Cytochrome P450 Oxidoreductase Deficiency: Identification and Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese Patients

Fukami, Maki; Nishimura, Gen; Homma, Keiko; Nagai, Toshiro; Hanaki, Keiichi; Uematsu, Ayumi; Ishii, Tomohiro; Numakura, Chikahiko; Sawada, Hirotake; Nakacho, Mariko; Kowase, Takanori; Motomura, Katsuaki; Haruna, Hidenori; Nakamura, Mihoko; Ohishi, Akira; Adachi, Masanori; Tajima, Toshihiro; Hasegawa, Yukihiro; Hasegawa, Tomonobu; Horikawa, Reiko; Fukui, Kenji; Ogata, Tsutomu

doi:10.1210/jc.2008-2816

Cited by 108 publications

(154 citation statements)

References 33 publications

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“…There are few data on puberty development (10,13,15). Our case presented partial pubertal development at age of 14, which was similar to the previous series of seven PORD patients, in which five female patients presented pubertal delay and large ovarian cysts were observed in all of them (10).…”

Section: Discussionsupporting

confidence: 89%

“…Our case, and other 46,XX patients who are homozygous for this mutation, presented with external genitalia virilization, in contrast to 46,XY patients who exhibit normal external genitalia. On the other hand, the most common mutation in the Japanese population, the p.R457H mutation, is associated with a higher prevalence of atypical genitalia in both 46,XX than 46,XY patients (100% versus 44%, respectively) (13). The degree of external genitalia virilization is moderate in most 46,XX PORD patients, which is differently than the 21-hydroxylase deficiency.…”

Section: Discussionmentioning

confidence: 96%

“…The adrenal insufficiency documented by cosyntropin was found in almost all patients in large cohorts, of those 50% needed permanent hydrocortisone (8,13). This phenotype is due to impairment of P450c17 activity with a concomitant deficiency of P450c21.…”

Section: Discussionmentioning

confidence: 99%

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Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

Bonamichi

Santiago

Bertola

et al. 2016

Arch. Endocrinol. Metab.

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SUMMARYP450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient. Arch Endocrinol Metab. 2016;60(5):500-4

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 96%

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Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

Bonamichi

Santiago

Bertola

et al. 2016

Arch. Endocrinol. Metab.

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“…Enzymatic residual activity in PORD has been reported to differ depending on genotype (17 ). The common mutation was R457H in Japanese PORD (7,18 ) and A287P in whites (19 ). R457H has 1%-3% supporting activity for 17␣-hydroxylase and virtually no activity for 17,20-lyase compared to wild type, whereas A287P has 40% activity for 17␣-hydroxylase and about 20% for 17,20-lyase (17,19,20 ).…”

Section: Biochemical Diagnosis Of C21ohd and Pordmentioning

confidence: 99%

Two-Step Biochemical Differential Diagnosis of Classic 21-Hydroxylase Deficiency and Cytochrome P450 Oxidoreductase Deficiency in Japanese Infants by GC-MS Measurement of Urinary Pregnanetriolone/ Tetrahydroxycortisone Ratio and 11β-Hydroxyandrosterone

et al. 2012

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BACKGROUND The clinical differential diagnosis of classic 21-hydroxylase deficiency (C21OHD) and cytochrome P450 oxidoreductase deficiency (PORD) is sometimes difficult, because both deficiencies can have similar phenotypes and high blood concentrations of 17α-hydroxyprogesterone (17OHP). The objective of this study was to identify biochemical markers for the differential diagnosis of C21OHD, PORD, and transient hyper 17α-hydroxyprogesteronemia (TH17OHP) in Japanese newborns. We established a 2-step biochemical differential diagnosis of C21OHD and PORD. METHODS We recruited 29 infants with C21OHD, 9 with PORD, and 67 with TH17OHP, and 1341 control infants. All were Japanese and between 0 and 180 days old; none received glucocorticoid treatment before urine sampling. We measured urinary pregnanetriolone (Ptl), the cortisol metabolites 5α- and 5β-tetrahydrocortisone (sum of these metabolites termed THEs), and metabolites of 3 steroids, namely dehydroepiandrosterone, androstenedione (AD4), and 11β-hydroxyandrostenedione (11OHAD4) by GC-MS. RESULTS At a cutoff of 0.020, the ratio of Ptl to THEs differentiated C21OHD and PORD from TH17OHP and controls with no overlap. Among metabolites of DHEA, AD4, and 11OHAD4, only 11β-hydroxyandrosterone (11HA), a metabolite of 11OHAD4, showed no overlap between C21OHD and PORD at a cutoff of 0.35 mg/g creatinine. CONCLUSIONS A specific cutoff for the ratio of Ptl to THEs can differentiate C21OHD and PORD from TH17OHP and controls. Additionally, the use of a specific cutoff of 11HA can distinguish between C21OHD and PORD.

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“…The mildest end of the POR spectrum presents as individual with only steroidogenesis defects (amenorrhea, polycystic ovarian syndrome and infertility) [Fukami et al, 2009].…”

Section: Antley-bixlermentioning

confidence: 99%

Current Issues Regarding Prenatal Diagnosis of Inborn Errors of Cholesterol Biosynthesis

Cardoso¹,

Barbosa²,

Fortuna³

et al. 2012

Prenatal Diagnosis - Morphology Scan and Invasive Methods

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Cytochrome P450 Oxidoreductase Deficiency: Identification and Characterization of Biallelic Mutations and Genotype-Phenotype Correlations in 35 Japanese Patients

Cited by 108 publications

References 33 publications

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

Two-Step Biochemical Differential Diagnosis of Classic 21-Hydroxylase Deficiency and Cytochrome P450 Oxidoreductase Deficiency in Japanese Infants by GC-MS Measurement of Urinary Pregnanetriolone/ Tetrahydroxycortisone Ratio and 11β-Hydroxyandrosterone

Current Issues Regarding Prenatal Diagnosis of Inborn Errors of Cholesterol Biosynthesis

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