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Cytochrome P450 oxidoreductase deficiency caused by a novel mutation in the POR gene in two siblings: case report and literature review

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Abstract

Introduction

P450 oxidoreductase (POR) deficiency is a rare form of congenital adrenal hyperplasia. In both genders, it can lead to ambiguous genitalia, impaired steroidogenesis, and skeletal findings similar to those of Antley-Bixler syndrome.

Cases

We describe two cases of POR deficiency. The first case was an 8.5-year-old girl who was admitted to our clinic due to ambiguous genitalia. Karyotype was 46, XX. There were mild dysmorphic facial findings and mild metacarpophalangeal joint deformity. The patient’s basal cortisol and ACTH levels were normal, while 17-hydroxyprogesterone (17OHP) levels were high. Peak cortisol response to the ACTH stimulation test was found to be insufficient. Our second case, a sibling of the first case, was admitted for routine checkup at the age of 15 months. As in our first case, there were dysmorphic facial findings and metacarpophalangeal joint deformity. The genital structure was normal. Karyotype was 46, XY. Basal cortisol and ACTH levels were normal, while 17OHP level was slightly high. Peak cortisol response to the ACTH stimulation test was found to be insufficient. Based on our findings, POR deficiency was considered in both of these cases and NM_000941.3:c.929_937delTCTCGGACT(p.Ile310_Ser313delinsThr) (homozygous) mutation was detected in the POR gene that had not previously been described.

Conclusion

We detected a novel variant in the POR gene in two sibling cases with adrenal insufficiency, dysmorphic face, and mild skeletal findings. While the detected mutation caused ambiguous genitalia in the female case, it did not cause ambiguous genitalia in the male case.

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References

  1. Fluck CE, Nicolo C, Pandey AV (2007) Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase. Fundam Clin Pharmacol 21:399–410

    Article  CAS  Google Scholar 

  2. Adachi M, Tachibana K, Asakura Y, Yamamoto T, Hanaki K, Oka A (2004) Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome. Am J Med Genet A 128A:333–339

    Article  Google Scholar 

  3. Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP, Malunowicz EM et al (2004) Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet. 363:2128–2135

    Article  CAS  Google Scholar 

  4. Pandey AV, Fluck CE, Huang N, Tajima T, Fujieda K, Miller WL (2004) P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes. Endocr Res 30:881–888

    Article  CAS  Google Scholar 

  5. Miller WL, Huang N, Fluck CE, Pandey AV (2004) P450 oxidoreductase deficiency. Lancet. 364:1663

    Article  Google Scholar 

  6. Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL (2004) Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet 36:228–230

    Article  Google Scholar 

  7. Burkhard FZ, Parween S, Udhane SS, Flück CE, Pandey AV (2017) P450 Oxidoreductase deficiency: analysis of mutations and polymorphisms. J Steroid Biochem Mol Biol 165(Pt A):38–50. https://doi.org/10.1016/j.jsbmb.2016.04.003

    Article  CAS  PubMed  Google Scholar 

  8. Bai Y, Li J, Wang X (2017) Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review. J Ovarian Res 10(1):16. https://doi.org/10.1186/s13048-017-0312-9

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sahakitrungruang T, Huang N, Tee MK, Agrawal V, Russell WE, Crock P, Murphy N, Migeon CJ, Miller WL (2009) Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients. J Clin Endocrinol Metab 94(12):4992–5000. https://doi.org/10.1210/jc.2009-1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Fluck CE, Miller WL (2005) Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 76:729–749

    Article  CAS  Google Scholar 

  11. Debeljak N, Fink M, Rozman D (2003) Many facets of mammalian lanosterol 14alpha-demethylase from the evolutionarily conserved cytochrome P450 family CYP51. Arch Biochem Biophys 409:159–171

    Article  CAS  Google Scholar 

  12. Laue K, Pogoda HM, Daniel PB, van Haeringen A, Alanay Y, von Ameln S, Rachwalski M, Morgan T, Gray MJ, Breuning MH et al (2011) Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid. Am J Hum Genet 89:595–606

    Article  CAS  Google Scholar 

  13. Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C (1985) Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia. N Engl J Med 313:1182–1191

