Simple-Virilizing Congenital adrenal hyperplasia sustained by five mutations on the CYP21A2 gene

Background: Classical congenital adrenal hyperplasia is a genetic disorder characterized by defects in the steroidogenesis cascade, mainly due to 21-hydroxylase enzyme deficiency. The phenotype can vary from the most severe salt-wasting syndrome to the less severe simple-virilizing form. The genotype-phenotype correlation is complex, and it is expected that the higher the number of mutations detected, the worse the phenotype would be. Moreover, when more than one mutation occurs in the same patient, the phenotype should be the result of the most severe mutation detected. Case Presentation: This is the case of a 49-year-old Caucasian man with simple virilizing congenital adrenal hyperplasia, diagnosed at two years of age due to neonatal presentation of ambiguous genitalia. The karyotype was 46, XX, the phenotype was male, and hormonal evaluations highlighted cortisol deficiency, which required cortisone acetate replacement therapy. Gonads were removed during infancy, surgical interventions were performed to align physical attributes with his male gender identity, and the patient underwent testosterone replacement therapy. During adulthood, while compensation for cortisone acetate was reached, managing testosterone therapy proved to be challenging, achieved after the introduction of a low dose of dexamethasone (0.125 mg daily) and testosterone gel 2% 30 mg daily. Genetic analysis unraveled five different heterozygous pathogenic variants on the CYP21A2 gene. One mutation was detected on the maternal allele, while the remaining four were found on the second allele. Three of these mutations were proven to be pathognomonic for the salt-wasting form. Conclusion: This case underscored the intricate and heterogeneous correlation between genotype and phenotype in simple-virilizing congenital adrenal hyperplasia, illustrated by a patient with a rare occurrence of five distinct pathogenic mutations on the CYP21A2 gene. Although three of the five mutations detected are related to the salt-wasting congenital adrenal hyperplasia, only a simple-virilizing form was detected here. Moreover, although it is supposed that the higher the number of mutations detected, the worse the phenotype should be, here we described a simple-virilizing form in a patient with five mutations on the CYP21A2 gene.