Introduction: Congenital adrenal hyperplasia (CAH) is the underlying diagnosis in most newborns presenting with 46,XX disorders of sex development (DSD). Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of CAH caused by inactivating mutations in the POR gene. POR is a crucial electron donor to all microsomal type 2 P450 cytochromes (CYPs), including 21-hydroxylase (CYP21A2) and 17alpha-hydroxylase (CYP17A1). The hallmark feature of PORD is combined sex-steroid and glucocorticoid deficiency. Skeletal malformations resembling the Antley-Bixler Syndrome are present in most patients with PORD. Androgen excess in 46,XX fetuses is thought to be a consequence of an active alternative backdoor pathway to androgens, which closes down after birth.
Case report and results: Clitoromegaly, fused labia majora and a single opening was noted after term birth. The karyotype was 46,XX. Hormonal investigations showed a normal 17OHP (3.6 nmol/l) but an insufficient cortisol increase after synacthen stimulation (baseline: 210 nmol/l; peak: 239 nmol/l), indicating glucocorticoid deficiency. Under the clinical assumption of CAH due to CYP21A2 deficiency, the patient was started on hydrocortisone and fludrocortisone replacement. No overt skeletal malformations were evident at birth, but mild midface hypoplasia and a closed fontanelle were noted at 5 months of age. Urinary steroid profiling performed by an external service lab at 7 days of age showed high amounts of 16-alpha hydroxypregnenolone, but steroid metabolites typically raised in common forms of CAH were not elevated, including 5-pregnendiol, a steroid marker metabolite commonly elevated in PORD. Next generation sequencing employing a multi-gene DSD panel revealed a homozygous mutation (p.Gly539Arg) of the PORgene. This mutation has been previously reported in four 46,XY DSD patients, who had no overt skeletal malformations, but were glucocorticoid and sex steroid deficient.
Summary and conclusions: This is the first 46,XX patient carrying the p.Gly539Arg PORmutation in homozygous state, which was shown to have a mild effect on CYP17A1 17-alpha hydroxylase catalytic activity in vitro. The diagnosis of PORD via urinary steroid profiling in a clinical service lab was not achieved, although impaired 17,20 lyase activity was suggested by accumulation of pregnenolone metabolites in an early neonatal sample. This case highlights the benefits for the management of DSD patients when employing a simultaneous approach of clinical, biochemical and genetic testing. Secondly, it emphasizes the challenges in establishing the correct diagnosis of rare steroidogenic disorders via urinary steroid profiling, in particular in neonatal samples.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology