Early diagnosis of CYP17A1 compound heterozygous mutations in a 46, XY child with disorders of sexual development

Abstract

17-Hydroxylase/17,20-lyase deficiency is a rare congenital disorder accounting for 1% of congenital adrenal hyperplasia. This disease is recessively expressed as autosomal inheritance through mutations in the CYP17A1 gene, leading to defective levels of glucocorticoids and sex hormones. Individuals with loss-of-function mutations usually present with phenotypic female genitalia, primary amenorrhea, or hypertension in puberty caused by excessive production of mineralocorticoids. In this report, we describe a girl with CYP17A1 mutations diagnosed even though the pathognomonic symptoms had not developed. Herein, we report a case of a 3-year-old girl who prenatally diagnosed as a 46, XY female. After birth, the baby had normal female-type external genitalia without symptoms. She underwent a gonadectomy at the age of 3 years. To explore the pathogenesis of her condition, her genomic data were reviewed for genes involved in disorders of sexual differentiation (DSDs) using high-throughput sequence data from a whole-exome study. Pathogenic variants causing frameshift mutation involving codon 329 of CYP17A1 and a concomitant missense mutation involving codon 358 of the same gene were detected, mutations which are likely to result in loss of function of the enzyme. Each mutation was inherited from each of the parents, both holding carrier status. In addition, her younger sister (46, XX) acquired those identical variants without any abnormal phenotypical traits. Loss-of-function mutations of CYP17A1 which may cause secondary hypertension are not commonly identified in early life because of the wide spectrum of clinical manifestations and various pathophysiologies, which manifest in different sexes. Affected cases usually present later in life with hypertension or primary amenorrhea. High-throughput sequencing is suggested in DSD cases as it may give a precise diagnosis, enabling a proactive treatment plan and prevention of sequelae that potentially occur in puberty.