POR – Congenital Adrenal Hyperplasia Due to Cytochrome P450 Oxidoreductase Deficiency

P450 oxidoreductase (POR) deficiency (PORD) is an autosomal recessive disorder characterized by impaired electron transfer to microsomal cytochrome P450 enzymes, leading to congenital adrenal hyperplasia with ambiguous genitalia, adrenal insufficiency, and skeletal malformations reminiscent of Antley-Bixler syndrome (PMID:15793702).

Genetic analyses across diverse cohorts have identified over 100 unrelated probands with bi-allelic POR mutations, including both homozygous and compound heterozygous variants. These variants segregate concordantly with disease in multiple families and ethnicities, with a Japanese founder mutation p.Arg454His (c.1361G>A) and recurrent p.Ala287Pro observed in whites (PMID:15793702; PMID:28288674).

The POR variant spectrum encompasses more than 60 pathogenic alleles: missense, nonsense, frameshift, splice-site, and small deletions. A representative pathogenic change, c.1361G>A (p.Arg454His), has been reported in multiple ethnic groups and is associated with severe impairment of microsomal P450 activities (PMID:15793702).

Functional studies have assessed >30 POR missense mutants by in vitro assays of P450c17-supported 17α-hydroxylase/17,20-lyase and CYP21A2 activities. Loss-of-function correlates with clinical severity: mutants such as A287P and R457H display markedly reduced Vmax/Km in steroidogenic assays, establishing a robust genotype–phenotype relationship (PMID:17505056).

Clinically, PORD presents in neonates with atypical genital development (HP:0000062), adrenal dysfunction, and variable skeletal anomalies. Maternal virilization and backdoor androgen excess may occur. Differential diagnosis includes 21-hydroxylase or aromatase deficiencies and FGFR2-related Antley-Bixler syndrome.

Integration of genetic and functional data supports a Definitive gene–disease association. PORD diagnosis relies on targeted sequencing of POR, supplemented by steroid profiling. Functional assays of novel POR variants aid pathogenic classification.

Key Take-home: POR deficiency is a definitive autosomal recessive cause of congenital adrenal hyperplasia with multisystem involvement; comprehensive molecular and functional evaluation is essential for accurate diagnosis and management.

References

• American journal of human genetics • 2005 • Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. PMID:15793702
• Journal of ovarian research • 2017 • Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review. PMID:28288674
• The Journal of clinical endocrinology and metabolism • 2009 • Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. PMID:19258400
• Molecular endocrinology • 2007 • Differential inhibition of CYP17A1 and CYP21A2 activities by the P450 oxidoreductase mutant A287P. PMID:17505056

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