Cytochrome P450 oxidoreductase deficiency

Cytochrome P450 oxidoreductase deficiency
Cytochrome P450 oxidoreductase deficiency
Other names	PORD
Specialty	Endocrinology

Cytochrome P450 oxidoreductase deficiency (PORD)^[1] is a rare disease and inborn error of metabolism caused by deficiency of cytochrome P450 oxidoreductase (POR). POR is a 2-flavin protein that is responsible for the transfer of electrons from NADPH to all 50 microsomal cytochrome P450 (CYP450) enzymes.^[2]^[3] This includes the steroidogenic enzymes CYP17A1 (17α-hydroxylase/17,20-lyase), CYP19A1 (aromatase), and CYP21A2 (21-hydroxylase); CYP26B1 (metabolizes retinoic acid); and the hepatic drug-metabolizing CYP450 enzymes (e.g., CYP3A4),^[4] among many other CYP450 enzymes.^[3] Virilization of female infants in PORD may also be caused by alternative biosynthesis of 5α-dihydrotestosterone via the so-called "androgen backdoor pathway".^[5]^[6] The ABS component of severe forms of PORD is probably caused by CYP26B1 deficiency, which results in retinoic acid excess and defects during skeletal embryogenesis.^[3] All forms of PORD in humans are likely partial, as POR knockout in mice results in death during prenatal development.^[3]

Symptoms and signs

Symptoms of severe forms of PORD include ambiguous genitalia in males and females, congenital adrenal hyperplasia, cortisol deficiency, and Antley–Bixler skeletal malformation syndrome (ABS), while symptoms of mild forms include polycystic ovary syndrome in women and hypogonadism in men.^[3] Maternal virilization also occurs in severe forms, due to aromatase deficiency^[7] in the placenta.^[3]

References

^ Flück, Christa E.; Pandey, Amit V. (2019-01-01), "Human P450 Oxidoreductase Deficiency", in Huhtaniemi, Ilpo; Martini, Luciano (eds.), Encyclopedia of Endocrine Diseases (Second Edition), Academic Press, pp. 431–443, doi:10.1016/b978-0-12-801238-3.64966-8, ISBN 978-0-12-812200-6, S2CID 80510456, retrieved 2020-02-18
^ Pandey, Amit V.; Flück, Christa E. (May 2013). "NADPH P450 oxidoreductase: structure, function, and pathology of diseases". Pharmacology & Therapeutics. 138 (2): 229–254. doi:10.1016/j.pharmthera.2013.01.010. ISSN 1879-016X. PMID 23353702.
^ ^a ^b ^c ^d ^e ^f Mark A. Sperling (10 April 2014). Pediatric Endocrinology E-Book. Elsevier Health Sciences. pp. 497–. ISBN 978-1-4557-5973-6.
^ Burkhard, Fabian Z.; Parween, Shaheena; Udhane, Sameer S.; Flück, Christa E.; Pandey, Amit V. (January 2017). "P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms". The Journal of Steroid Biochemistry and Molecular Biology. 165 (Pt A): 38–50. doi:10.1016/j.jsbmb.2016.04.003. ISSN 1879-1220. PMID 27068427.
^ Masiutin, Maxim; Yadav, Maneesh (2023). "Alternative androgen pathways". WikiJournal of Medicine. 10: X. doi:10.15347/WJM/2023.003. S2CID 257943362.
^ Reisch N, Taylor AE, Nogueira EF, Asby DJ, Dhir V, Berry A, Krone N, Auchus RJ, Shackleton CH, Hanley NA, Arlt W (October 2019). "Alternative pathway androgen biosynthesis and human fetal female virilization". Proceedings of the National Academy of Sciences of the United States of America. 116 (44): 22294–22299. Bibcode:2019PNAS..11622294R. doi:10.1073/pnas.1906623116. PMC 6825302. PMID 31611378.
^ Parween, Shaheena; Fernández-Cancio, Mónica; Benito-Sanz, Sara; Camats, Núria; Velazquez, Maria Natalia Rojas; López-Siguero, Juan-Pedro; Udhane, Sameer S.; Kagawa, Norio; Flück, Christa E.; Audí, Laura; Pandey, Amit V. (2020-02-15). "Molecular basis of CYP19A1 deficiency in a 46, XX patient with R550W mutation in POR: Expanding the PORD phenotype". The Journal of Clinical Endocrinology and Metabolism. 105 (4): e1272–e1290. doi:10.1210/clinem/dgaa076. ISSN 1945-7197. PMID 32060549.