Clinical and Genetic Analyses of Two Unrelated 46,XX Girls with Combined 17α-hydroxylase/17,20-lyase Deficiency from China

Abstract

Cytochrome P450 17α-hydroxylase (P450c17) enzyme, encoded by the CYP17A1 gene, catalyzes 17a-hydroxylation and 17,20-lyase reactions essential for cortisol and sex steroid synthesis. 17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive disease caused by CYP17A1 mutations, classified into complete and partial forms based on P450c17 defect severity. We report two unrelated girls diagnosed with 17OHD at the age of 15 and 16. Both presented with primary amenorrhea, infantile genitalia, absent axillary and pubic hair, and hypergonadotropic hypogonadism. Case 1 exhibited undeveloped breasts, nocturnal enuresis, hypertension, hypokalemia, and reduced cortisol and 17α-hydroxyprogesterone. Case 2 showed a growth spurt, spontaneous breast development, elevated corticosterone, and decreased aldosterone. Both had a 46,XX karyotype. Genetic analysis revealed a homozygous p.S106P mutation in Case 1 and compound heterozygous p.R347C/p.R362H mutations in Case 2, with the latter representing a novel combination. Based on the clinical, laboratory and genetic findings, Case 1 and Case 2 were definitively diagnosed as complete and partial forms of 17OHD, respectively. Both received estrogen and glucocorticoid replacement therapy, leading to gradual development of the uterus and breasts, and the onset of first menstruation. In Case 1, hypertension, hypokalemia, and nocturnal enuresis were significantly alleviated. In conclusion, we report the first case of complete 17OHD accompanied by nocturnal enuresis and identify a novel compound heterozygote (p.R347C / p.R362H) of CYP17A1 gene in a case of partial 17OHD.