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Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns

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Abstract

Background and Objective

Congenital adrenal hyperplasia involves a series of autosomal recessive disorders where adrenal steroidogenesis is affected. We present a detailed molecular investigation of 13 newborns affected from the severe form of congenital adrenal hyperplasia related to 21-hydroxylase deficiency.

Methods

All patients were diagnosed with classical congenital adrenal hyperplasia in the neonatal period due to adrenal crisis and/or ambiguous genitalia presentation. None of the infants was identified through a congenital adrenal hyperplasia newborn screening program. A molecular analysis of the CYP21A2 gene and a familiar segregation analysis were performed.

Results

Adrenal crisis was the most severe manifestation in the male salt-wasting newborns while all female patients presented with atypical genitalia. Newborns were correctly genotyped and no genotype-phenotype divergences were found. Two novel severe genotypes, not previously reported, were identified. The novel CYP21A2 frameshift mutations (c.793delG and c.297dupG) were added to the other 45 variants recently reported in the literature, leading to a total count of 279 pathogenic variants affecting the gene.

Conclusions

We have successfully genotyped 13 infants diagnosed with classical congenital adrenal hyperplasia after birth. Our molecular approach led to the identification of two novel frameshift CYP21A2 pathogenic variants related to the salt-wasting form of congenital adrenal hyperplasia.

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Authors and Affiliations

  1. Department of Laboratory and Infectious Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy

    Paola Concolino

  2. Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy

    Rosa Maria Paragliola

  3. Unit of Endocrinology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

    Rosa Maria Paragliola

Authors
  1. Paola Concolino
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Correspondence to Paola Concolino.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

Paola Concolino and Rosa Maria Paragliola have no conflicts of interest that are directly relevant to the content of this article.

Ethical approval

Ethical review and approval were waived for this study, due to the diagnostic aim of the investigation. All procedures were performed in accordance with the ethical standards of the Ethics Committee of Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome.

informed consent

Informed consent was obtained from all subjects involved in the study.

Availability of Data and Material

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ Contributions

PC and RMP performed the diagnostic investigations and prepared manuscript. All authors have read and approved the final article.

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Concolino, P., Paragliola, R.M. Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns. Mol Diagn Ther 25, 327–337 (2021). https://doi.org/10.1007/s40291-021-00520-y

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