Non‐classical 21‐hydroxylase deficiency in children: association of adrenocorticotropic hormone‐stimulated 17‐hydroxyprogesterone with the risk of compound heterozygosity with severe mutations
Abstract
Aim: To investigate the association between levels of 17‐hydroxyprogesterone (17‐OHP) and the risk of being compound heterozygous for severe mutations in children with non‐classical 21‐hydroxylase deficiency (NC21OHD). Methods: In 86 Spanish NC21OHD children (75 families) an analysis of the 21‐hydroxylase (21‐OH) gene was performed by CYP21B‐specific polymerase chain reaction amplification, allele‐specific oligonucleotide hybridization and Southern blotting. Familial analysis established how the alleles segregated, and allowed the selection of 21‐OH‐genotyped normal and carrier children, which proved useful in determining a more precise definition of the cut‐off for diagnosis. Receiver operating characteristics (ROC) curve analyses were performed to determine the potential value of 17‐OHP in predicting compound heterozygosity for severe mutations. Results: Thirty‐four of the 86 children (39%) were found to carry one severe 21‐OH mutation (7.3% deletions or conversions, 2.7% 655G, 2.7% Q318X, 1.3% I172N, 1.3% R356W, and 3.3% double microconversions or small conversions involving single exons). The predominant mutation was V281L (56.7%). P453S and P30L were less frequent (3.3 and 2%). No patient showed two severe mutations. The degree of enzymic deficiency, as measured by basal or adrenocorticotropic hormone (ACTH)‐stimulated 17‐OHP levels in fully genotyped patients, but not clinical severity (age and number of symptoms at diagnosis), was found to be significantly greater in children with the severe/mild genotype. ROC curve analyses revealed a strong association between ACTH‐17‐OHP and genotype (area under the curve 0.908, SE 0.057). Conclusion: ACTH‐stimulated 17‐OHP may predict the risk of severe mutations in compound heterozygosity in children (maximum predictive value 93% sensitivity and 83% specificity for a cut‐off at 151 nmol 1‐1), although a certain overlap in individual values is observed and performance of molecular analysis should never be obviated in the genetic counselling of these patients.
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No signs or symptoms of adrenal insufficiency were reported by any of the patients in this cohort or in previous studies.
“No signs or symptoms consistent with adrenal insufficiency were either reported by any of our patients or those included in the previous studies (28).”
From Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche (2011) · cites this paper as [28]
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- Authors
- Ezquieta, B., Cueva, E., Varela, J., Oliver, A., Fernández, J., & Jariego, C.
- Affiliations
- Hospital Universitario La Paz (ES)
- Corresponding author
- Ezquieta, B
- Venue
- Acta Paediatrica
- Publisher
- Wiley
- Published
- 2002-08
- Volume
- 91
- Issue
- 8
- Pages
- 892-898
- ISSN
- 0365-1436 (ISSN-L)
- 0803-5253
- 1651-2227
- OpenAlex
- W2029203009
- Cited by
- 47
- References
- 20
- Citations by year
- 2026: 1 · 2022: 1 · 2020: 6 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 4 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 0.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Paediatrica (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
- 17-hydroxyprogesterone, ACTH stimulation test, compound heterozygosity, genotype prediction, children, familial analysis, diagnostic thresholds
- MeSH terms
- Adrenal Hyperplasia, Congenital, Adrenocorticotropic Hormone, Age Factors, Child, Female, Heterozygote, Humans, Male, Mutation, Predictive Value of Tests, Risk Factors, Sensitivity and Specificity, Severity of Illness Index, Stimulation, Chemical, 17-alpha-Hydroxyprogesterone
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