SFEBES2009 Poster Presentations Growth and development (8 abstracts)
Phenotypic presentation of P450 oxidoreductase deficiency during puberty
Jan Idkowiak 1 , Stephen O’Riordan 2 , Nicole Reisch 1 , Vivek Dhir 1 , Ewa Malunowicz 3 , Michiel Kerstens 4 , Dominique Maiter 5 , Felicity Collines 6 , Martin Silink 7 , Mehul Dattani 2 , Cedric Shackleton 1 , Nils Krone 1 & Wiebke Arlt 1
1School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; 2Developmental Endocrinology Research Group, Clinical and Molecular Genetics, Institute of Child Health, University College London, London, UK; 3Division of Endocrinology, The Children’s Memorial Health Institute, Warsaw, Poland; 4Department of Endocrinology, University Medical Centre Groningen, Groningen, The Netherlands; 5Department of Endocrinology, University Hospital Saint Luc, Brussels, Belgium; 6Department of Clinical Genetics, Children’s Hospital at Westmead, Sydney, Australia; 7Department of Paediatric Endocrinology, Children’s Hospital at Westmead, Sydney, Australia.
P450 oxidoreductase (POR) transfers electrons to all microsomal P450 enzymes including CYP21A2 and CYP17A1, key enzymes of glucocorticoid and andogen synthesis, respectively. Mutant POR results P450 oxidoreductase deficiency (ORD) manifesting with glucocorticoid deficiency and disordered sex development in both sexes. Neonatal presentation with undervirilisation in boys and virilisation in girls is well described. However, there is a paucity of data on the pubertal phenotype in ORD. Here we present the pubertal phenotype in five ORD patients (three females, two males). In all cases, we confirmed ORD by urinary steroid analysis (GC/MS) and direct sequencing of the POR gene. In addition, missense mutations were confirmed as disease causing using a yeast-based co-expression system. Case 1 (46,XX; homozygous p.A287P) developed hypergonodatropic hypogonadism and large bilateral ovarian cysts at 11 years of age that required surgical intervention and resolved only following combined treatment with oestradiol, GnRH superagonist and dexamethasone. Case 2 (46,XX; homozygous p.A287P) showed no pubertal development until 17 years when oestradiol/progesterone replacement was initiated. However, large bilateral ovarian cysts were observed at 24 years after brief discontinuation of oestradiol, resolving upon reintroduction of HRT. Case 3 (46,XX; p.T142A/p.Y376LfsX74) presented with oligomenorrhoea and partially delayed puberty at 19 years, gonadotropins were elevated and a large ovarian cyst was observed before initiation of oestradiol treatment. Case 4 (46,XY; p.R457H/p.Y576X) presented at 12 years with manifest hypogonadism and subsequently required induction of puberty by testosterone. Case 5 (46,XY; pA287P/c.830+2dupT) presented with hypogonadism at the age of 12 years and no apparent signs of pubertal development except for a left testicular volume of 12 ml. Pubertal development was initiated by testosterone. In summary, patients with ORD develop symptoms of hypergonadotropic hypogonadism during puberty, resulting in lack of pubertal development in both sexes, further complicated by large ovarian cysts due to gonadotrophin stimulation in affected 46,XX individuals.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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