P450 Oxidoreductase Deficiency (ORD) is a novel form of congenital adrenal hyperplasia with biochemical evidence of combined 21-hydroxylase and 17α-hydroxylase deficiency. Mutations in P450 oxidoreductase (POR), a crucial electron donor to microsomal P450 enzymes including CYP17 and CYP21, have recently been identified as the cause of disease. Clinical features in ORD include ambiguous genitalia, glucocorticoid deficiency and craniofacial malformations resembling the Antley-Bixler phenotype. Here we have performed prenatal diagnosis in two pregnancies affected by ORD, utilizing GC/MS analysis of maternal urinary steroid excretion and direct sequencing of the POR gene in DNA from cultured amniocytes. Case 1 was the second pregnancy of non-consanguineous parents with a first child (46, XX) affected by ORD caused by a homozygous A287P mutation and manifest with craniofacial malformations and virilised genitalia. The maternal urine contained excessive amounts of androgen and pregnenolone metabolites, indicative of ORD. This was confirmed by direct sequencing revealing a homozygous A287P mutation also in this second child (46, XY), which will therefore require special perinatal care. Case 2 is the first pregnancy to healthy, non-consanguineous parents. A routine ultrasound scan at 16 weeks revealed an abnormally shaped skull and bowed femora. Follow-up scans also showed underdeveloped external genitalia in the foetus (46, XY). In view of the malformations the parents decided for termination of pregnancy and autopsy showed coronal synostosis, midface hypoplasia, radiohumeral synostosis, a small penis and an absent scrotum. Sequencing analysis commenced after termination of pregnancy revealed a paternally inherited heterozygous A287P mutation, the maternal mutation has yet to be found. Again, urine analysis was suggestive of ORD. Prenatal diagnosis is demanding with regard to its ethical implications and important immediate clinical consequences but may become a valuable tool in families affected by ORD, benefiting the optimum perinatal care based on imminent advances in genotype-phenotype analysis.
01 - 05 Apr 2006
European Society of Endocrinology