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Cited by 370Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: Implications for genetic diagnosis and association with disease manifestation

Wedell, A.·1994·Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.78.5.1145
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Abstract

We have characterized the disease-causing mutations in the steroid 21-hydroxylase genes of 127 patients with different clinical forms of congenital adrenal hyperplasia, representing 186 unrelated chromosomes. The gene was completely absent on 29.8% of the chromosomes, and this together with the I2 splice (27.7%), I173N (20.8%), V282L (5.4%), and R357W (3.8%) mutations constitute 87.5% of all affected chromosomes. In total, 15 different sequence aberrations combine to form 19 different disease-causing alleles. The results confirm that genotyping is an efficient means of diagnosing steroid 21-hydroxylase deficiency, although special consideration is needed to resolve genotypes when full families are not available. Clinical presentations of the different combinations of mutations indicate that genotyping is reliable for prediction of clinical outcome in patients with 21-hydroxylase deficiency. It is especially helpful in determining whether in utero treatment of affected females is indicated and in classifying the severity of 21-hydroxylase deficiency in children diagnosed through neonatal screening, before symptoms have appeared.

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Crossref · 10.1210/jc.78.5.1145

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8 of 8 references verified0 citation errors · 0 not checkable

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  • Functional in vitro studies classify CYP21A2 pathogenic variants into four groups based on residual enzymatic activity: group 0 (null, 0%), group A (<2%), group B (3-7%), and group C (20-60%).

    “Functional in vitro studies have allowed classification of CYP21A2 pathogenic variants into four groups based on residual enzymatic activity: group 0 (null, 0%), group A (<2%), group B (3-7%), and group C (20-60%), as summarized in Table 1 (18, 31, 48–50).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [31]

  • In European and North American populations, large gene deletions and CYP21A1P/CYP21A2 chimeric conversions, predominantly associated with salt-wasting phenotypes, constitute 20-30% of pathogenic alleles.

    “In European and North American population, where long-standing newborn screening programs facilitate early detection, large gene deletions and CYP21A1P/CYP21A2 chimeric conversions, predominantly associated with SW phenotypes, constitute 20-30% of pathogenic alleles (25, 28, 30, 31).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [31]

  • In most populations, targeted genotyping methods achieve a detection rate of approximately 90-95% of known pathogenic alleles.

    “In most populations, these methods achieve a detection rate of approximately 90-95% of known pathogenic alleles, providing a balance between analytical precision, efficiency and reproducibility, making it suitable for detecting recurrent CYP21A2 variants in diagnostic laboratories during the 1990s and early 2000s (27, 31, 47, 71, 72).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [31]

  • CAH-X is associated with joint hypermobility, chronic arthralgia, joint subluxations, hernias, and cardiac defects.

    “CAH-X is associated with joint hypermobility, chronic arthralgia, joint subluxations, hernias, and cardiac defects (193,194).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [194]

  • Genotype consistently predicts phenotype in very severe and very mild cases of 21-hydroxylase deficiency.

    “It is clear that genotype consistently predicts phenotype in very severe and very mild cases of 21-hydroxylase deficiency (361, 362).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [362]

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Authors
Wedell, A.
Affiliations
Karolinska University Hospital (SE)
Venue
Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1994-05-01
Volume
78
Issue
5
Pages
1145-1152
ISSN
0021-972X (ISSN-L)
DOI
10.1210/jc.78.5.1145
OpenAlex
W2077894644
Cited by
370
References
8
Citations by year
2026: 1 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 10 · 2019: 12 · 2018: 8 · 2017: 8 · 2016: 11 · 2015: 7 · 2014: 12 · 2013: 14 · 2012: 11
FWCI
3.29
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
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, CYP21, congenital adrenal hyperplasia, 21-hydroxylase deficiency, mutation spectrum, pathogenic variants, genotype-phenotype correlation, genotyping, in utero treatment, newborn screening, disease severity classification, Sweden
MeSH terms
Adrenal Hyperplasia, Congenital, Alleles, Female, Genotype, Humans, Male, Mutation, Phenotype, Steroid 21-Hydroxylase

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