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CYP21 Gene Mutation Analysis in 198 Patients with 21-Hydroxylase Deficiency in The Netherlands: Six Novel Mutations and a Specific Cluster of Four Mutations
Open accessAbstract
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. The aim of this study was to assess the frequencies of CYP21 mutations and to study genotype-phenotype correlation in a large population of Dutch 21-hydroxylase deficient patients. From 198 patients with 21-hydroxylase deficiency, 370 unrelated alleles were studied. Gene deletion/conversion was present in 118 of the 370 alleles (31.9%). The most frequent point mutations were I2G (28.1%) and I172N (12.4%). Clustering of pseudogene-derived mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele was found in seven unrelated alleles (1.9%). This cluster had been reported before in two other Dutch patients and in two patients in a study from New York, but not in other series worldwide. Six novel mutations were found: 995-996insA, 1123delC, G291R, S301Y, Y376X, and R483Q. Genotype-phenotype correlation (in 87 well documented patients) showed that 28 of 29 (97%) patients with two null mutations and 23 of 24 (96%) patients with mutation I2G (homozygous or heterozygous with a null mutation) had classic salt wasting. Patients with mutation I172N (homozygous or heterozygous with a null or I2G mutation) had salt wasting (2 of 17, 12%), simple virilizing (10 of 17, 59%), or nonclassic CAH (5 of 17, 29%). All six patients with mutation P30L, V281L, or P453S (homozygous or compound heterozygous) had nonclassic CAH. The frequency of CYP21 mutations and the genotype-phenotype correlation in 21-hydroxylase deficient patients in The Netherlands show in general high concordance with previous reports from other Western European countries. However, a cluster of four pseudogene-derived point 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 novel CYP21 gene mutations were found.
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“In both American(195,223) and German (201) data, median (interquartile range) Prader virilization scores (Figure4) for females in Groups 0, A, B and C are 4 (3-5), 4 (3-5), 3 (2-4) and 0 (0-2) respectively.(201).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [201]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Deletions, the splice site mutation in intron 2 (c.293-13A/C>G) and p.Ile172Asn (I172N) are the most common mutations in most populations (189,195-213).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [201]
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“Basal levels of 17OHP are also correlated with genotype(195,200,201,225), with different studies reporting mean levels (in ng/dl) in Groups 0/A, B and C of 23-41,000, 10-18,000, and 3-8000, respectively.”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [201]
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“In descending order of compromised 21-hydroxylase activity, 4 general groups of CYP21A2 mutations have been established to predict the phenotype (Figure 3) (195,196,201,203,208,213,216).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [201]
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A simple salting out procedure for extracting DNA from human nucleated cells
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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency*
White, P. C., & Speiser, P. W. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.3.0398 · Cited by 1,432
Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
White, P. C. (2000) · Endocrine Reviews · doi:10.1210/er.21.3.245 · Cited by 877
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Wedell, A. (1994) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.78.5.1145 · Cited by 370
Steroid 21-hydroxylase deficiency: genotype may not predict phenotype
Wilson, R. C. (1995) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.80.8.2322 · Cited by 324
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Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556
Self-citationNew, M. I., Abraham, M., Gonzalez, B., Dumic, M., Razzaghy-Azar, M., Chitayat, D., Sun, L., Zaidi, M., Wilson, R. C., & Yuen, T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300057110 · Cited by 365
Genetics of congenital adrenal hyperplasia
Krone, N., & Arlt, W. (2009) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2008.10.014 · Cited by 312
Forest, M. G. (2004) · Human Reproduction Update · doi:10.1093/humupd/dmh047 · Cited by 200
Carmina, E., Dewailly, D., Escobar-Morreale, H. F., Keleştimur, F., Morán, C., Oberfield, S. E., Witchel, S. F., & Azziz, R. (2017) · Human Reproduction Update · doi:10.1093/humupd/dmx014 · Cited by 206
Metadata
- Authors
- Stikkelbroeck, N. M. M. L., Hoefsloot, L. H., de Wijs, I. J., Otten, B. J., Hermus, A. R. M. M., & Sistermans, E. A.
- Affiliations
- Radboud University Nijmegen (NL)
- Human Genetics (E.A.S., I.J.d.W., L.H.H.), 6500 HB Nijmegen, The Netherlands
- Departments of Pediatric Endocrinology (N.M.M.L.S., B.J.O.), 6500 HB Nijmegen, The Netherlands
- Endocrinology (A.R.M.M.H.), University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands
- Corresponding author
- Sistermans, Erik A.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-08-01
- Volume
- 88
- Issue
- 8
- Pages
- 3852-3859
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2138979064
- Cited by
- 171
- References
- 54
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 9 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 14 · 2018: 5 · 2017: 5 · 2016: 11 · 2015: 5 · 2014: 6 · 2013: 11 · 2012: 11
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- 21-hydroxylase deficiency, congenital adrenal hyperplasia, CYP21 mutations, genotype-phenotype correlation, novel mutations, mutation clustering, salt wasting, compound heterozygosity, Dutch patients, mutation frequency, gene conversion
- MeSH terms
- Adrenal Hyperplasia, Congenital, Alleles, DNA Mutational Analysis, Multigene Family, Genotype, Humans, Mutation, Netherlands, Pedigree, Phenotype, Steroid 21-Hydroxylase, Frameshift Mutation, DNA, Complementary
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