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

Autor: Luitgard Graul-Neumann, Martin Silink, Maria Szarras-Czapnik, Jan Idkowiak, Ewa M. Malunowicz, Mehul T. Dattani, Michiel N. Kerstens, Nicole Reisch, Dominique Maiter, Nils Krone, Felicity Collins, Cedric H. L. Shackleton, Birgit Köhler, Stephen M. P. O'Riordan, Wiebke Arlt
Přispěvatelé: Guided Treatment in Optimal Selected Cancer Patients (GUTS)
Rok vydání: 2011
Předmět:
Male
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
POINT MUTATIONS
OVARIAN CYSTS
Biochemistry
Cohort Studies
0302 clinical medicine
Endocrinology
JCEM Online: Hot Topics in Translational Endocrinology
Gonadal Steroid Hormones
Amenorrhea
Gonadal Dysgenesis
46
XY
0303 health sciences
030219 obstetrics & reproductive medicine
Reverse Transcriptase Polymerase Chain Reaction
MEIOSIS
Menstruation
Phenotype
CYP17A1
RC Internal medicine
Androgens
Female
Steroids
Glucocorticoid
medicine.drug
DISORDERED STEROIDOGENESIS
medicine.medical_specialty
Adolescent
Hormone Replacement Therapy
medicine.drug_class
030209 endocrinology & metabolism
Biology
Young Adult
03 medical and health sciences
AROMATASE DEFICIENCY
Internal medicine
medicine
Adrenal insufficiency
Humans
Congenital adrenal hyperplasia
Genitalia
CYTOCHROME-P450 OXIDOREDUCTASE
NADPH-Ferrihemoprotein Reductase
Hydrocortisone
030304 developmental biology
Adrenal Hyperplasia
Congenital
Ovary
Puberty
Biochemistry (medical)
Infant
Newborn
ANTLEY-BIXLER-SYNDROME
medicine.disease
GENE
Estrogen
Sex steroid
Karyotyping
Aromatase deficiency
RETINOIC ACID HOMEOSTASIS
INACTIVATING MUTATIONS
Zdroj: The Journal of Clinical Endocrinology and Metabolism
The Journal of Clinical Endocrinology & Metabolism; Vol 96
Journal of Clinical Endocrinology and Metabolism, 96(3), E453-E462. ENDOCRINE SOC
ISSN: 1945-7189
0163-769X
0021-972X
DOI: 10.1210/edrv.32.1.zef155a
Popis: Adolescents with oxidoreductase deficiency present with impaired pubertal development, manifesting in girls with hypergonadotropic hypogonadism and ovarian cysts while boys may show delayed but spontaneous pubertal progression.
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.
Databáze: OpenAIRE
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