Linking Antley–Bixler syndrome and congenital adrenal hyperplasia: A novel case of P450 oxidoreductase deficiency

Abstract

The Antley-Bixler syndrome (ABS) is a multiple congenital malformation syndrome with craniosynostosis, radiohumeral synostosis, femoral bowing, choanal atresia or stenosis, joint contractures, urogenital abnormalities and, often, early death. Autosomal recessive and dominant inheritance have been postulated, as has fluconazole teratogenesis. Mutations in POR (P450 (cytochrome) oxidoreductase, an essential electron donor to enzymes participating in cholesterol biosynthesis), have been identified in some patients with the ABS phenotype. Recent evidence suggests that these mutations cause attenuated steroid hydroxylation, which in turn, causes congenital adrenal hyperplasia (CAH) with ambiguous genitalia in both sexes and glucocorticoid deficiency. Here, we report on a new patient with findings of both ABS and CAH that further illustrates how low maternal estriol at prenatal screening can serve as a marker steroid facilitating early diagnosis.

Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

“…NN, Neonatal; Y, yes; N, no; n/a, not available; ND, not done; PL, Poland; D, Germany; USA, United States of America; UK, United Kingdom; NL, The Netherlands; CAN, Canada; PAK, Pakistan; ITA, Italy; AUT, Austria; MEX, Mexico; AUS, Australia. Mutation: —, Alleles without identified disease-causing mutation.aPatients whose geno- and phenotype was reported in a previous publication: P01 [case 1 (4)], P03 [case 2 (4)], P04 [case 3 (4)]; P08 (33); P11 (34); and P24 (32). …”

“…aPatients whose geno- and phenotype was reported in a previous publication: P01 [case 1 (4)], P03 [case 2 (4)], P04 [case 3 (4)]; P08 (33); P11 (34); and P24 (32). …”

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

“…In this regard, A287P is common in Caucasian patients (4,5), and clinical studies in 10 A287P-positive patients including three homozygotes (five with 46,XY and five with 46,XX) have suggested phenotypic similarities and differences between R457H-positive patients and A287P-positive patients: 1) skeletal phenotype is usually obvious and appears to be grossly dependent on the A287P dosage; 2) 46,XY DSD is variable and is apparently independent of the A287P dosage; 3) 46,XX DSD is also variable and absent in one A287P homozygote and one of four compound heterozygotes with A287P; and 4) maternal virilization during pregnancy is not described (1,2,5,31,32). Thus, skeletal phenotype would be explained by assuming that both R457H and A287P have drastically lost supporting activities for CYP51A1 and/or SQLE involved in cholesterologenesis, although functional studies have not been performed.…”

Cytochrome P450 oxidoreductase deficiency: Rare congenital disorder leading to skeletal malformations and steroidogenic defects

“…The first patients with POR mutations were identified in 2004 by Flück et al . More than 60 patients were reported within a few years after the initial report, indicating that PORD is a relatively common form of CAH . This review article provides an overview of the current understanding of the molecular basis and clinical manifestations of this newly characterized disorder.…”