Two families, two pathways: a case series of 46, XY DSD with 17α-hydroxylase deficiency and isolated 17,20-lyase deficiency due to novel CYB5A variant

Rakesh Garg; Manasvini Bhatt; Ashutosh Kumar Arya; Viveka P. Jyotsna; Rajesh Khadgawat

doi:10.1515/jpem-2024-0613

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Two families, two pathways: a case series of 46, XY DSD with 17α-hydroxylase deficiency and isolated 17,20-lyase deficiency due to novel CYB5A variant

Rakesh Garg , Manasvini Bhatt , Ashutosh Kumar Arya , Viveka P. Jyotsna and Rajesh Khadgawat

Published/Copyright: March 25, 2025

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 6

Abstract

Objectives

17α-Hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene mapped at chromosome 10q, and are required for the synthesis of sex steroids and cortisol. 17α-hydroxylase deficiency causes a decrease in cortisol and androgen with a subsequent overproduction of adrenocorticotrophic hormone (ACTH), gonadotropin, and 11-deoxycorticosterone. However, isolated 17,20-lyase deficiency is a rare condition that results in sex steroid deficiency with normal serum cortisol. This case series aims to report a novel canonical splice site CYB5A variant causing isolated 17,20-lyase deficiency and highlight the utility of steroid metabolomics in diagnosing 17α-hydroxylase and isolated 17,20-lyase deficiencies.

Case presentation

We describe four patients with ambiguous genitalia who were accurately diagnosed through steroid metabolomics using liquid chromatography- mass spectroscopy (LC-MS). Genetic testing identified a novel homozygous likely pathogenic 5′ canonical splice site variant, c.129 + 1G>A in intron 1 of CYB5A gene, resulting in isolated 17, 20 lyase deficiency.

Conclusions

Here, we report four patients with 46, XY disorder of sexual development (DSD) from two families with 17α-hydroxylase deficiency and isolated 17,20-lyase deficiency due to cytochrome b5 variant with a variable spectrum of under-virilization who had received inadequate treatment for a prolonged period of time due to incorrect diagnosis.

Keywords: CYB5a; 17OHD; DSD

Corresponding author: Manasvini Bhatt, Senior Resident, Department of Endocrinology and Metabolism, AIIMS Delhi, New Delhi, India, E-mail: bhaman93@gmail.com

Acknowledgments

The authors would like to thank the patients and their family for providing blood samples and agreeing to participate in this research. We would like to express our sincere gratitude to Harleen Kaur for her invaluable assistance in the molecular genetic interpretation in this article.

Research ethics: Not applicable.
Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

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Received: 2024-12-21

Accepted: 2025-03-10

Published Online: 2025-03-25

Published in Print: 2025-06-26

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Articles in the same Issue

https://doi.org/10.1515/jpem-2024-0613

Keywords for this article

CYB5a; 17OHD; DSD