Novel compound heterozygous CYP17A1 mutations identified in a family with two siblings affected by 17α-hydroxylase/17,20-lyase deficiency.

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17α-Hydroxylase/17,20-lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), caused by mutations in the CYP17A1 gene. It typically manifests clinically as variable degree of hypertension, hypokalemia, and disorders of sexual development (DSD), which can include abnormal sexual differentiation in males and sexual infantilism in females. Over 100 mutations in CYP17A1 have been identified, with most cases involving missense mutations or small deletions. This study examined the clinical features, biochemical profiles, and genetic background of two 46, XY siblings from the same family, both diagnosed with 17OHD-a scenario that is uncommonly seen in clinical practice. We performed a genetic analysis of the CYP17A1 gene in two generations of the family to confirm the diagnosis. Both patients are phenotypically female, presenting with hypertension, hypokalemia, primary amenorrhea, and absent secondary sexual characteristics. Genetic analysis revealed two novel compound heterozygous mutations in the CYP17A1 gene: R45WfsTer5 (a frameshift mutation) and L361P (a missense mutation). Neither variant is reported in the ClinVar database, and the frameshift mutation (R45WfsTer5) is newly identified. The discovery of these two novel CYP17A1 mutations expands the genetic spectrum of 17OHD and provides new insights into the genetic underpinnings of the disease. Personalized treatment plans are necessary, and the choice of glucocorticoids with stronger sodium retention effects may be required to manage hypertension and electrolyte imbalances in select patients.