Background: P450 oxidoreductase deficiency (PORD) is characterised by glucocorticoid and sex steroid deficiency and skeletal malformations, resembling AntleyBixler 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.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology