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Cited by 20Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Genetics and Pathophysiology of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

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Yang, Ming, White, Perrin C·2025·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgae535PMC PMC11749890
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Abstract

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease that manifests clinically in varying forms depending on the degree of enzyme deficiency. CAH is most commonly caused by 21-hydroxylase deficiency (21OHD) due to mutations in the CYP21A2 gene. Whereas there is a spectrum of disease severity, 21OHD is generally categorized into 3 forms. The classic form encompasses salt-wasting and simple virilizing CAH and the least affected form is termed nonclassic CAH. The classic form of 21OHD occurs in ∼1 in 16 000 births with the most severe salt-wasting cases presenting in the neonatal period with cortisol and aldosterone deficiencies and virilization of external female genitalia. Cortisol deficiency removes normal feedback on the hypothalamic-pituitary-adrenal axis leading to elevations in ACTH and adrenal androgen levels, which often accelerate skeletal maturation, leading to premature epiphyseal growth plate closure. Additionally, supraphysiologic doses of glucocorticoids are necessary to suppress androgen levels, adversely affecting final adult height. This paper highlights a brief history of 21OHD and provides an overview of the genetic basis and pathophysiology of 21OHD.

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  • Only 5-10% of small pathogenic variants in CYP21A2 occur independently of gene conversion events, and some of these have founder effects.

    “In contrast, only 5-10% of small pathogenic variants in CYP21A2 occur independently of gene conversion events; some of these have founder effects, providing valuable insights into population history and migration patterns (5, 16, 19–22).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [19]

    The Molecular Genetics of CAH section says over 90% of mutations causing 21-hydroxylase deficiency result from intergenic recombination and lists more than 200 pseudogene-independent mutations. This supports the existence of independently arising variants, but it does not give a 5–10% estimate specifically for small pathogenic variants or say that any have founder effects (page unavailable). (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Microconversion events, in which one or more deleterious pseudogene-derived variants are transferred into CYP21A2 during meiosis, represent 70-75% of all cases.

    “Among these, microconversion events, in which one or more deleterious pseudogene-derived variants are transferred into CYP21A2 during meiosis, represent 70–75% of all cases (5, 16, 19, 20).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [19]

    The Molecular Genetics of CAH section says that gene conversion transfers deleterious variants from CYP21A1P to CYP21A2 and accounts for approximately 70–75% of disease-causing CYP21A2 mutations. It does not give that percentage for all cases or specifically for microconversion events, and it says conversions may arise through either meiotic or mitotic events, not only during meiosis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Population-based studies reveal rare or population-specific alleles, highlighting extensive allelic heterogeneity of 21-OHD and the necessity of using ethnically tailored genetic panels for accurate diagnosis and effective genetic counseling.

    “Nevertheless, population-based studies continue to reveal rare or population-specific alleles, highlighting the extensive allelic heterogeneity of 21-OHD and the necessity of using ethnically tailored genetic panels for accurate diagnosis and effective genetic counseling (5, 16, 19, 22, 28, 33–35).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [19]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • The remaining 20-25% of pathogenic CYP21A2 variants are attributable to unequal meiotic crossovers, giving rise to large deletions, duplications, and chimeric CYP21A1P/CYP21A2 genes.

    “The remaining 20–25% are attributable to unequal meiotic crossovers, giving rise to extensive genomic rearrangements, including large deletions, duplications, and the formation of chimeric CYP21A1P/CYP21A2 genes.”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [19]

    In “Molecular Genetics of CAH” (page unavailable), the paper says unequal meiotic crossing-over generates deletions accounting for approximately 20% of mutant alleles, and describes chimeric CYP21A1P/CYP21A2 genes. It does not give a 20–25% range for these rearrangements; it assigns that range to a splice mutation in “Genotype-phenotype Correlation.” Its figure also says the chromosome with three CYP21 copies produced by crossing-over is not associated with disease, so duplications are not supported as pathogenic variants here. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • High homology and tandem configuration make the RCCX region prone to meiotic misalignment, fostering recurrent recombination through unequal crossover and gene conversion, which are the predominant mechanisms underlying pathogenic variants in 21-OHD.

    “The abovementioned high degree of homology and tandem configuration make this region particularly prone to meiotic misalignment, which fosters recurrent recombination through unequal crossover and gene conversion. These processes constitute the predominant mechanisms underlying pathogenic variants in 21-OHD (16–19).”

    From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [19]

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Sorted by citations

Authors
Yang, M., & White, P. C.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
White, Perrin C
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2025-01-21
Volume
110
Issue
Supplement_1
Pages
S1-S12
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgae535
PMC
PMC11749890
OpenAlex
W4406634358
Cited by
20
References
46
Citations by year
2026: 18 · 2025: 2
FWCI
1.77
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • 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
congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 gene, salt-wasting CAH, simple virilizing CAH, autosomal recessive inheritance, ACTH excess, adrenal androgen excess, premature epiphyseal closure, glucocorticoid therapy, adult height
MeSH terms
Adrenal Hyperplasia, Congenital, Female, Humans, Mutation, Steroid 21-Hydroxylase

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