Sixteen Years of Clinical Data Including Genetic Analysis to Explain Delayed Puberty in a Chinese Boy with...

In 21-hydroxylase deficiency (21-OHD), impaired 21-hydroxylase activity causes 17-hydroxyprogesterone (17-OHP) accumulation and androgen excess, typically manifesting as hyperandrogenism. The POR gene encodes cytochrome P450 oxidoreductase (POR), the essential electron donor for all microsomal cytochrome P450 enzymes. While POR deficiency impairs multiple steroidogenic enzymes, its phenotypic impact on 21-OHD patients remains poorly characterized.

We report a male 21-OHD patient with homozygous CYP21A2 variant (c.293-13C>G) who presented atypically with absent hyperandrogenism and persistently low testosterone levels before puberty. Medication withdrawal revealed significantly elevated adrenocorticotropic hormone and 17-OHP, but only mildly elevated androstenedione (AD) and relatively low testosterone, suggesting impaired 17-OHP-to-AD conversion due to 17,20-lyase deficiency. Whole-exome sequencing (WES) identified a concurrent heterozygous pathogenic POR variant (c.1660C>T, p.Arg554Ter). The patient presented with delayed puberty during disease progression but achieved spontaneous puberty after 1.3 years of cumulative GnRH pump therapy, consistent with disease-related functional delayed puberty.

This 16-year follow-up case demonstrates that heterozygous POR variants may modulate the phenotype and hormonal profile in 21-OHD. These findings highlight the importance of WES in atypical 21-OHD cases to identify potential modifiers of steroidogenic pathways.