| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Pediatric Endocrinology (N.M.M.L.S., B.J.O.), Human Genetics (E.A.S., I.J.d.W., L.H.H.), and Endocrinology (A.R.M.M.H.), University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands
Address all correspondence and requests for reprints to: Dr. Erik A. Sistermans, 120 Department of Human Genetics, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: e.sistermans{at}antrg.umcn.nl.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The CAH phenotype depends on the degree of enzyme deficiency: complete enzyme deficiency leads to prenatal virilization in females and life-threatening salt-wasting crisis in the neonatal phase in both sexes (classic salt-wasting form). Partial enzyme deficiency leads to the classic simple virilizing form, characterized by prenatal virilization in females and pseudoprecocious puberty in males and females. The mildest deficiency leads to nonclassic disease with pseudoprecocious puberty, hirsutism, acne, or subfertility (1).
The prevalence of classic 21-hydroxylase deficiency has been reported to be 1:10,000 to 1:18,000 (1); in The Netherlands, neonatal CAH screening revealed a prevalence of 1:12,000 (2). The prevalence of nonclassic 21-hydroxylase deficiency is estimated to be 1:1,700 in the general population (1, 3), but the diagnosis can be easily missed, because signs of androgen excess can be difficult to detect, especially in males.
The 21-hydroxylase gene (CYP21) is located on chromosome 6, close to the pseudogene (CYP21P). To date, deletion or conversion of the CYP21 gene, pseudogene-derived point mutations, and some other mutations of the CYP21 gene have been reported. As the disorder is autosomal recessive, the mildest of the two mutations is considered to determine the phenotype in compound heterozygosity; the genotype-phenotype correlation is reported to be 80–90% (4, 5, 6, 7).
Since CYP21 analysis has been made available in many countries, reports about CYP21 mutations in large national and international patient series have provided an insight into specific mutation distributions. This study analyzed CYP21 mutations and assessed their frequencies in a large Dutch population of 21-hydroxylase-deficient patients (370 unrelated alleles) and compared them with previous reports from other countries. In addition, genotype-phenotype correlation was studied in a subgroup of 87 well documented patients to provide more evidence for using genotype as a reliable predictive tool in clinical practice.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The results of CYP21 gene analysis in 198 patients with 21-hydroxylase deficiency from 184 independent families in The Netherlands were studied. All samples had been sent in for routine CYP21 mutation analysis to our clinical molecular genetics laboratory, which is the Dutch national reference center for CYP21 analysis. If samples from the parents were present, independent segregation of alleles was confirmed. The samples had usually been obtained after the diagnosis was suspected based on clinical and biochemical data. Besides the 198 study subjects in whom the diagnosis was genetically confirmed, there were individuals in whom CYP21 mutation analysis (including sequence analysis) did not confirm the suspected diagnosis (i.e. showed only 1 or no abnormal allele). As clinical and biochemical data for these individuals were not available, they were not included in this study.
Of the 198 patients in this study, extensive clinical and hormonal data were available from 87 patients (the majority of whom was treated in our hospital). In the other 111 genetically confirmed patients, these data were limited. Phenotype classification was made in the subgroup of the 87 well documented patients, based on clinical and hormonal criteria. The classic salt-wasting form was defined as salt-wasting crisis (dehydration, hyponatremia, and hyperkalemia), ambiguous external genitalia in females, elevated levels of serum 17-hydroxyprogesterone (17OHP), androstenedione, and plasma renin activity or plasma renin concentration. The classic simple virilizing form was defined as ambiguous external genitalia in females, no salt-wasting crisis, pseudoprecocious puberty, acceleration of growth, advanced bone age, and elevated levels of serum 17OHP (before and after stimulation with iv administered ACTH1–24 (Synacthen, Novartis Pharma B.V., Arnhem, The Netherlands). The nonclassic form was defined as pseudoprecocious puberty in both sexes with normal genitalia at birth in females, hirsutism or menstrual disorders, and mildly elevated levels of serum 17OHP (before and after stimulation). To better differentiate between classic simple virilizing and nonclassic disease in males, the age of onset of clinical symptoms was also considered, as suggested by White et al. (1); presentation before the age of 4 yr was considered an additional argument for the simple virilizing form, and presentation after the age of 4 yr was considered an additional argument for the nonclassic form.
