Biochemical and genetic diagnosis of 21-hydroxylase deficiency

Falhammar, Henrik; Wedell, Anna; Nordenström, Anna

doi:10.1007/s12020-015-0731-6

Cited by 80Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Biochemical and genetic diagnosis of 21-hydroxylase deficiency

Falhammar, Henrik, Wedell, Anna, Nordenström, Anna·2015·Endocrine

DOI 10.1007/s12020-015-0731-6

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Abstract

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene and is often fatal in its classic forms if not treated with glucocorticoids. In contrast, non-classic CAH (NCCAH), with a prevalence from 0.1 % up to a few percentages in certain ethnic groups, only results in mild partial cortisol insufficiency and patients survive without treatment. Most NCCAH cases are never identified, but unnecessary suffering due to hyperandrogenism, especially in females, can be avoided by a correct diagnosis. A 17-hydroprogesterone (17OHP) level above 300 nmol/L indicates classic CAH while 30-300 nmol/L in adult males or females (follicular phase or if anovulatoric) indicates NCCAH. The gold standard for diagnosing NCCAH is the ACTH stimulation test. Deletion, large gene conversions, and nine microconversion-derived mutations are the most common CYP21A2 mutations. However, almost 200 rare mutations have been described. Since there is a good genotype-phenotype relationship, genotyping provides valuable diagnostic, as well as prognostic information. Neonatal screening for CAH is now performed in an increasing number of countries with the main goal of reducing mortality and morbidity due to salt-losing adrenal crises in the newborn period. In addition, screening may shorten the time to diagnosis in virilized girls. Neonatal screening misses some patients with milder classic CAH and most NCCAH cases. In conclusion, diagnosing classic CAH is life-saving, but diagnosing NCCAH is also important to prevent unnecessary suffering.

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In 21OHD, 17OHP, the steroid before 21-hydroxylase, accumulates and is traditionally used to diagnose 21OHD.
“In 21OHD, 17OHP, the steroid before 21-hydroxylase, accumulates and is traditionally used to diagnose 21OHD (1,134,135).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
No general guidelines exist for the management and follow-up of patients with NC CAH, and the overall evidence of recommendations for NC CAH is low.
“In contrast to classic CAH, no general guidelines exist for the management and follow-up of these patients and the overall evidence of recommendations for NC CAH is low (134,342,417-419).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
Most patients diagnosed with NC CAH are females suffering from mild adrenal androgen excess without clinically relevant deficiencies of gluco- and mineralocorticoids.
“Most patients diagnosed with NC CAH are females suffering from mild adrenal androgen excess without clinically relevant deficiencies of gluco-and mineralocorticoids (134,429).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
The Endocrine Society guidelines do not recommend routine treatment with glucocorticoid in asymptomatic individuals with NC CAH.
“the Endocrine Society guidelines do not recommend routine treatment with glucocorticoid in asymptomatic individuals (134).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
In many cases glucocorticoid treatment may be discontinued after reaching adult height, if the individual is otherwise asymptomatic.
“In many cases glucocorticoid treatment may be discontinued after reaching adult height, if the individual is otherwise asymptomatic (134).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]

Clinical studies comparing different treatment approaches in adults with NC CAH are lacking.
“Clinical studies comparing different treatment approaches in adults with NC CAH are lacking;”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
Adjustments in glucocorticoid (and fludrocortisone) dose are usually necessary during pregnancy in women with CAH, especially in the third trimester.
“Adjustments in glucocorticoid (and fludrocortisone) dose are usually necessary, especially in the third trimester (134), similar to pregnancies in women with primary adrenal insufficiency (668,669).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
Multidisciplinary transition clinics involving pediatric and adult endocrinologists, gynecologists, urologists and psychologists may promote good medical adherence among adults with CAH.
“Multidisciplinary transition clinics involving pediatric and adult endocrinologists, gynecologists, urologists and psychologists may promote good medical adherence among adults with CAH (134).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
All patients with CAH should be aware of the risk of reduced fertility with poor medical adherence.
“All patients should be aware of the risk of reduced fertility with poor medical adherence (134).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
Elevated adrenal androgens may activate the hypothalamic-pituitary-gonadal axis.
“because elevated adrenal androgens may activate the hypothalamic-pituitary-gonadal axis (134).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]
Endocrine societies and others have stated that prenatal dexamethasone treatment is experimental and should only be performed in centers taking part in long-term research studies of these treated pregnancies.
“Endocrine societies and others have stated that the treatment is experimental and should only be performed in centers taking part in long-term research studies of these treated pregnancies (134,328,375,377,447).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [134]

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Authors: Falhammar, H., Wedell, A., & Nordenström, A.
Affiliations: Karolinska University Hospital (SE)
Corresponding author: Falhammar, Henrik
ORCID: Falhammar, Henrik
Nordenström, Anna
Venue: Endocrine
Publisher: Springer Science and Business Media LLC
Published: 2015-09-04
Volume: 50
Issue: 2
Pages: 306-314
ISSN: 0969-711X (ISSN-L)
1355-008X
1559-0100
DOI: 10.1007/s12020-015-0731-6
OpenAlex: W1224223593
Cited by: 80
References: 92
Citations by year: 2026: 6 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 13 · 2020: 9 · 2019: 7 · 2018: 12 · 2017: 7 · 2016: 6 · 2015: 1
FWCI: 0.84
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Endocrine (publishedVersion)
PubMed (publishedVersion)
Funders: Magnus Bergvalls Stiftelse
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 deficiency, congenital adrenal hyperplasia, non-classical congenital adrenal hyperplasia, CYP21A2 mutations, ACTH stimulation test, genotype-phenotype correlation, newborn screening, hyperandrogenism, glucocorticoid therapy
MeSH terms: Adrenal Hyperplasia, Congenital, Humans

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Biochemical and genetic diagnosis of 21-hydroxylase deficiency

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