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Cited by 16Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Genotype Is Associated to the Degree of Virilization in Patients With Classic Congenital Adrenal Hyperplasia

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Neocleous, Vassos, Fanis, Pavlos, Phylactou, Leonidas A., Skordis, Nicos·2018·Frontiers in Endocrinology
DOI 10.3389/fendo.2018.00733PMC PMC6286958
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Abstract

Background: Molecular defects of CYP21A2 consistently decrease 21-hydroxylase activity and result in a variable expression of disease severity in patients with congenital adrenal hyperplasia (CAH). Aim: The genotype and biochemical findings were examined in an attempt to reveal any association to the degree of virilization in classic CAH patients. Methods: The study included 18 CAH patients with complete characterization of CYP21A2 mutations and were sorted based on the severity of the inherited mutations and the expected % of 21-hydroxylase enzyme activity. Results: Eleven out of the 18 patients manifested the SW form with the remaining 7 to exhibit the SV form. The most frequent genetic defect in the classic salt-wasting (SW) and simple virilising (SV) forms was the IVS2-13A/C>G (36.1%) mutation, followed by delEX1-3 (19.4%) and p.Ile172Asn (19.4%). Four patients, who shared a combination of 2 mutations belonging to the most severe type, manifested only the SW form. Four out of 5 patients who shared in homozygosity the IVS2-13A/C>G mutation demonstrated the SW form and only one the SV form. All four patients who shared the p.Ile172Asn mutation either in homozygous or compound heterozygous state manifested the SV form. Interestingly, a female neonate with SW bearing the IVS2-13A/C>G/Large del exhibited complete male virilisation (Prader 5). The remaining four affected female new-borns also exhibited the SW form, with two of them virilised as Prader 3 and the other two as Prader 4. Virilisation with clitoromegaly was also observed in a female, who presented with premature adrenarche and carried the less severe p.Pro30Leu mutation. Conclusion: The frequency of the underlying mutations in our patients with the classic form of CAH is variable but quite similar with the ones reported in the Mediterranean region. Therefore, the identification of the severe CYP21A2 defects in Cypriot patients and their comparison with the incidence and severity in different populations will make a valuable diagnostic tool for genetic counselling in the classic form of CAH.

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  • The pathogenic IVS2-13A/C > G comprises 20 to 25% of CYP21A2 mutant alleles and translates to the most severe SW forms of the disease when inherited in homozygosity.

    “Several reports in European, Mediterranean, Middle Eastern, and Chinese populations confirmed a high frequency of the pathogenic IVS2-13A/C > G and found it to comprise 20 to 25% of the CYP21A2 mutant alleles and to translate to the most severe SW forms of the disease when inherited in homozygosity [1, 4, 27, 39–43].”

    From Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene (2023) · cites this paper as [4]

    The Methods and results section reports that IVS2-13A/C>G was the most frequent mutation in this Greek-Cypriot cohort, but it accounted for 36.11% of the alleles, not 20–25%; the paper does not establish that percentage across the populations named in the claim. The Abstract reports salt-wasting disease in four of five patients homozygous for the mutation, while one had the simple-virilising form. The Discussion associates the most severe salt-wasting phenotype with IVS2-13A/C>G combined with a large deletion, not with homozygosity alone. Page numbers were not available in our copy. (LLM, conf=0.90)

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Authors
Neocleous, V., Fanis, P., Phylactou, L. A., & Skordis, N.
Affiliations
  • The Cyprus Institute of Neurology & Genetics - Postgraduate Education (CY)
  • St George's, University of London (GB)
Corresponding author
  • Phylactou, Leonidas A.
  • Skordis, Nicos
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2018-12-03
Volume
9
Pages
733-733
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2018.00733
PMC
PMC6286958
OpenAlex
W2902448146
Cited by
16
References
18
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 3
FWCI
0.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
A.G. Leventis Foundation
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
classic congenital adrenal hyperplasia, CYP21A2 mutations, 21-hydroxylase deficiency, masculinization, salt-wasting form, genotype-phenotype correlation, compound heterozygosity, clitoromegaly, premature adrenarche, genetic counseling

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