Sample preparation and mutation analysis
DNA was extracted from white blood cells using a standard salt extraction method (8). To detect a deletion/conversion event in the CYP21 gene, Southern blotting was used as previously described (9). In short, Taq1-digested DNA was separated on a 0.7% agarose gel, blotted onto a nylon membrane (Genescreen, Dallas, TX), and hybridized with a radioactively labeled CYP21 probe. After autoradiography, the intensities of CYP21 (3.7-kb) and CYP21P (3.2-kb) fragments were compared using densitometry to determine the absence or presence of one or two deletions/conversions of the CYP21 allele. Hybridization with an anonymous control probe derived from chromosome 19 was used to correct for the differences in DNA loading of the gel.
For detection of mutation 
708–715, a 2.6-kb CYP21-specific fragment was generated with primers (reverse, 5'-AATTAAGCCTCAATCCTCTGCAGCG-3'; forward, 5'-GGGGCATATCTGGTGGGGAG-3') using PCR specific for the CYP21 gene as previously described (10). The generated fragment was used as a template in the subsequent secondary amplification using primers (forward, 5'-ACCCTCCAGCCCCCACCTCCTC-3'; reverse, 5'-CCGAGGTGGCCTCAGGAGCCC-3') surrounding the mutation, with a FAM-labeled reverse primer. The resulting fragments (210 bp for wild-type, 202 bp for mutated alleles) were analyzed on an automated sequencer (no. 310 or 3100, PE Applied Biosystems, Foster City, CA).
For detection of mutations P30L and 656A/C>G (I2G) a primary CYP21-specific fragment of 969 bp was generated with primers (forward, 5'-AGGTCAGGGTTGCATTTCCCTTCC-3'; reverse, 5'-CAGAGCAGGGAGTAGTCTC-3') using the expand high fidelity PCR system (Roche, Almere, The Netherlands). For mutation P30L, a secondary step with primers (forward, 5'-GAGCTATAAGTGGCACCTCAGGGC-3'; reverse, 5'-AGCAAGTGCAAGAAGCCCGGGGCAACTG-3') was followed by PstI digestion. The reverse primer introduces a PstI site in case the mutation is present (wild-type fragment, 164 bp; mutant, 133 and 31 bp). For mutation 656A/C>G (I2G), the secondary step consisted of three separate PCR reactions containing a forward primer specific for the A (forward, 5'-ACCCTCCAGCCCCCAA-3'), C (forward, 5'-ACCCTCCAGCCCCCAC-3'), or G (forward, 5'-ACCCTCCAGCCCCCAG-3') residue. All reactions contained the same reverse primer (reverse, 5'-CAGAGCAGGGAGTAGTCTC-3') and a control forward primer (forward, 5'-CGGAGGTGACGGAGAGGGTCCT-3') to check for the integrity of the reaction. Fragments were analyzed on a 2% agarose gel. Alternatively, the primary 969-bp fragment was sequenced (see below).
For detection of mutations I172N, the E6 cluster (I236N, V237E, and M239K), F281L, F306 + 1nt, Q318X, and R356W, a primary CYP21-specific fragment of 2048 bp was generated with primers (forward, 5'-GACCTGTCCTTGGGAGACTAC-3'; reverse, 5'-AAACTGAGGTACCCGGCTGGCATC-3'). Using this fragment as a template, mutation I172N was detected in two separate PCR reactions containing a reverse primer specific for the A (reverse, 5'-CCGAAGGTGAGGTAACAGA-3') or T (reverse, 5'-CCGAAGGTGAGGTAACAGT-3') residue. All reactions contained the same forward primer (forward, 5'-GACCTGTCCTTGGGAGACTAC-3') and a control reverse primer (reverse, 5'-CGGTAGCATCACTGGCTGTGG-3') to check for the integrity of the reaction. Fragments were analyzed on a 2% agarose gel (control fragment, 808 bp; test fragments, 328 bp). Detection of the E6 cluster (I236N, V237E, and M239K) was performed by secondary amplification on the 2048-bp fragment with primers (forward, 5'-CTGAACTGAAAGTACTCCCTCCTTTTC-3'; reverse, 5'-AGCCTTTTGCTTGTCCCCAGG-3'), followed by restriction digestion with DraIII (New England Biolabs, Inc., Beverly, MA). The wild-type fragment generates three fragments of 398, 291, and 27 bp, whereas the mutant allele generates two fragments of 398 and 318 bp. Fragments were analyzed on a 2% agarose gel.