    Article  CAS  Google Scholar 

  14. Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K, Ogata T (2009 May) Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. J Clin Endocrinol Metab 94(5):1723–1731. https://doi.org/10.1210/jc.2008-2816

    Article  CAS  PubMed  Google Scholar 

  15. Krone N, Reisch N, Idkowiak J, Dhir V, Ivison HE, Hughes BA, Rose IT, O’Neil DM, Vijzelaar R, Smith MJ, MacDonald F, Cole TR, Adolphs N, Barton JS, Blair EM, Braddock SR, Collins F, Cragun DL, Dattani MT, Day R, Dougan S, Feist M, Gottschalk ME, Gregory JW, Haim M, Harrison R, Olney AH, Hauffa BP, Hindmarsh PC, Hopkin RJ, Jira PE, Kempers M, Kerstens MN, Khalifa MM, Köhler B, Maiter D, Nielsen S, O’Riordan SM, Roth CL, Shane KP, Silink M, Stikkelbroeck NM, Sweeney E, Szarras-Czapnik M, Waterson JR, Williamson L, Hartmann MF, Taylor NF, Wudy SA, Malunowicz EM, Shackleton CH, Arlt W (2012) Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. J Clin Endocrinol Metab 97(2):257–267. https://doi.org/10.1210/jc.2011-0640

    Article  CAS  Google Scholar 

  16. Fukami M, Horikawa R, Nagai T, Tanaka T, Naiki Y, Sato N, Okuyama T, Nakai H, Soneda S, Tachibana K, Matsuo N, Sato S, Homma K, Nishimura G, Hasegawa T, Ogata T (2005 Jan) Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab 90(1):414–426

    Article  CAS  Google Scholar 

  17. Fukami M, Homma K, Hasegawa T, Ogata T (2013) Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development. Dev Dyn 242:320–329

    Article  CAS  Google Scholar 

  18. Fluck CE, Pandey AV (2011) Clinical and biochemical consequences of p450 oxidoreductase deficiency. Endocr Dev 20:63–79

    Article  CAS  Google Scholar 

  19. Shackleton C, Marcos J, Arlt W, Hauffa BP (2004) Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype. Am J Med Genet A 129a:105–112

    Article  Google Scholar 

  20. Pandey AV, Kempna P, Hofer G, Mullis PE, Fluck CE (2007) Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase. Mol Endocrinol 21:2579–2595

    Article  CAS  Google Scholar 

  21. Homma K, Hasegawa T, Nagai T, Adachi M, Horikawa R, Fujiwara I, Tajima T, Takeda R, Fukami M, Ogata T (2006) Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone. J Clin Endocrinol Metab 91:2643–2649

    Article  CAS  Google Scholar 

  22. Auchus RJ (2004) The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab 15:432–438

    Article  CAS  Google Scholar 

  23. Hershkovitz E, Parvari R, Wudy SA, Hartmann MF, Gomes LG, Loewental N, Miller WL (2008) Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency. J Clin Endocrinol Metab 93:3584–3588

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Endocrinology, Gazi Yaşargil Training and Research Hospital, Diyarbakır, Turkey

    Edip Unal, Meliha Demiral, Funda Feryal Taş & Mehmet Nuri Özbek

  2. Department of Pediatric Endocrinology, Diyarbakır Children’s Hospital, Diyarbakır, Turkey

    Ruken Yıldırım

  3. Department of Medical Genetics, Intergen Genetic Diagnosis Center, Ankara, Turkey

    Serdar Ceylaner

Authors
  1. Edip Unal
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  2. Meliha Demiral
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  3. Ruken Yıldırım
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  4. Funda Feryal Taş
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  5. Serdar Ceylaner
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  6. Mehmet Nuri Özbek
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Correspondence to Edip Unal.

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Unal, E., Demiral, M., Yıldırım, R. et al. Cytochrome P450 oxidoreductase deficiency caused by a novel mutation in the POR gene in two siblings: case report and literature review. Hormones 20, 293–298 (2021). https://doi.org/10.1007/s42000-020-00249-z

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  • DOI: https://doi.org/10.1007/s42000-020-00249-z

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