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P450 oxidoreductase (POR) Deficiency

المؤلف:  Wass, J. A. H., Arlt, W., & Semple, R. K. (Eds.).

المصدر:  Oxford Textbook of Endocrinology and Diabetes

الجزء والصفحة:  3rd edition , p939

2026-08-18

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P450 oxidoreductase (POR; OMIM *124015) deficiency (PORD; OMIM #201750) presents biochemically and clinically as ap parent combined CYP17A1- CYP21A2 deficiency and with a mal formation phenotype resembling the Antley– Bixler syndrome (ABS, OMIM #207410). The incidence of PORD remains unclear, but it is likely the third most common CAH variant, after 21OHD and 11OHD. POR serves as an electron donor enzyme to CYP21A2, CYP17A1, and CYP19A1 (P450 aromatase). PORD impacts on both glucocorticoid and sex steroid synthesis and can result in mineralocorticoid excess with hypertension, albeit milder than in other CAH variants and often only manifesting in adulthood. The PORD phenotype usually consists of adrenal insufficiency, DSD or normal sex development in both sexes and presentations with or without skeletal and other malformations. In contrast to other hyperandrogenic CAH forms, virilization does not progress after birth. Primary hypogonadism and lack or delayed pubertal development has been reported in both sexes. PORD is a multisystem disorders as it affects all microsomal CYP enzymes relying on POR for their enzymatic function (Table 1). The POR gene (GeneID 5447; GenbankID NC_ 000007.12) spans 32.9 kb and located on 7q11.2. It consists of 15 translated exons encoding for a 680 amino acid protein. An untranslated exon is located approximately 30.5 kb upstream of the first translated exon (Figure 1). POR is highly poly morphic with 140 genetic variants identified in a large cohort of healthy individuals and over 60 disease- causing mutations have been described. No clear mutational hot spot exists for POR- inactivating mutations apart from two frequently detected mutations. The p.Ala287Pro mutation accounts for approximately 50% of mutated alleles in Caucasians, whereas the p.Arg457His mutation is the most common mutation (50– 70% of alleles) in the Japanese population. Some studies have explored the genotype- phenotype correlation in PORD. The phenotypic expression of a specific genotype is variable. Carriers of two mild mutations commonly present with a milder phenotype than com pound heterozygotes for a mild and a severe mutation. Generally, mutations causing 46,XY DSD present with normal female ex ternal genitalia in 46,XX individuals and variants associated with 46,XX DSD lead to normal external male genitalia in 46,XY individuals. In carriers of severe genotypes, more severe skeletal and other complex malformation can be found. The variable genotype- phenotype correlation is likely to be caused by the differential impact of POR mutations on the catalytic activity of different microsomal CYP enzymes; the malformation phenotype is explained by impairment of POR- dependent CYP enzymes in volved in sterol biosynthesis and retinoic acid metabolism.

Table1. Differential diagnosis of congenital adrenal hyperplasia— clinical, biochemical, and genetic characteristics

Fig1. Genomic organization of genes causing different forms of congenital adrenal hyperplasia. (1) Genes encoding steroidogenic Cytochrome P450 type II enzymes: (a) The 21- hydroxylase (CYP21A2) gene consists of 10 exons and it is typically amplified in two overlapping fragments. (b) The 17- hydroxylase (CYP17A1) gene consists of 8 exons and different strategies have been employed either amplifying the gene in five or in two fragments. (2) Genes encoding steroidogenic Cytochrome P450 type I enzymes: (c) The 11- hydroxylase (CYP11B1) gene consists of 9 exons and is usually amplified in three overlapping fragments, although non- overlapping strategies have been described. (d) The P450 side chain cleavage (CYP11A1) gene consists of 9 exons and it is usually amplified in small non- overlapping fragments, although different PCR strategies have been described. (e) The aldosterone synthase (CYP11B2) gene consists of 9 exons normally amplified in either two overlapping fragments or three non- overlapping fragments. (3) Genes encoding hydroxysteroid dehydrogenases: (f) The hydroxysteroid dehydrogenase type 2 (HSD3B2) gene has 4 exons; exon 1 and the 5- prime part of exon 2 are not translated. (4) Gene encoding the electron donor of steroidogenic cytochrome P450 type II: (g) The P450 oxidoreductase (POR) gene has 15 translated exons and an untranslated exon (1U). PCR amplification is performed in several small fragments. (5) Gene encoding for a cholesterol transporter: (h) The steroid acute regulatory protein (StAR) gene consists of 7 exons commonly amplified in five fragments.