Cited by 171Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

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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

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Stikkelbroeck, Nike M. M. L., Hoefsloot, Lies H., de Wijs, Ilse J., Otten, Barto J., Hermus, Ad R. M. M., Sistermans, Erik A.·2003·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2002-021681

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Abstract

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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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.
ORCID: Hoefsloot, Lies H.
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
DOI: 10.1210/jc.2002-021681
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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CYP21 Gene Mutation Analysis in 198 Patients with 21-Hydroxylase Deficiency in The Netherlands: Six Novel Mutations and a Specific Cluster of Four Mutations

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