Journal article

Publication year: 2013

Pages: K19-K26

Journal: European journal of endocrinology

Volume number: 168

Issue number: 2

ISSN: 0804-4643

eISSN: 1479-683X

Open access status: Green

DOI Link: https://doi.org/10.1530/EJE-12-0628

Publisher: Oxford University Press

Abstract: 

Context: Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism.

Objective: To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases.

Design: Clinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics.

Results: Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management.

Conclusions: Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS). European Journal of Endocrinology 168 K19-K26

Harvard Citation style: Lavery, G., Idkowiak, J., Sherlock, M., Bujalska, I., Ride, J., Saqib, K., et al. (2013) Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling, European journal of endocrinology, 168(2), pp. K19-K26. https://doi.org/10.1530/EJE-12-0628

APA Citation style: Lavery, G., Idkowiak, J., Sherlock, M., Bujalska, I., Ride, J., Saqib, K., Hartmann, M., Hughes, B., Wudy, S., De Schepper, J., Arlt, W., Krone, N., Shackleton, C., Walker, E., & Stewart, P. (2013). Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling. European journal of endocrinology. 168(2), K19-K26. https://doi.org/10.1530/EJE-12-0628