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Cited by 572Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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Speiser, P W, Dupont, J, Zhu, D, Serrat, J, Buegeleisen, M, Tusie-Luna, M T, Lesser, M, New, M I +1 more·1992·Journal of Clinical Investigation
DOI 10.1172/jci115897PMC PMC443137
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Abstract

Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A----G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172----Asn (16%), and Val-281----Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy.

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  • 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 [361]

    The Discussion reports a general correlation between genotype and disease severity, but explicitly says that each of the three mutation groups contained patients whose phenotype differed from what was predicted. That includes the severe and mild groups, so the paper contradicts the claim that genotype consistently predicts phenotype in those cases. (LLM, conf=0.88)

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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 [48]

    Table I (Methods) classifies CYP21 mutations by enzyme activity, but it uses three groups, A–C, rather than four: group A has no activity, group B has about 2%, and group C has moderate residual activity. The Results likewise assign patients to A, B, or C. This supports activity-based classification, but not the claimed group 0 or the stated A and B activity ranges. (LLM, conf=0.88)

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  • 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 [48]

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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 [48]

  • Southern blot enabled detection of common CYP21A2 deletions or conversions but lacked resolution for single-nucleotide variants.

    “This technique enabled the detection of common CYP21A2 deletions or conversions but lacked resolution for single-nucleotide variants.”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [48]

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Research works printed but not linked: 2

  1. [1]1. New, M. I., P. C. White, S. Pang, B. Dupont, and P. W. Speiser. 1989. The adrenal hyperplasias. In The Metabolic Basis of Inherited Disease. 6th ed. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York. 1881-1917.
  2. [7]7. Amor, M., K. L. Parker, H. Globerman, M. I. New, and P. C. White. 1988. A mutation in the CYP2IBgene(ILE 172 to ASN 172)causessteroid21-hydrox- ylase deficiency. Proc. Nat!. Acad. Sci. USA. 85:1600-1604.

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Authors
Speiser, P. W., Dupont, J., Zhu, D., Serrat, J., Buegeleisen, M., Tusie-Luna, M. T., Lesser, M., New, M. I., & White, P. C.
Affiliations
Cornell University (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1992-08-01
Volume
90
Issue
2
Pages
584-595
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci115897
PMC
PMC443137
OpenAlex
W2059708085
Semantic Scholar
bcef2ddf3fcae562b2eeb94e64c1885cd6805d9d
Cited by
572
References
48
Citations by year
2026: 4 · 2025: 14 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 14 · 2020: 16 · 2019: 19 · 2018: 11 · 2017: 11 · 2016: 18 · 2015: 12 · 2014: 7 · 2013: 20 · 2012: 15
FWCI
5.70
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-37867)
  • National Center for Research Resources (RR 47)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 00072)
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
congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21, CYP21 mutations, genotype-phenotype correlation, gene conversion, 17-hydroxyprogesterone, aldosterone, sodium balance, salt-wasting phenotype, prenatal diagnosis, phenotypic variability
MeSH terms
Adrenal Hyperplasia, Congenital, Alleles, Base Sequence, Chromosome Deletion, Gene Frequency, Humans, Molecular Sequence Data, Mutation, Oligodeoxyribonucleotides, Pedigree, Phenotype, Steroid 21-Hydroxylase, Oligonucleotide Probes

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