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Cytochrome P450 Oxidoreductase Gene Mutations and Antley-Bixler Syndrome with Abnormal Genitalia and/or Impaired Steroidogenesis: Molecular and Clinical Studies in 10 Patients

Department of Endocrinology and Metabolism (M.F., N.S., T.Og.), National Research Institute for Child Health and Development, Tokyo 154-8567; National Center for Child Health and Development (R.H., T.T., Y.N., T.Ok., N.M.), Tokyo 154-8535; Departments of Pediatrics (T.N.) and Urology (H.N.), Dokkyo University School of Medicine Koshigaya Hospital, Koshigaya 343-8555; Department of Pediatrics (S.So.), Saint Marianna University School of Medicine, Kawasaki 216-8511; Division of Endocrinology and Metabolism (K.T.), Kanagawa Children’s Medical Center, Yokohama 232-8555; Departments of Pediatrics (N.M., S.Sa., T.H.) and Laboratory Medicine (K.H.), Keio University School of Medicine, Tokyo 160-8582; and Division of Radiology (G.N.), Tokyo Metropolitan Kiyose Children’s Hospital, Kiyose 204-8567, Japan

Address all correspondence and requests for reprints to: Dr. T. Ogata, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3–35-31 Taishido, Setagaya, Tokyo 154-8567, Japan. E-mail: tomogata{at}nch.go.jp.

We report on molecular and clinical findings in 10 Japanese patients (four males and six females) from eight families (two pairs of siblings and six isolated cases) with Antley-Bixler syndrome accompanied by abnormal genitalia and/or impaired steroidogenesis. Direct sequencing was performed for all the 15 exons of cytochrome P450 oxidoreductase gene (POR), showing two missense mutations (R457H and Y578C), a 24-bp deletion mutation resulting in loss of nine amino acids and creation of one amino acid (L612_W620delinsR), a single bp insertion mutation leading to frameshift (I444fsX449), and a silent mutation (G5G). R457H has previously been shown to be a pathologic mutation, and computerized modeling analyses indicated that the 15A>G for G5G could disturb an exonic splicing enhancer motif, and the remaining three mutations should affect protein conformations. Six patients were compound heterozygotes, and three patients were R457H homozygotes; no mutation was identified on one allele of the remaining one patient. Clinical findings included various degrees of skeletal features, such as brachycephaly, radiohumeral synostosis, and digital joint contractures in patients of both sexes, normal-to-poor masculinization during fetal and pubertal periods in male patients, virilization during fetal life and poor pubertal development without worsening of virilization in female patients, and relatively large height gain and delayed bone age from the pubertal period in patients of both sexes, together with maternal virilization during pregnancy. Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities. The results suggest that Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis is caused by POR mutations, and that clinical features are variable and primarily explained by impaired activities of POR-dependent CYP51A1, CYP17A1, CYP21A2, and CYP19A1.

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