Clinical Guidance

While individuals with the same pathogenic variants (even sibs) can show phenotypic variations, some commonalities are observed among individuals with the same genotype. The broad phenotypic spectrum of PORD may be caused by the effect of various POR pathogenic variants on different enzymatic reactions [, , , , ]. Three studies report the investigation of genotype-phenotype correlations in larger cohorts of individuals with PORD . The observations from these studies include the following.

Skeletal malformations

Source: GeneReviews — "Cytochrome P450 Oxidoreductase Deficiency"

Diagnostic Criteria

Suggestive Findings

Cytochrome P450 oxidoreductase deficiency (PORD) is an autosomal recessive disorder with a broad phenotypic spectrum including skeletal malformations resembling the Antley-Bixler syndrome (ABS) phenotype and abnormalities in adrenal steroid biosynthesis resulting in congenital adrenal hyperplasia (CAH).

Clinical Findings

Skeletal abnormalities. PORD should be suspected in individuals with features of ABS. Affected individuals may present with the following congenital craniofacial and skeletal anomalies:

Source: GeneReviews — "Cytochrome P450 Oxidoreductase Deficiency"

Differential Diagnosis

Congenital adrenal hyperplasia (CAH) is a heterogeneous group of autosomal recessive conditions that result in impaired synthesis of cortisol, mineralocorticoids, and/or sex steroids. Based on this definition, the term CAH can be used to describe cytochrome P450 oxidoreductase deficiency (PORD). PORD and the following etiologies of CAH may be distinguished by differences in urinary steroid profiles, molecular genetic testing, and/or the presence of skeletal anomalies, as skeletal anomalies are never found in other forms of CAH, but may occur in PORD. POR acts as an electron donor to two major steroidogenic enzymes, CYP21A2 and CYP17A1. Therefore, individuals with POR show biochemical features of both 21-hydroxylase and 17-hydroxylase deficiency.

• 21-hydroxylase deficiency

Source: GeneReviews — "Cytochrome P450 Oxidoreductase Deficiency"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PORD, the following evaluations are recommended:

• Evaluations by appropriate specialists in endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology

• Assessment for airway problems in individuals with skeletal malformations

• Functional adrenal studies (cosyntropin test) to assess glucocorticoid deficiency, regardless of the presence or absence of genital abnormalities

• Additional studies that may be indicated:

• Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth

• Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures

• Echocardiogram if a heart defect is suspected

• Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls.

Treatment of Manifestations

Cortisol deficiency

• Regular hydrocortisone replacement therapy is indicated if baseline serum cortisol concentrations are low.

• Stress-dose steroids should be provided perioperatively and during times of physiologic stress in individuals in whom cortisol response to ACTH stimulation (cosyntropin test) is below normal .

Genital abnormalities

Source: GeneReviews — "Cytochrome P450 Oxidoreductase Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Cytochrome P450 Oxidoreductase Deficiency"

Surveillance Guidelines

Individuals with PORD should be seen by a specialist tertiary pediatric endocrine service throughout childhood to closely monitor their development and adjust steroid supplementation. Because of the presence of developmental delays in many individuals with ABS, periodic formal developmental assessments may be indicated. However, interpretation of these assessments may be complicated by the physical limitations of the disorder. Screening evaluations are likely to underestimate cognitive abilities. Therefore, evaluations should be done in centers with expertise and experience in developmental testing.

Source: GeneReviews — "Cytochrome P450 Oxidoreductase Deficiency"