Top

Journal of Ovarian Research

Published in:

Open Access 01-12-2017 | Case report

Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review

Authors: Yang Bai, Jinhui Li, Xiaoli Wang

Published in: Journal of Ovarian Research | Issue 1/2017

Abstract

Background

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations. It can be difficult to differentiate with other diseases such as 21-hydroxylase deficiency (21-OHD), polycystic ovary syndrome (PCOS) and Antley–Bixler syndrome (ABS). Nearly 100 cases of PORD have been reported worldwide. However, the genetic characters and clinical management are still unclear, especially in China.

Case presentation

In this study, we report a 27-year-old female Chinese patient who first presented with amenorrhea and recurrence of large ovary cyst. She was misdiagnosed with PCOS and non-classical 21-OHD due to ovary cysts and elevated 17-hydroxy-progesterone. The patient’s complaining of a mild difficulty of bending the metacarpophalangeal joints reminded us to consider PORD, which usually presents with skeletal deformities and sexual dysfunction. The diagnosis of PORD was confirmed by genetic analyses, which showed the patient harboring a homozygous missense mutation in the POR gene (R457H) and her parents carrying the heterozygous mutation. The patient was treated with low-dose corticosteroids and estrogen/progesterone sequential therapy, and her ovarian cyst gradually reduced with regular menstruation in the follow-up. Moreover, the clinical and genetic characteristics of 104 previously reported PORD cases were also summarized and analyzed.

Conclusions

PORD is a very rare disease which can be easily misdiagnosed in mild cases. Clinicians should keep in mind of this disease in patients with sexual dysfunction, especially combined with special skeletal deformities. Our data could provide a consciously understanding of this disease for clinic practicers. Low-dose corticosteroids combined with estrogen/progesterone sequential therapy will be effective in PORD patients with recurrence of large ovary cyst. The fact that the reported PORD patients in China carrying an identical variant R457H in POR gene also give us a viewpoint that R457H mutation in POR gene maybe important in causing PORD in Chinese as same as in Japanese.

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

Adachi M, Tachibana K, Asakura Y, Yamamoto T, Hanaki K, Oka A. Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome. Am J Med Genet A. 2004;128A:333–9.CrossRefPubMed

Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP, Malunowicz EM, et al. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet. 2004;363:2128–35.CrossRefPubMed

Pandey AV, Fluck CE, Huang N, Tajima T, Fujieda K, Miller WL. P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes. Endocr Res. 2004;30:881–8.CrossRefPubMed

Miller WL, Huang N, Fluck CE, Pandey AV. P450 oxidoreductase deficiency. Lancet. 2004;364:1663.CrossRefPubMed

Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004;36:228–30.CrossRefPubMed

Peterson RE, Imperato-McGinley J, Gautier T, Shackleton C. Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia. N Engl J Med. 1985;313:1182–91.CrossRefPubMed

Fukami M, Homma K, Hasegawa T, Ogata T. Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development. Dev Dyn. 2013;242:320–9.CrossRefPubMed

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

10.

Shackleton C, Marcos J, Arlt W, Hauffa BP. 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. 2004;129a:105–12.CrossRefPubMed

11.

Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Fluck CE, Miller WL. Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet. 2005;76:729–49.CrossRefPubMedPubMedCentral

12.

Agrawal V, Huang N, Miller WL. Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomics. 2008;18:569–76.CrossRefPubMed

13.

Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, et al. Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients. J Clin Endocrinol Metab. 2009;94:1723–31.CrossRefPubMed

14.

Idkowiak J, O’Riordan S, Reisch N, Malunowicz EM, Collins F, Kerstens MN, Kohler B, Graul-Neumann LM, Szarras-Czapnik M, Dattani M, et al. Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. J Clin Endocrinol Metab. 2011;96:E453–62.CrossRefPubMed

15.

Tomalik-Scharte D, Maiter D, Kirchheiner J, Ivison HE, Fuhr U, Arlt W. Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. Eur J Endocrinol. 2010;163:919–24.CrossRefPubMedPubMedCentral

16.

Krone N, Reisch N, Idkowiak J, Dhir V, Ivison HE, Hughes BA, Rose IT, O’Neil DM, Vijzelaar R, Smith MJ, et al. Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. J Clin Endocrinol Metab. 2012;97:E257–67.CrossRefPubMed

17.

Debeljak N, Fink M, Rozman D. Many facets of mammalian lanosterol 14alpha-demethylase from the evolutionarily conserved cytochrome P450 family CYP51. Arch Biochem Biophys. 2003;409:159–71.CrossRefPubMed

18.

