ESPE Abstracts

Background: P450 oxidoreductase deficiency (PORD) is characterised by glucocorticoid and sex steroid deficiency and skeletal malformations, resembling Antley–Bixler syndrome (ABS, MIM 124015), a skeletal malformaton phenotype also present in patients with fibroblast growth factor receptor 2 mutations (FGFR2, MIM 176943). While genetic testing confirms both conditions, establishing the exact diagnosis on clinical grounds can be challenging.

Objective and hypotheses: To characterise cause of disease in a patient with 46,XY DSD and complex malformations.

Methods: A now 2-year-old child of non-consanguineous parents was investigated immediately after birth for 46,XY DSD (female external genitalia, palpable labial testicles) and complex malformations, including ABS (craniosynostosis, midface hypoplasia, arachnodactily, rocker-bottom feet, and bilateral talipes), spinal dysraphism and right bronchial stenosis. We performed hormonal investigations, urinary steroid profiling by gas chromatography mass-spectrometry (GC/MS) and genetic analysis of the POR gene.

Results: A short Synacthen test revealed adrenal insufficiency and the patient was started on hydrocortisone replacement. 17OHP was moderately elevated (20.6 nmol/l). Urinary steroid profiling at 2 months of age showed combined 21-hydroxylase and 17α-hydroxylase/17,20 lyase deficiency, indicative of PORD. POR gene analysis revealed compound heterozygosity for a novel missense mutation p.A200T and a novel intronic c.1248+1G>T mutation, predicted to cause aberrant mRNA splicing. The child was raised as a girl and gonadectomy was performed at 11 months of age. Shortly thereafter the mother fell pregnant again and GC/MS analysis of maternal urine confirmed that the foetus was unaffected; the mother subsequently delivered a healthy baby.

Conclusion: This case of PORD presented with complex malformations rarely observed in PORD and more typical for FGFR2 mutations while 46,XY DSD indicated PORD. GC/MS analysis reliably detects PORD in affected children and can help with prenatal diagnosis in further pregnancies. Assessment of adrenal function should be part of the early investigations in complex DSD.