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Steroid Biomarkers and Genetic Studies Reveal Inactivating Mutations in Hexose-6-Phosphate Dehydrogenase in Patients with Cortisone Reductase Deficiency

Division of Medical Sciences (G.G.L., E.A.W., A.T., C.H.L.S., J.W.T., W.A., P.M.S.), and School of Biosciences (J.P.R.), University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Medical Research Council Blood Pressure Group (J.M.C.C.), University of Glasgow, G12 8TA Glasgow, Scotland, United Kingdom; Endocrine Sciences Research Group (D.W.R.), University of Manchester, Manchester M13 9PT, United Kingdom; University Children’s Hospital (A.B.-L.), CH-8032 Zürich, Switzerland; and Department of Laboratory Diagnostics (E.M.M.), The Children’s Memorial Health Institute, 04-736 Warsaw, Poland

Address all correspondence and requests for reprints to: Paul M. Stewart, M.D., FRCP, FmedSci, Professor of Medicine, Division of Medical Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk.

Context: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11β-HSD1 oxoreductase activity requires the reduced nicotinamide adenine dinucleotide phosphate-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligo-amenorrhea, and infertility in females and premature pseudopuberty in males. Recent association studies have failed to corroborate findings that polymorphisms in the genes encoding H6PDH (R453Q) and 11β-HSD1 (Intron 3 inserted adenine) interact to cause CRD.

Objective: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD.

Design: We analyzed 24-h urine collection for steroid biomarkers by gas chromatography/mass spectrometry and sequenced the HSD11B1 and H6PD genes in our CRD cohort.

Patients: Patients included four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD.

Results: Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960GA and D620fsX3) for mutations in H6PD. No mutations affecting enzyme activity were identified in the HSD11B1 gene. Expression and activity assays demonstrate loss of function for all reported H6PDH mutations.

Conclusions: CRD is caused by inactivating mutations in the H6PD gene, rendering the 11β-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11β-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.