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

The cytochrome P450 17α-hydroxylase (P450c17) enzyme, encoded by Cytochrome P450 Fam􀵴ly 17 Subfamily A Member 1 (CYP17A1) gene, catalyzes both the 17a-hydroxylation and 17,20-lyase reactions required for the production of cortisol and sex steroids. 17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive disease caused by homozygous or compound heterozygous mutations in CYP17A1 gene. 17OHD can be classified into complete form and partial form based on the phenotypes resulting from P450c17 enzyme defects of different severities. Here we report two unrelated girls diagnosed with 17OHD at the age of 15 and 16 respectively. Both patients presented with primary amenorrhea, infantile female external genitalia and absent axillary or pubic hair. Hypergonadotropic hypogonadism was detected in both patients. Besides, Case 1 showed undeveloped breast, primary nocturnal enuresis, hypertension, hypokalemia and reduced 17α-hydroxyprogesterone and cortisol levels, while Case 2 had growth spurt, spontaneous breast development, elevated corticosterone and decreased aldosterone. The chromosome karyotype for both patients was 46, XX. Clinical exome sequencing was used to detect the underlying genetic defect in the patients, and the potential pathogenic mutations were validated by Sanger sequenc􀵴ng of the patients and their parents. The homozygous p.S106P mutation of CYP17A1 gene detected in Case 1 has been reported previously. Although the p.R347C and p.R362H mutations have been reported separately before, their compound heterozygote was firstly ident􀵴fied 􀵴n Case 2. Based on the clinical, laboratory and genetic findings, Case 1 and Case 2 were definitely diagnosed as complete and partial form of 17OHD respectively. Both patients received estrogen and glucocorticoid replacement therapy. Their uterus and breasts developed gradually, and first menstruation occurred. Hypertension, hypokalemia and nocturnal enuresis in Case 1 were relieved. In conclusion, we described a case of complete 17OHD accompanied by nocturnal enuresis for the first time. Moreover, we identified a new compound heterozygote (p.R347C and p.R362H) of CYP17A1 gene in the case with partial 17OHD.