Fifty (45 genotyped) patients were personally examined, and the documents for all patients were thoroughly scrutinized by one of the authors (J.J.). From the retrospective data, the age at diagnosis, prenatal virilization in females, symptoms and signs of mineralocorticoid deficiency, postnatal virilization in females, premature isosexual development in males, as well as acceleration of growth were recorded.
Mineralocorticoid deficiency was classified as severe, mild, or absent. It was considered severe if the patient developed signs of a SW crisis during his/her first 8 weeks of life (either hypovolemic shock, or serum Na+ <125 mmol/L, serum K+ >6 mmol/L, or serum Na+ <128 mmol/L with serum K+ >5 mmol/L). It was classified as mild if the patient still had high PRA after the initiation of glucocorticoid substitution, but had not had any signs of severe SW. The Prader classification (21) was used in the evaluation of prenatal virilization in females. There were some females who possibly had become virilized prenatally but were diagnosed only after infancy. For these females, virilization was considered to have occurred prenatally when there was labial fusion. If the female had only clitoromegaly, virilization was considered as postnatal. As the genitalia of a newborn boy with a classical form of 21-OHD may look normal, genital appearance was not evaluated in infant boys.
Genotyping of disease-causing mutations in CYP21
CYP21 mutations were determined essentially as described in our
recent report (20), in which a mutation/haplotype analysis of 59 of the
present patients and their family members was described. For the
remaining 19 patients, for whom no family members were available for
study, the mutation screening was as follows. A gene-specific PCR
amplification was first used to separate the highly homologous
functional CYP21 genes and CYP21P pseudogenes (and to detect homozygous
deletions/large conversions). Second, mutation-specific PCR, direct DNA
sequencing, and/or PCR/RFLP were employed to detect the presence of
each of the common pseudogene-derived mutations (7) as well as the more
rare P453S substitution, which has been reported in several different
ethnic populations (7). Patient samples, in whom none of the above
mutations was detected, were examined for further aberrations by
partial or complete (CYP21 coding sequence, exon-intron boundaries,
5'-promoter region) DNA sequence determination. The determination of
heterozygous large deletions or conversions in these 19 samples was
based on our previous data showing that only 2 major types of deletions
(recombination break-points between exons 3 and 4 or 7 and 8) and large
conversions (break-points between exons 3 and 4) are frequent in the
Finnish population (19, 20, 22). One of the deletions and both
conversions can be detected by an appropriate set of PCR primers (20)
and are designated del or conv in Table 1
. In cases in which no evidence for
these deletions/conversions was detected, the samples were designated,
for example, I172N/I172N or del or conv. In other words, homozygocity
could not be distinguished from hemizygocity.
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The patients were divided into five different genotype groups
(Table 1
) according to the predicted severity of the mutations. The
principle of the division was essentially as described by Wedell
et al. (10). In this classification, mutations causing a
complete loss of 21-OH activity constitute the group 0 (null). Category
A consists of patients carrying the I2 splice mutation, which has been
shown to result in low, but measurable, enzymatic activity (7), as the
determining allele. In addition, one patient with the combination of
I172N and P453S mutations in the determining allele was, with respect
to a recent study (23), considered to belong to this category. Category
B comprises the known I172N mutation as well as the rare allele R356Q
(20, 24), both of which result in approximately 1–2% of the normal
enzymatic activity. Category C consists of the V281L mutation, which
causes only a partial loss of activity and has been traditionally
associated with the NC or late-onset disease. Finally, category D
represents unique mutations, whose effect on enzymatic activity has not
yet been determined in vitro, or sequence aberrations that
have been unknown to date.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Blood samples for genotyping could be obtained from 78 (65%) of the
120 patients. The genotyped patients well represented the total patient
population with respect to their sex ratio and clinical subtypes. The
individual genotypes and general disease expression in different
genotype categories are presented in Table 1. More than half (40 of 78;
51.3%) of all genotyped patients fell into group B, i.e.
they had I172N as the determining mutation. Group B is followed by
group 0 (null), which had a frequency of 28.2% (22 of 78). It is of
note that only 5.1% (4 of 78) of the genotyped patients fell into
category C, i.e. they carried the typical NC allele
V281L.
The variability of clinical phenotype was low in categories 0 and A, which comprise the most drastic mutations. Patients were invariably diagnosed in early infancy; they suffered from severe mineralocorticoid deficiency, and all of the females presented with moderate or severe prenatal virilization. However, the age at diagnosis was slightly higher in a few cases. A boy with the I2 splice/Q318X genotype developed a SW crisis (Na+, 119 mmol/L; K+, 6,6 mmol/L; PRA, 97 µg/L·h; 17-OHP, 548 nmol/L) and was not diagnosed until 8 weeks of age. Another boy, who was a compound heterozygote carrying a 30-kilobase (kb) deletion and the I172N and P453S mutations presented with a SW crisis at the age of 4 weeks (Na+, 101 mmol/L; K+, 6.2 mmol/L).
