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Cited by 200Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Forest, M. G.·2004·Human Reproduction Update
DOI 10.1093/humupd/dmh047
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Abstract

Congenital adrenal hyperplasias (CAH) are inherited defects of cortisol biosynthesis. More than 90% of CAH are caused by 21-hydroxylase deficiency (21-OHD), found in 1:10 000 to 1:15 000 live births. Females with 'classical' 21-OHD, being exposed to excess androgens prenatally, are born with virilized external genitalia. Potentially lethal adrenal insufficiency is characteristic of two-thirds to three-quarters of patients with the classical salt wasting (SW) form of 21-OHD. Non-SW 21-OHD may be diagnosed on genital ambiguity in affected females, and/or later on the occurrence of androgen excess in both sexes. Non-classical 21-OHD, detected in > or =1:100 of certain populations, may present as precocious pubarche in children or polycystic ovarian syndrome in young women. 21-OHD is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombination between CYP21 and the closely linked CYP21P pseudogene. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disorder. This close association between genotype and phenotype makes it possible to predict clinical outcome in affected subjects. The risk of SW and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment, but additional therapies are being developed. A first trimester prenatal diagnosis should be proposed in families in whom molecular studies have been performed previously. The state of heterozygotism can be predicted by hormonal testing and confirmed by molecular studies. Prenatal diagnosis by direct mutation detection in previously genotyped families permits prenatal treatment of affected females in order to avoid or minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before SW crises develop, reducing mortality in this disorder.

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  • 17-hydroxypregnenolone also accumulates and is readily converted to DHEA, and subsequently to androstenedione and testosterone, resulting in severe prenatal virilization of female fetuses.

    “However, 17-hydroxypregnenolone also accumulates and is readily converted to DHEA, and subsequently to androstenedione and testosterone, resulting in severe prenatal virilization of female fetuses (350 -354).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [354]

    The Introduction (page unavailable) says that steroid precursors can be shunted into androgen biosynthesis and that excess androgens virilize female fetuses with classical 21-hydroxylase deficiency. It does not state that 17-hydroxypregnenolone accumulates and is readily converted through DHEA to androstenedione and testosterone. The Classical forms section also describes the degree of masculinization as variable, rather than uniformly severe. (LLM, conf=0.86)

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  • 21-Hydroxylase deficiency, caused by mutations in P450c21, is the most common form of CAH and one of the most common inborn errors of metabolism.

    “21-Hydroxylase deficiency, caused by mutations in P450c21, is the most common form of CAH and one of the most common inborn errors of metabolism.”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [354]

    The Abstract states that CYP21 mutations cause 21-hydroxylase deficiency and that it accounts for more than 90% of CAH; the Introduction identifies P450c21 as the enzyme involved. The Introduction calls the deficiency a common monogenic defect, but the copy does not establish the stronger claim that it is one of the most common inborn errors of metabolism. P450c21 is the enzyme, rather than the gene named as mutated. (LLM, conf=0.83)

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2 of the 150 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. [49]49. Guidollet-Tardy V (2002) Le de ´ficit en 21-hydroxylase Mise au point de l'exploration mole ´culaire de 1538 patients et 188 he ´te ´rozygotes; Corre ´- lations ge ´notype-phe ´notype. PhD Thesis, University Lyon I, 256pp.

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Authors
Forest, M. G.
Affiliations
Inserm (FR)
Corresponding author
Forest, M. G.
Venue
Human Reproduction Update
Publisher
Oxford University Press (OUP)
Published
2004-09-23
Volume
10
Issue
6
Pages
469-485
ISSN
  • 1355-4786 (ISSN-L)
  • 1460-2369
DOI
10.1093/humupd/dmh047
OpenAlex
W2135400812
Semantic Scholar
1bdf692960096ceca79298e51fbe52efbd96ea29
Cited by
200
References
150
Citations by year
2026: 4 · 2025: 1 · 2024: 2 · 2023: 10 · 2022: 8 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 10 · 2015: 9 · 2014: 14 · 2013: 14 · 2012: 16
FWCI
0.58
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction Update (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
congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21, intergenic recombination, genotype-phenotype correlation, salt wasting, adrenal insufficiency, precocious pubarche, polycystic ovary syndrome, glucocorticoid replacement therapy, mineralocorticoid replacement, prenatal diagnosis, newborn screening, overtreatment
MeSH terms
Adrenal Hyperplasia, Congenital, Body Height, Dose-Response Relationship, Drug, Female, Fertility, Genetic Counseling, Glucocorticoids, Heterozygote, Humans, Infant, Newborn, Mineralocorticoids, Mutation, Pregnancy, Prenatal Diagnosis, Steroid 21-Hydroxylase, Obstetric Surgical Procedures, Incidence, Neonatal Screening, Treatment Outcome

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