Formas virilizantes simples de hiperplasia suprarrenal congénita: adaptación y validación prospectiva del cribado molecular de diagnóstico

Santomé Collazo, José Luis; Cirujano Segura, Ana; Ferreiro Fernández, Belén; Casado Fúnez, Consolación; Muñoz-Pacheco, Rafael; Ezquieta Zubicaray, Begoña

doi:10.1016/j.medcli.2009.11.039

Cited by 10Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Formas virilizantes simples de hiperplasia suprarrenal congénita: adaptación y validación prospectiva del cribado molecular de diagnóstico

Santomé Collazo, José Luis, Cirujano Segura, Ana, Ferreiro Fernández, Belén, Casado Fúnez, Consolación, Muñoz-Pacheco, Rafael, Ezquieta Zubicaray, Begoña·2010·Medicina Clínica

DOI 10.1016/j.medcli.2009.11.039

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Abstract

Background and objective Congenital Adrenal Hyperplasia (CAH) is not an infrequent genetic disorder for which mutation-based analysis for CYP21A2 gene is a useful tool. Contrarily to salt-wasting forms the basic mutation screening accounts only for 83% of simple virilising (SV) phenotypes. Rare alleles with a local distribution not included in the basic panel may reduce its diagnostic accuracy. Our aim is to explore underlying prevalent mutations among our partially characterised SV forms and to evaluate their potential impact in the mutation screening. Patients and methods Preliminary study: CYP21A2 gene sequencing in 13 SV patients partially characterised. Retrospective targeted study: 2,097 DNA samples (561 patients) were re-analysed for p.R426H mutation. Prospective targeted study: incorporation of the p.R426H mutation to the initial exploration of CAH in 1,041 DNA samples to validate this extended screening. Results p.R426H mutation was detected in five patients in the preliminary analysis and in ten more during targeted studies. A frequency for this mutation was 0.71% in the whole group and 7.14% in SV forms. Associated haplotypes were identical thus suggesting a preferential dissemination. The observed phenotypes correlated and confirmed the moderate-to-severe effect on the enzymatic activity. Conclusions Our data relative to allelic frequency of the p.R426H mutation and its strong association to SV forms justify the incorporation of the p.R426H mutation into the basic screening panel because of the significant improvement in the initial characterization of affected patients, especially among those with SV forms. Two new cases detected remark the usefulness of this novel approach.

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The p.(Arg426His) variant is described in Austrian and Spanish cohorts, where it consistently correlates with the salt-wasting phenotype and severe enzymatic impairment.
“The p.(Arg426His) variant demonstrates a similar founder pattern, described in Austrian and Spanish cohorts, where it consistently correlates with the salt-wasting phenotype and severe enzymatic impairment (41, 44).”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [41]
In a large Brazilian cohort, nine novel or rare variants were identified, several of which exhibited clear founder effects and shared haplotypes with Spanish and Portuguese patients.
“In a large Brazilian cohort, nine novel or rare variants were identified, several of which (p.(Arg408Cys), c.1450_1451insC, p.(His365Tyr), c.293-2C>G, p.(Gly424Ser) exhibited clear founder effects and shared haplotypes with Spanish and Portuguese patients, reflecting the historical Iberian contribution to Brazilian ancestry (22, 27, 40, 41).”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [41]

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Authors: Santomé Collazo, J. L., Cirujano Segura, A., Ferreiro Fernández, B., Casado Fúnez, C., Muñoz-Pacheco, R., & Ezquieta Zubicaray, B.
Venue: Medicina Clínica
Publisher: Elsevier BV
Published: 2010-07
Volume: 135
Issue: 5
Pages: 195-201
ISSN: 0025-7753 (ISSN-L)
DOI: 10.1016/j.medcli.2009.11.039
OpenAlex: W2027396846
Cited by: 10
References: 30
Citations by year: 2026: 1 · 2022: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2012: 1
FWCI: 0.39
Type: journal article
Language: es
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Medicina Clínica (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, CYP21A2 mutations, molecular diagnosis, haplotypes, allele frequency, enzyme activity
MeSH terms: Adolescent, Adrenal Hyperplasia, Congenital, Adult, Child, Child, Preschool, Female, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Mutation, Pedigree, Prospective Studies, Virilism

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Formas virilizantes simples de hiperplasia suprarrenal congénita: adaptación y validación prospectiva del cribado molecular de diagnóstico

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