Clinical expression varied in category B. Two thirds of the patients (26 of 40; 65%) had the presumed SV form of the disease, showing either absent or mild mineralocorticoid deficiency. As expected, most girls presented with ambiguous genitalia at birth and were diagnosed relatively early (median age, 2.0 yr), whereas boys presented with precocious isosexual development and were diagnosed later in childhood (median age, 4.5 yr). At one end of the phenotypic spectrum, however, there were evident salt wasters: for example, a boy with I172N/deletion genotype presented with a SW crisis at 4 weeks of age (Na+, 125 mmol/L; K+, 5.5 mmol/L; PRA, 112.3 µg/L·h; 17-OHP, 550 nmol/L). In addition, a girl with the mutations I172N/I2 splice had Prader 4 prenatal virilization and hyperpotassemia (7.5 mmol/L) at the age of 1 week, and another girl carrying the I172N/deletion genotype showed Prader 3 prenatal virilization and hyperpotassemia (6.2 mmol/L) at 3 weeks of age. At the other end of the continuum, this group included one female patient with a homozygous I172N mutation presenting with obvious NC 21-OHD. Homozygosity was confirmed by both mutational and haplotype analysis in the family. This patient was diagnosed at the age of 3.5 yr; she had no detectable clitoromegaly or labial fusion and has consistently had normal PRA without mineralocorticoid substitution or extra salt. Interestingly, she has a son with the identical genotype, but presenting with the SV disease.
The clinical variation in category B was studied in further
detail in selected patients. We have previously shown that as a result
of the founder effect, a limited number of different mutation-haplotype
combinations account for a substantial portion of the affected
chromosomes in Finnish patients with 21-OHD (19, 20). The most common
one, with a frequency of about 20%, carries the I172N mutation
together with haplotype markers A24 B40 S01 DRB110801. Eight patients,
of whom six were unrelated, had this combination on one chromosome and
a 30-kb CYP21 gene deletion on the other chromosome; their genotypes,
haplotypes, and clinical outcome are shown in Table 2. As the allele with a 30-kb gene
deletion is unable to produce any functional enzyme, all the functional
21-OH in these patients must come from the CYP21 gene associated with
the A24 B40 S01 DRB110801 haplotype. The entire CYP21 gene in one of
these patients has been sequenced previously and shown to carry only
the I172N mutation (20). We could not find any other sequence
aberrations when the patients’ CYP21 genes were screened for other
known mutations and when nucleotide sequencing, including the
5'-promoter region in three additional unrelated samples, was carried
out. Nevertheless, some variation in the clinical manifestation of
21-OHD in these patients with obviously identical CYP21 genes was
observed. For example, two girls (patients 1 and 2 in Table 2), were
both diagnosed as neonates, and they showed Prader stage 4 and 3
virilization, respectively. Patient 1, however, was classified as
having the SV form, whereas patient 2 presented with a clear SW form of
21-OHD. In the six male patients with verified testicular tissue, the
age at diagnosis varied considerably, from 3 weeks to 7 yr. Four of
them showed no signs of mineralocorticoid deficiency. However, patients
3 and 4 are early diagnosed brothers with identical HLA haplotypes and
CYP21 genes, but, interestingly, patient 3 presented with only mild
mineralocorticoid deficiency, whereas his brother presented with an
evident SW crisis at the age of 4 weeks.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As suggested by our previous report of Finnish girls with premature adrenarche (25), the prevalence of NC 21-OHD in Finland was considerably lower than that reported for other populations, where it may be even as high as 3.7% (6). The genuine number of NC patients is higher, as genetically affected males have not been diagnosed, but in women with any sign of hyperandrogenism this condition is actively sought.
Our present study agrees with the previous results of Speiser et al. (9) and Wedell et al. (10) in that the genotype-phenotype correlation in 21-OHD is generally rather good. In some other studies variation has been detected in patients with the I2 splice site mutation (11, 12, 13, 14, 15, 16), whereas all of our patients as well as those reported previously (9, 10) with I2 splice as the determining mutation presented with severe mineralocorticoid deficiency. On the other hand, we found that those patients with the I172N mutation revealed clinical variation. The I172N mutation is known to result in clearly reduced enzymatic activity, about 1–2% of that found in the wild type (7), and it is usually associated with the SV form (9, 10), although patients with the I172N/deletion genotype with the SW form have been reported (9, 11). In the present study, the severity of both mineralocorticoid deficiency and prenatal virilization in females varied excessively. Although we formally cannot rule out some additional mutations in CYP21 that might explain the observed clinical heterogeneity, their existence is unlikely, as DNA sequence analysis, including the 5'-promotor region, revealed no additional variation. In addition, in a subset of patients carrying the I172N mutation associated with a particular chromosomal haplotype, some phenotypic variation could be found, even between HLA-identical siblings. This variation could be due to the variable activity of other gene products that can influence masculinization and salt retention.
Regarding the discrepancies reported with the I2 splice mutation (11, 12, 13, 14, 15, 16), it is of interest that accurate analysis of this mutation requires exclusion of KCl from the PCR buffer; results obtained using a standard buffer were not reliable (20, 26). In addition to these technical difficulties in mutation detection, discrepancies in genotype-phenotype correlation may result from de novo conversions, more than one partially inactivating mutation on a single allele, or unique single-family mutations, whose frequency does not seem to be negligible (7, 10, 11, 23, 26).
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Acknowledgments |
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Footnotes |
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2 J.J. and A.L. contributed equally to this work.
Received December 9, 1996.
Revised April 4, 1997.
Accepted June 20, 1997.
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