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Cited by 119Sexual Differentiation and DisordersAdrenal Hormones and DisordersOvarian function and disorders

Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort

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Krone, Nils, Rose, Ian T., Willis, Debbie S., Hodson, James, Wild, Sarah H., Doherty, Emma J., Hahner, Stefanie, Parajes, Silvia +9 more·2013·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2012-3343PMC PMC3651585
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Abstract

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. OBJECTIVE: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. RESEARCH DESIGN AND METHODS: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. RESULTS: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. CONCLUSIONS: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

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  • Most affected individuals are compound heterozygotes, and clinical outcome is typically determined by the allele that maintains the highest residual enzyme activity.

    “Most affected individuals are compound heterozygotes, and the clinical outcome is typically determined by the allele that maintains the highest residual enzyme activity.”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [47]

    In Patients and Methods (page unavailable), the paper assigns genotype groups by the less severe mutation, supporting the residual-activity rule for predicting disease phenotype. It does not establish that most affected individuals are compound heterozygotes. Its Discussion (page unavailable) also says that most current health problems in treated adults do not correlate with genotype severity, so the rule should not be extended to adult clinical outcomes. (LLM, conf=0.86)

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  • A strong correlation between genotype and phenotype has been consistently reported across multiple populations in 21-OHD.

    “In 21-OHD, a strong correlation between genotype and phenotype has been consistently reported across multiple populations (22, 26, 46, 47).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [47]

    The paper states that a strong genotype–phenotype correlation has been established for salt wasting and impaired adrenomedullary function; its Discussion also finds a similar genotype–salt-loss relationship in children and UK adults. But the Discussion says correlations with genital virilization have been variably reported, and its adult cohort found no association between genotype and most health outcomes. The unqualified claim of a consistently strong correlation across phenotypes is therefore broader than this source supports (page numbers unavailable). (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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 [47]

    The introductory passage (page not provided) says common CYP21A2 mutations are detected in more than 95% of patients with 21-hydroxylase deficiency, and the Methods describe targeted genotyping. It does not establish a 90–95% detection rate for known pathogenic alleles across most populations; the Methods also describe using full-gene sequencing when no common mutation was detected. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The salt-wasting form generally results from combinations of two severe alleles (groups 0 or A); the simple-virilizing form arises in patients homozygous for group B variants or compound heterozygous for group B with null/A; the nonclassical phenotype usually manifests in carriers of two mild alleles (group C) or combinations of mild and severe variants.

    “Consequently, the SW form generally results from combinations of two severe alleles (groups 0 or A), whereas the SV form arises in patients homozygous for group B variants, or compound heterozygous of group B variants with groups null or A. The NC phenotype usually manifests in carriers of two mild alleles (group C) or combinations of mild and severe (groups null, A or B) variants (22, 26, 47, 48)”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [47]

  • Sanger sequencing has been regarded as the gold standard for CYP21A2 analysis and remains the reference method in diagnostic and research laboratories worldwide.

    “For more than three decades, Sanger sequencing has been regarded as the gold standard for CYP21A2 analysis and remains the reference method in diagnostic and research laboratories worldwide (22, 47, 53).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [47]

    The Patients and Methods section (page unavailable) describes targeted multiplex minisequencing and direct DNA sequencing when no common mutations were detected. It does not identify either method as Sanger sequencing or address the claimed gold-standard status, three-decade history, or worldwide use as a reference method. Searches for those terms found no supporting passage. (LLM, conf=0.77)

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Authors
Krone, N., Rose, I. T., Willis, D. S., Hodson, J., Wild, S. H., Doherty, E. J., Hahner, S., Parajes, S., Stimson, R. H., Han, T. S., Carroll, P. V., Conway, G. S., Walker, B. R., MacDonald, F., Ross, R. J., Arlt, W., & (CaHASE), F. T. U. K. C. A. H. A. S. E.
Affiliations
  • University of Birmingham (GB)
  • Society for Endocrinology (GB)
  • National Health Service (GB)
  • University of Edinburgh (GB)
  • University of Würzburg (DE)
  • British Heart Foundation Centre for Cardiovascular Science (GB)
  • University College Hospital (GB)
  • Birmingham Women's Hospital (GB)
  • University of Sheffield (GB)
  • University Hospitals Birmingham NHS Foundation Trust (GB)
Corresponding author
Ross, Richard J.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2013-02-01
Volume
98
Issue
2
Pages
E346-E354
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2012-3343
PMC
PMC3651585
OpenAlex
W1993728185
Cited by
119
References
36
Citations by year
2026: 9 · 2025: 8 · 2024: 4 · 2023: 12 · 2022: 8 · 2021: 14 · 2020: 4 · 2019: 10 · 2018: 11 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 11 · 2013: 8
FWCI
4.33
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc)
Funders
  • Wellcome Trust (GR079865MA)
  • British Heart Foundation (RG/11/4/28734)
  • Society for Endocrinology
  • Medical Research Council (0900567)
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
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 mutations, genotype-phenotype correlation, adult patients, glucocorticoid dose, fludrocortisone, health status, insulin resistance, novel mutations
MeSH terms
Adolescent, Adrenal Hyperplasia, Congenital, Adult, Aged, Alleles, Female, Genotype, United Kingdom, Humans, Male, Middle Aged, Mutation, Phenotype, Steroid 21-Hydroxylase, Cohort Studies, Genetic Association Studies

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