Clinical characteristics: Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.

Diagnosis/testing: The diagnosis of PORD can be established by urinary steroid profiling using gas chromatography / mass spectrometry (GC/MS), which documents combined impairment of 17α-hydroxylase (CYP17A1) and 21-hydroxylase (CYP21A2) enzymatic activity located at key branch points of cortisol, aldosterone, and sex steroid synthesis. Identification of biallelic POR pathogenic variants on molecular genetic testing confirms the diagnosis. Molecular genetic testing is desirable for all individuals affected by PORD to confirm the diagnosis, but is mandatory if clinical and laboratory features are inconclusive.

Management: Treatment of manifestations: Glucocorticoid replacement therapy for cortisol deficiency including stress-dose cover in intercurrent illness; surgery as needed for craniosynostosis, hypospadias, and cryptorchidism in males and clitoromegaly and vaginal hypoplasia in females; dihydrotestosterone treatment has been successful in some males with micropenis; testosterone replacement in males in whom testosterone levels remain relatively low after onset of puberty; females with absent pubertal development may require estrogen replacement therapy; treatment with estradiol to reduce the size of ovarian cysts; endotracheal intubation, nasal stints or tracheotomy, and tracheostomy as needed; physical and occupational therapy for joint contractures and help with fine and gross motor skills.

Prevention of secondary complications: Supplementation with appropriate steroid hormones in individuals who are deficient has helped alleviate adrenal crisis, lack of or poor pubertal development in males and females, sleepiness, and fatigue. Early intervention services may improve the outcome for individuals at risk for developmental delays and learning difficulties.

Surveillance: Evaluations with a specialist tertiary pediatric endocrine service throughout childhood to closely monitor development and adjust steroid supplementation. Periodic formal developmental assessments in centers with expertise and experience in developmental testing.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

Genetic counseling: PORD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal genetic testing for pregnancies at increased risk are possible if the POR pathogenic variants have been identified in the family. In addition, noninvasive testing of maternal urine steroid excretion by GC/MS can indicate whether the unborn child is affected by PORD from gestational week 12 onwards.