BES2005 Oral Communications Oral Communication 2: Reproduction and growth (8 abstracts)
Pathophysiology and genetics of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency
V Dhir 1 , HE Ivison 1 , EA Walker 1 , ND Draper 1 , F Hammer 1 , EM Malunowicz 2 , PM Stewart 1 , CHL Shackleton 1,3 & W Arlt 1
1Division of Medical Sciences, University of Birmingham, UK; 2Children's Health Memorial Institute, Warsaw, Poland; 3Children's Hospital Oakland Research Institue, Oakland, CA, USA.
We have recently identified inactivating mutations in the electron donor enzyme P450 oxidoreductase as the cause of disease in patients with apparent combined P450c17 and P450c21 deficiency, a variant of congenital adrenal hyperplasia (CAH) (1). Additionally, we suggested that P450 oxidoreductase deficiency (ORD) reveals the existence of an alternative pathway in human androgen synthesis present in fetal life only, explaining the concurrent presence of low circulating androgens and virilized genitalia in affected girls (1). Here we report the clinical presentation, biochemical and genetic analysis of 16 ORD patients (ten female, six male) from 15 unrelated families. Seven girls presented with virilized genitalia and three boys with undermasculinization. As an additional feature, 12 of the 16 patients showed evidence of cranio-facial malformations resembling the Antley-Bixler malformation syndrome. GC/MS analysis of urinary steroid metabolite excretion was available in 13 of 16, showing the typical ORD pattern with increased pregnenolone and progesterone metabolites. The degree of glucocorticoid deficiency was variable. Genetic analysis revealed a A284P mutation in exon 8 to be most prevalent, affecting at least one allele in two thirds of all patients sequenced. In addition, A284P was present as a homozygous mutation in three of the patients while all other patients were compound heterozygotes. In addition to six mutations encoding for a single amino acid change we identified three mutations in immediate proximity of an exon-intron junction, predicted to result in abnormal splicing. Functional analysis by bacterial expression of recombinant mutant OR proteins and yeast co-expression of P450c17 and wild-type and mutant OR confirmed the inactivating nature of the identified mutations. Analysis of phenotype-genotype variability in ORD will help to further characterize the importance of intracellular redox potential regulation in the differential control of steroidogenesis. (1) Lancet 2004, 363:2128-2135. The authors wish to thank the referring physicians.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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