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.

Objective: 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.

Methods: 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.