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

19.

Subramanian M, Agrawal V, Sandee D, Tam HK, Miller WL, Tracy TS. Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3. Pharmacogenet Genomics. 2012;22:590–7.CrossRefPubMed

20.

Pandey AV, Fluck CE. NADPH P450 oxidoreductase: structure, function, and pathology of diseases. Pharmacol Ther. 2013;138:229–54.CrossRefPubMed

21.

Pandey AV, Fluck CE, Mullis PE. Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase. Biochem Biophys Res Commun. 2010;400:374–8.CrossRefPubMed

22.

Fluck CE, Mullis PE, Pandey AV. Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism. Biochem Biophys Res Commun. 2010;401:149–53.CrossRefPubMed

23.

Sandee D, Morrissey K, Agrawal V, Tam HK, Kramer MA, Tracy TS, Giacomini KM, Miller WL. Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. Pharmacogenet Genomics. 2010;20:677–86.CrossRefPubMed

24.

Huang N, Agrawal V, Giacomini KM, Miller WL. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci U S A. 2008;105:1733–8.CrossRefPubMedPubMedCentral

25.

Parween S, Roucher-Boulez F, Fluck CE, Lienhardt-Roussie A, Mallet D, Morel Y, Pandey AV. P450 oxidoreductase deficiency: loss of activity caused by protein instability from a novel L374H mutation. J Clin Endocrinol Metab. 2016;101:4789–98.CrossRefPubMed

26.

Bonamichi BD, Santiago SL, Bertola DR, Kim CA, Alonso N, Mendonca BB, Bachega TA, Gomes LG. Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency. Arch Endocrinol Metab. 2016;60:500–4.CrossRefPubMed

27.

Tzetis M, Konstantinidou A, Sofocleous C, Kosma K, Mitrakos A, Tzannatos C, Kitsiou-Tzeli S. Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in POR gene: Antley-bixler syndrome phenotype in three sibling fetuses. Birth Defects Res A Clin Mol Teratol. 2016;106:536–41.CrossRefPubMed

28.

Koika V, Armeni AK, Georgopoulos NA. Delayed diagnosis of disorder of sex development (DSD) due to P450 oxidoreductase (POR) deficiency. Hormones (Athens). 2016;15:277–82.CrossRef

29.

Fluck CE, Mallet D, Hofer G, Samara-Boustani D, Leger J, Polak M, Morel Y, Pandey AV. Deletion of P399_E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency. Biochem Biophys Res Commun. 2011;412:572–7.CrossRefPubMed

30.

Sahakitrungruang T, Huang N, Tee MK, Agrawal V, Russell WE, Crock P, Murphy N, Migeon CJ, Miller WL. Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients. J Clin Endocrinol Metab. 2009;94:4992–5000.CrossRefPubMedPubMedCentral

31.

Ko JM, Cheon CK, Kim GH, Yoo HW. A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene. Eur J Pediatr. 2009;168:877–80.CrossRefPubMed

32.

Hershkovitz E, Parvari R, Wudy SA, Hartmann MF, Gomes LG, Loewental N, Miller WL. Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency. J Clin Endocrinol Metab. 2008;93:3584–8.CrossRefPubMedPubMedCentral

33.

Scott RR, Gomes LG, Huang N, Van Vliet G, Miller WL. Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2007;92:2318–22.CrossRefPubMed

34.

Fukami M, Horikawa R, Nagai T, Tanaka T, Naiki Y, Sato N, Okuyama T, Nakai H, Soneda S, Tachibana K, et al. 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. 2005;90:414–26.CrossRefPubMed

35.

Adachi M, Asakura Y, Matsuo M, Yamamoto T, Hanaki K, Arlt W. POR R457H is a global founder mutation causing Antley-Bixler syndrome with autosomal recessive trait. Am J Med Genet A. 2006;140:633–5.CrossRefPubMed

Title: Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review
Authors: Yang Bai
Jinhui Li
Xiaoli Wang
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2017
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/s13048-017-0312-9

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review

Abstract

Background

Case presentation

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Case presentation

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency

Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo

Racial health disparities in ovarian cancer: not just black and white

Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression

PMS2 gene mutation results in DNA mismatch repair system failure in a case of adult granulosa cell tumor

Impact of oocytes with CLCG on ICSI outcomes and their potential relation to pesticide exposure