Mutations V281L, Q318X, and R356W were detected on the same secondary fragment that was amplified from the 2048-bp fragment using primers (forward, 5'-CAGCCCGCTCCTTTCACCCTC-3'; reverse 5'-CACTCATCCCCAACCCTCGGG-3'). Mutation V281L was detected using digestion with BsaAI (New England Biolabs, Inc.; normal fragments, 501 and 131 bp; mutant 632 bp), mutation Q318X was detected by digestion with PstI (New England Biolabs; normal fragments, 298 and 192 bp; mutant, 490 bp; constant fragments, 121 and 21 bp), and mutation R356W was detected by digestion with AciI (New England Biolabs, Inc.; normal fragments, 189 and 30 bp; mutant fragment, 219 bp; constant fragments, 272, 56, 46, and 34 bp). Fragments were analyzed on a 3% agarose gel.
For detection of mutation F306 + 1nt, a secondary fragment generated with primers 5'-GCAGCCGAGCATGGAAGAGGG-3' (forward) and 5'-AGCCTTTTGCTTGTCCCCAGG-3' (reverse; FAM-labeled) on the 2048-bp fragment was analyzed using a PE Applied Biosystems 310/3100 automated sequencer. The wild-type fragments are 168 bp; the mutant fragments are 169 bp.
All other mutations were determined by sequence analysis of either the primary 969-bp fragment or the 2048-bp fragment, using the BigDye terminator kit (PE Applied Biosystems) in combination with primers chosen to cover the whole coding area, the intron-exon boundaries, and more than 90% of the intronic sequences.
Nucleotides were numbered as described by White et al. (1), beginning with the A in the initial ATG of the coding sequence including introns (11). In addition, nucleotides were numbered by cDNA according to the guidelines of the Nomenclature Working group, as described by Antonarakis et al. (12) (see Table 1
).
|
The classification of mutations previously described (4, 5, 7) was used to perform genotype and phenotype correlations. In this classification the disease-causing mutations were divided into four groups, based on the in vitro established residual enzyme activity and on the assumption that in compound heterozygotes, the mildest mutation determines the phenotype. Group null contained mutations that lead to a complete enzyme deficiency (Del/con, G1108nt, E6 cluster, F306 + 1nt, Q318X, R356W). Group A contained mutation I2G (which has some residual enzyme activity), homozygous or compound heterozygous with a null mutation. Group B contained mutation I172N (<10% residual enzyme activity), homozygous or compound heterozygous with a null or A mutation. Group C contained mutations P30L, V281L, and P453S (7–75% residual enzyme activity), homozygous or compound heterozygous with a null, A, or B mutation. Group D consisted of the remaining unclassified known mutations and new mutations.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
From 198 patients with 21-hydroxylase deficiency (184 independent families), 370 unrelated alleles were studied (Table 1
): 182 families had 2 independent alleles, and 2 families had 3 independent alleles each (Fig. 1). Homozygosity was found in 52 of the 184 unrelated patients (28.3%); compound heterozygosity was present in the other 132 unrelated patients (71.7%). Gene deletion/conversion was present in 118 of the 370 unrelated alleles (31.9%). The most frequent mutations were I2G (28.1%) and I172N (12.4%). The frequency of the common CYP21 mutations did not differ substantially from the frequencies reported in Western European countries (Table 2) (7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Clustering of pseudogene-derived mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele was found in 7 unrelated alleles (1.9%).
|
|
In one patient three affected alleles were found (Fig. 1B). Routine analysis for mutation I2G revealed three different alleles in her father. This was confirmed by quantitative Southern blot analysis; the father had three copies of both the normal and the pseudogene. In the paternal alleles two mutations were found (I2G and Q318X). The mother was the carrier of mutation I2G. The daughter had inherited the maternal mutated allele and two paternal alleles. As the daughter was affected, it was most likely that the two paternal mutations were on separate copies.
