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Cited by 64Sexual Differentiation and DisordersAdrenal Hormones and DisordersOvarian function and disorders

Pubertal Presentation in Seven Patients with Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency

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Idkowiak, Jan, O'Riordan, Stephen, Reisch, Nicole, Malunowicz, Ewa M., Collins, Felicity, Kerstens, Michiel N., Köhler, Birgit, Graul-Neumann, Luitgard Margarete +7 more·2011·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2010-1607PMC PMC3124345
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Abstract

CONTEXT: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. OBJECTIVE: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. DESIGN: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. RESULTS: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. CONCLUSION: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.

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  • Several PORD patients underwent only formal adrenal testing many years after presenting with DSD and/or skeletal malformations.

    “In contrast to other reports (3, 6, 7, 13), none of our patients presented with clinical signs and symptoms of adrenal insufficiency, and several of our patients (18) underwent only formal testing many years after presenting with DSD and/or skeletal malformations.”

    From Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency (2012) · cites this paper as [18]

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Authors
Idkowiak, J., O'Riordan, S., Reisch, N., Malunowicz, E. M., Collins, F., Kerstens, M. N., Köhler, B., Graul-Neumann, L. M., Szarras-Czapnik, M., Dattani, M., Silink, M., Shackleton, C. H. L., Maiter, D., Krone, N., & Arlt, W.
Affiliations
  • University of Birmingham (GB)
  • Developmental Endocrinology Research Group (S.O., M.D.), Clinical and Molecular Genetics, Institute of Child Health, University College London, London WC1E 6BT, United Kingdom;
  • Department of Biochemistry and Experimental Medicine (E.M.M.) The Children's Memorial Health Institute, 20 04-830 Warsaw, Poland;
  • Children's Hospital at Westmead (AU)
  • University Medical Center Groningen (NL)
  • Charité – Universitätsmedizin Berlin (DE)
  • Department of Metabolic Diseases, Endocrinology, and Diabetology (M.S.-C.), The Children's Memorial Health Institute, 20 04-830 Warsaw, Poland;
  • University College London (GB)
  • Cliniques Universitaires Saint-Luc (BE)
Corresponding author
Arlt, Wiebke
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2011-03-01
Volume
96
Issue
3
Pages
E453-E462
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2010-1607
PMC
PMC3124345
OpenAlex
W2107820088
Cited by
64
References
8
Citations by year
2026: 5 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 4 · 2012: 5
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • University of Birmingham Institutional Research Archive (University of Birmingham) (acceptedVersion)
  • DIAL (Catholic University of Leuven) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc)
Funders
  • Wellcome Trust (0900567, GR079865MA)
  • Medical Research Council (0900567)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
P450 oxidoreductase deficiency, congenital adrenal hyperplasia, delayed puberty, ovarian cysts, adrenal insufficiency, hypergonadotropic hypogonadism, meiosis-activating sterols, CYP51A1, testosterone production
MeSH terms
Adolescent, Adrenal Hyperplasia, Congenital, Amenorrhea, Androgens, Female, Genitalia, Gonadal Dysgenesis, 46,XY, Humans, Infant, Newborn, Karyotyping, Male, Menstruation, NADPH-Ferrihemoprotein Reductase, Ovarian Cysts, Ovary, Phenotype, Puberty, Gonadal Steroid Hormones, Steroids, Cohort Studies, Reverse Transcriptase Polymerase Chain Reaction, Hormone Replacement Therapy, Young Adult

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