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Endocrine Abstracts (2018) 59 CC1 | DOI: 10.1530/endoabs.59.CC1

SFEBES2018 Featured Clinical Cases Featured Clinical Cases (10 abstracts)

Pitfalls in the diagnosis of an infant with 46,XX DSD with Congenital Adrenal Hyperplasia due to Cytochrome P450 Oxidoreductase deficiency - the value of simultaneous genetic analysis to the diagnosis in DSD

Jan Idkowiak 1, , Zainaba Mohamed 1, , Stephanie Allen 2, , Harish Chandran 5 , Liam McCarthy 5 , Jeremy Kirk 1, , Trevor Cole 2, & Nils Krone 1,

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1Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK; 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK; 3Institute of Metabolism and Systems Research, University of Birminham, Birmingham, UK; 4West Midlands Regional Genetic Service, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK; 5Department of Paediatric Urology, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK; 6Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.


Background: Congenital adrenal hyperplasia (CAH) is the underlying diagnosis in most newborns presenting with 46,XX disorders of sex development (DSD). Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of CAH caused by inactivating mutations in the POR gene. The hallmark feature of PORD is combined sex-steroid and glucocorticoid deficiency due to impairment of CYP17A1 and CYP21A2. Skeletal malformations resembling the Antley-Bixler Syndrome phenotype are common in PORD.

Case report: Clitoromegaly, fused labia majora and a single opening was noted after term birth of the infant (46,XX). No overt skeletal malformations were evident. Her 17OHP was normal (3.6 nmol/l) with insufficient cortisol increase after synacthen (baseline: 210 nmol/l; peak: 239 nmol/l). Under the clinical assumption of CAH due to CYP21A2 deficiency, hydrocortisone and fludrocortisone replacement was initated. Urinary steroid profiling performed by an external service lab at 7 days of age showed high amounts of 16-alpha hydroxypregnenolone, but steroid metabolites typically raised in common forms of CAH were not elevated. Next generation sequencing employing a multi-gene DSD panel revealed a homozygous mutation (p.Gly539Arg) of the PORgene previously reported in four 46,XY DSD patients.

Summary and conclusions: This is the first 46,XX patient carrying the p.Gly539Arg PORmutation, which was shown to have a mild effect on CYP17A1 17-alpha hydroxylase catalytic activity in vitro. The diagnosis of PORD via urinary steroid profiling in a clinical service lab was not achieved, although impaired 17,20 lyase activity was suggested by accumulation of pregnenolone metabolites in an early neonatal sample. This case highlights the benefits for the management of DSD patients when employing a simultaneous approach of clinical, biochemical and genetic testing. Secondly, it emphasizes the challenges in establishing the correct diagnosis of rare steroidogenic disorders via urinary steroid profiling, in particular in neonatal samples.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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