Sequencing of the CYP21 gene in patients in whom 1 common mutation had been found (7 independent families), revealed 6 mutations that have not been reported to date in CAH patients: 2 frameshift mutations in exon 4 (995–996insA) and in exon 5 (1123delC), 1 nonsense mutation in exon 9 Y376X (2254 C>A), and 3 missense mutations in exon 7 G291R (1715 G>C) and S301Y (1746C>A) and in exon 10 R483Q (2672 G>A). The new missense mutations in exons 7 and 10 were not found by sequencing in 92 and 100 control alleles, respectively.
Correlation between genotype and phenotype
The genotype-phenotype correlation is presented in Table 3 for the 87 well documented patients (46 males and 41 females). The 10 sibling pairs in this group (4 brother-brother pairs, 4 brother-sister pairs, and 2 sister-sister pairs) showed similar phenotypes.
|
In group A, 23 of the 24 patients (95.8%) had the salt-wasting form, and 1 patient was diagnosed with simple virilizing CAH. This patient had been detected by neonatal screening in 2001. He had only mildly elevated levels of serum 17OHP and androstenedione, and at the time of this study he still had a plasma renin concentration in the normal range, which did not require mineralocorticoid substitution. In group B, of the 17 patients 2 (11.8%) had the salt-wasting form, 10 (58.8%) had the simple virilizing form, and 5 (29.4%) had the nonclassic form. In group C, all 6 patients had the nonclassic form.
Group D contained the phenotypes of patients with two known (but as yet unclassified) mutations and the six new mutations. Among the patients with the new mutations, salt-wasting CAH was found in two sisters with mutation 1123delC (compound heterozygous with the cluster V281L-F3061nt-Q318X-R356W), in one patient with 995–996insA (compound heterozygous with deletion/conversion), and in one patient with Y376X (compound heterozygous with deletion/conversion). Simple virilizing CAH was found in one patient with G291R (compound heterozygous with I172N); she had presented at the age of 1.5 yr with the onset of virilization, and at the age of 45 yr, an elevated plasma renin concentration was found. Nonclassic CAH was found in three patients with S301Y (all compound heterozygous with I2G) from two unrelated families. In one family the girl had presented at the age of 15 yr with hirsutism and primary amenorrhea. In the other family the girl had presented at the age of 13.5 yr with hirsutism and clitoromegaly. After the diagnosis had been made, her brother (aged 15 yr) was also found to be affected. Retrospectively, he had early pubertal development and a relatively short final height. Nonclassic CAH was also diagnosed in one patient with R483Q (compound heterozygous with deletion/conversion). He had been detected by neonatal screening in 2000, and he had only slightly elevated levels of serum 17OHP and androstenedione (which decreased without treatment during the first year of life) and no salt loss or elevated plasma renin concentration at the time of this study.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Clustering of point mutations on one allele can occur in CYP21 gene mutations, as illustrated by the E6 cluster. In this Dutch population we have found a uniform clustering of 4 mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele in 1.9% of the unrelated alleles. All patients from the 7 families with this clustering of mutations on a single allele were compound heterozygous. The cluster has been reported previously by Koppens et al. (23) in 2 Dutch patients (2 of 75 unrelated alleles) and worldwide only once before by Wilson et al. (24) in 2 patients (2 of 394 unrelated alleles). This finding suggests that this particular cluster of 4 point mutations is rather specific for the Dutch population, and that it may have resulted from a common founder. Other clusters of 3 of these 4 point mutations in exons 7 and 8 have been previously reported: F3061nt-Q318X-R356W (4, 25, 26, 27, 28), V281L-Q318X-R356W (15, 29), V281L-F3061nt-R356W (29), and V281L-F3061nt-Q318X (30).
In the present study, six CYP21 mutations were found that had not been reported to date. Although no expression studies were performed, there is substantial theoretical support to suggest pathogenicity in all six new mutations. The two frameshift mutations in exons 4 and 5 and the nonsense mutation in exon 9 (premature stop codon) were likely to result in no residual 21-hydroxylase activity. This is supported by the observation that the four patients who were compound heterozygous with one of these mutations and a null mutation had classic salt-wasting 21-hydroxylase deficiency.
