CoChat
Sign Up
Cited by 171Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

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 access
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
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/jc.2002-021681

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In both American and German data, median Prader virilization scores for females in Groups 0, A, B and C are 4 (3-5), 4 (3-5), 3 (2-4) and 0 (0-2) respectively.

    “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]

    The Correlation between genotype and phenotype section reports female phenotypes by mutation group and mentions Prader stage II–III for one patient. It does not report median or interquartile-range Prader scores for Groups 0, A, B and C, or present those figures as American and German data. Page numbers are unavailable in our copy. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • 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.

    “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]

    The Mutation analysis section and Table 1 identify deletion/conversion, the intron 2 splice-site mutation (I2G), and I172N as the three most frequent mutations in the Dutch sample. Table 2 shows they are generally common across the Western European populations compared, but it does not establish that they are the most common in most populations worldwide; I172N is also less frequent than other mutations in some listed countries. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Basal levels of 17OHP are also correlated with genotype, 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.

    “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]

    The Abstract and ‘Correlation between genotype and phenotype’ section link genotype groups to disease forms characterized by differing 17OHP elevations, providing qualitative support. The paper does not report a correlation of basal 17OHP with genotype or the claimed group-specific mean ranges in ng/dl. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • In descending order of compromised 21-hydroxylase activity, 4 general groups of CYP21A2 mutations have been established to predict the phenotype.

    “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]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

9 of the 54 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

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
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review