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

Research Institute (M.F., T.O.) and Hospital (R.H.), National Center for Child Health and Development, Tokyo 157-8535, Japan; Division of Radiology (G.N.) and Endocrinology and Metabolism Unit (Y.H.), Tokyo Metropolitan Kiyose Children’s Hospital, Kiyose 204-8567, Japan; Departments of Laboratory Medicine (K.Ho.) and Pediatrics (T.I., T.H.), Keio University Hospital, Tokyo 160-8582, Japan; Department of Pediatrics (T.N.), Dokkyo Medical University Koshigaya Hospital, Koshigaya 343-8555, Japan; Department of Pediatrics and Perinatology (K.Ha.), Tottori University Hospital, Yonago 683-8503, Japan; Division of Endocrinology and Metabolism (A.U.), Shizuoka Children’s Hospital, Shizuoka 420-8660, Japan; Department of Pediatrics (C.N.), Yamagata University Hospital, Yamagata 990-9585, Japan; Department of Pediatrics (H.S.), University of Miyazaki Hospital, Miyazaki 889-1692, Japan; Department of Pediatrics (M.Nakac.), Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan; Department of Pediatrics (T.K.), Gunma University Hospital, Maebashi 371-8511, Japan; Division of Pediatrics (K.M.), Nagasaki University Hospital, Nagasaki 852-8102, Japan; Department of Pediatrics and Adolescent Medicine (H.H.), Juntendo University Hospital, Tokyo 113-8421, Japan; Department of Pediatrics, Kagoshima University Hospital (M.Nakam.), Kagoshima 890-8520, Japan; Department of Pediatrics (A.O.), Hamamatsu University Hospital, Hamamatsu 431-3192, Japan; Division of Endocrinology and Metabolism (M.A.), Kanagawa Children’s Medical Center, Yokohama 232-8555, Japan; Department of Pediatrics (T.T.), Hokkaido University, Sapporo 060-8638, Japan; and Department of Pediatrics (K.F.), Asahikawa Medical Collage Hospital, Asahikawa 078-8510, Japan

Address all correspondence and requests for reprints to: Dr. M. Fukami, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan. E-mail: mfukami{at}nch.go.jp.

Context: Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, disorders of sex development (DSD), and maternal virilization during pregnancy. Although multiple studies have been performed for this condition, several matters remain to be clarified, including the presence of manifesting heterozygosity and the underlying factors for clinical variability.

Objective: The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations.

Patients: Thirty-five Japanese patients with POR deficiency participated in the study.

Results: Mutation analysis revealed homozygosity for R457H in cases 1–14 (group A), compound heterozygosity for R457H and one apparently null mutation in cases 15–28 (group B), and other combinations of mutations in cases 29–35 (group C). In particular, FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent R457H homozygote, transcription failure of apparently normal alleles in three R457H heterozygotes, and nonsense mediated mRNA decay in two frameshift mutation-positive cases examined. Genotype-phenotype correlations indicated that skeletal features were definitely more severe, and adrenal dysfunction, 46,XY DSD, and pubertal failure were somewhat more severe in group B than group A, whereas 46,XX DSD and maternal virilization during pregnancy were similar between two groups. Notable findings also included the contrast between infrequent occurrence of 46,XY DSD and invariable occurrence of 46,XX DSD and pubertal growth pattern in group A mimicking that of aromatase deficiency.

Conclusions: The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.

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