The three missense mutations fulfill the criteria outlined in the paper by Cotton et al. (31): they are nonconservative amino acid changes of conserved residues, and they are only found in patients and not in 100 control alleles. Missense mutation G291R (1715 G
C) leads to a nonconservative amino acid change in the enzyme region that is important for substrate binding (32). The previously reported mutations G291S (33) and G291C (25) have been associated with the salt-wasting phenotype and in vitro G291C allowed no residual enzyme activity (34). This suggests that G291R may also lead to severe enzyme impairment. Our patient was compound heterozygous (G291R-I172N) and had a simple virilizing phenotype. This does not provide additional arguments for the effect of G291R, because the phenotype is determined by the mildest mutation, which could be I172N in this case.
The missense mutations S301Y (1746 CA) and R483Q (2672 GA) also result in nonconservative amino acid changes. Three patients with S301Y (all compound heterozygous with an I2G mutation) had presented with nonclassic 21-hydroxylase deficiency. This suggests that the mutation S301Y is the mildest of the two mutations and causes only mild enzyme deficiency. The patient with the mutation R483Q was compound heterozygous, with a deletion/conversion, and after detection by neonatal screening he was diagnosed with nonclassic CAH. This phenotype suggests that R483Q allows some residual enzymatic activity. The known mutation R483P has been identified first by Wedell et al. (35), who suggested that it caused mild 21-hydroxylase deficiency. Barbat et al. (18), however, presented one patient with deletion/conversion and R483P with salt-wasting CAH.
Genotype and phenotype correlation showed high concordance in mutation groups null, A, and C. In group null, only 1 of the 29 patients did not have the expected salt-wasting phenotype, but had an unusual genotype-phenotype combination of homozygous deletion/conversion and simple virilizing. A case with homozygous deletion/conversion and nonclassic CAH has been described before by L’Allemand et al. (36). The patient they reported was found to have a novel CYP21P/21 hybrid gene characterized by a junction site before intron 2. It differed from the normal CYP21 gene only by the P30L mutation in exon 1 and the promoter region of the CYP21P pseudogene. The P30L results in an enzyme activity of 30–60%; the CYP21P promoter reduced the transcription to 20% of normal. In our patient this explanation could not be provided until now, and the discongruence between genotype and phenotype remains to be revealed.
In group A, 23 of 24 patients (96%) had the expected salt-wasting phenotype; this percentage is similar to the 90–100% previously reported by other researchers (5). One patient in group A had a simple virilizing phenotype. This patient was detected by neonatal screening, and at the time of the study, he was 5 months old and still had normal plasma renin levels. Clearly, there is no obvious salt wasting, but it cannot be excluded that subtle salt wasting will develop in the near future. This is, however, not self-evident, as shown by some researchers who reported that the phenotype varied from salt wasting to asymptomatic among individuals carrying the I2G mutation homozygously or with a null mutation (24, 37, 38).
In group B, eight of the nine male patients had the simple virilizing form, and one had the nonclassic form. In the female patients, two had salt wasting, two had simple virilizing, and four had nonclassic disease. This phenotypic variability is in accordance with previous reports showing that phenotypes in mutation group B are rather heterogeneous (6, 7). Salt wasting in this mutation group is relatively rare, although mild mineralocorticoid deficiency has been described even in homozygous I172N (6). Both patients in group B with salt-wasting CAH had I172N and a null mutation. Regarding the nonsalt-wasting patients in group B, we assume that a major cause of the reported phenotypic variability (simple virilizing or nonclassic) is the difficulty to designate a phenotype in nonsalt-wasting patients, especially in young patients. In boys, we used the age of presentation with pseudoprecocious puberty as an additional argument to differentiate, but the age of presentation might not give the real time of onset of clinical symptoms. Thus, in boys the distinction between simple virilizing and nonclassic CAH appears to be rather artificial. In girls, the presence of mild virilization at birth is an important criterion for simple virilizing vs. nonclassic, but sometimes it is unclear in retrospect whether mild virilization at birth was present.
In group C all patients had the nonclassic form. The absence of male patients in this mutation group may be explained by the fact that the symptoms in male patients with mild 21-hydroxylase deficiency may show overlap with physiological pubertal development or that patients may be asymptomatic. As a result, most reports on nonclassic patients focus on female patients (39) or contain only a male minority (40, 41).
Most reports about genotype and phenotype in 21-hydroxylase deficiency, including the present study, show a good correspondence between genotype and phenotype, especially in the mutation categories null, A, and C (1). Between the extremes, however, phenotypic variability can be observed, especially with the I172N mutation, which is the third most frequent mutation in our study. Phenotypic variability has also been observed in several other autosomal recessive disorders and has led to the recognition that simple Mendelian traits are, in fact, complex traits, influenced by additional, independently inherited genetic variations and/or environmental factors (42). This recognition implies that although genotype seems to be a good phenotype predictor in most cases of 21-hydroxylase deficiency, the predictive value of the CYP21 genotype can still be limited in some cases.
In conclusion, mutation analysis and genotype-phenotype correlation in a large population of 21-hydroxylase-deficient patients in The Netherlands showed, in general, high concordance with previous reports on CYP21 gene mutations in other Western European countries. However, a cluster of four pseudogene derived 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 six mutations were found that had not been described previously in 21-hydroxylase-deficient patients.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received October 28, 2002.
Accepted May 1, 2003.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  H. L. Claahsen-van der Grinten, B. J. Otten, F. C. G. J. Sweep, P. N. Span, H. A. Ross, E. J. H. Meuleman, and A. R. M. M. Hermus Testicular Tumors in Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Show Functional Features of Adrenocortical Tissue J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3674 - 3680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Scott, L. G. Gomes, N. Huang, G. Van Vliet, and W. L. Miller Apparent Manifesting Heterozygosity in P450 Oxidoreductase Deficiency and Its Effect on Coexisting 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2318 - 2322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Claahsen-van der Grinten, B. J. Otten, S. Takahashi, E. J. H. Meuleman, C. Hulsbergen-van de Kaa, F. C. G. J. Sweep, and A. R. M. M. Hermus Testicular Adrenal Rest Tumors in Adult Males with Congenital Adrenal Hyperplasia: Evaluation of Pituitary-Gonadal Function before and after Successful Testis-Sparing Surgery in Eight Patients J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 612 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Robins, J. Carlsson, M. Sunnerhagen, A. Wedell, and B. Persson Molecular Model of Human CYP21 Based on Mammalian CYP2C5: Structural Features Correlate with Clinical Severity of Mutations Causing Congenital Adrenal Hyperplasia Mol. Endocrinol., November 1, 2006; 20(11): 2946 - 2964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Moran, R. Azziz, N. Weintrob, S. F. Witchel, V. Rohmer, D. Dewailly, J. A. M. Marcondes, M. Pugeat, P. W. Speiser, D. Pignatelli, et al. Reproductive Outcome of Women with 21-Hydroxylase-Deficient Nonclassic Adrenal Hyperplasia J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3451 - 3456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Janner, A. V Pandey, P. E Mullis, and C. E Fluck Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein. Eur. J. Endocrinol., July 1, 2006; 155(1): 143 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Claahsen-van der Grinten, K. Noordam, G. F. Borm, and B. J. Otten Absence of Increased Height Velocity in the First Year of Life in Untreated Children with Simple Virilizing Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1205 - 1209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Grigorescu Sido, M. M. Weber, P. Grigorescu Sido, S. Clausmeyer, U. Heinrich, and E. Schulze 21-Hydroxylase and 11{beta}-Hydroxylase Mutations in Romanian Patients with Classic Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5769 - 5773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V Dolz;an, J Solyom, G Fekete, J Kovacs, V Rakosnikova, F Votava, J Lebl, Z Pribilincova, S. Baumgartner-Parzer, S Riedl, et al. Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia Eur. J. Endocrinol., July 1, 2005; 153(1): 99 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Riepe, S. Tatzel, W. G. Sippell, J. Pleiss, and N. Krone Congenital Adrenal Hyperplasia: The Molecular Basis of 21-Hydroxylase Deficiency in H-2aw18 Mice Endocrinology, June 1, 2005; 146(6): 2563 - 2574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Robins, M. Barbaro, S. Lajic, and A. Wedell Not All Amino Acid Substitutions of the Common Cluster E6 Mutation in CYP21 Cause Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2148 - 2153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Forest Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency Hum. Reprod. Update, November 1, 2004; 10(6): 469 - 485. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
