Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency
| Autor: | Krone, Nils, Reisch, Nicole, Idkowiak, Jan, Dhir, Vivek, Ivison, Hannah E., Hughes, Beverly A., Rose, Ian T., O'Neil, Donna M., Vijzelaar, Raymon, Smith, Matthew J., MacDonald, Fiona, Cole, Trevor R., Adolphs, Nicolai, Barton, John S., Blair, Edward M., Braddock, Stephen R., Collins, Felicity, Cragun, Deborah L., Dattani, Mehul T., Day, Ruth, Dougan, Shelley, Feist, Miriam, Gottschalk, Michael E., Gregory, John W., Haim, Michaela, Harrison, Rachel, Olney, Ann Haskins, Hauffa, Berthold P., Hindmarsh, Peter C., Hopkin, Robert J., Jira, Petr E., Kempers, Marlies, Kerstens, Michiel N., Khalifa, Mohamed M., Koehler, Birgit, Maiter, Dominique, Nielsen, Shelly, O'Riordan, Stephen M., Roth, Christian L., Shane, Kate P., Silink, Martin, Stikkelbroeck, Nike M. M. L., Sweeney, Elizabeth, Szarras-Czapnik, Maria, Waterson, John R., Williamson, Lori, Hartmann, Michaela F., Taylor, Norman F., Wudy, Stefan A., Malunowicz, Ewa M., Shackleton, Cedric H. L., Arlt, Wiebke, Smith, M.J. |
|---|---|
| Přispěvatelé: | Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| Jazyk: | angličtina |
| Předmět: |
Male
Models Molecular Antley–Bixler syndrome Endocrinology Diabetes and Metabolism Clinical Biochemistry DNA Mutational Analysis Medizin Disorders of Sex Development STEROID-METABOLISM Compound heterozygosity Biochemistry Cohort Studies 0302 clinical medicine Endocrinology Missense mutation Child Gonadal Steroid Hormones 0303 health sciences POR Deficiency 3. Good health Metabolome Female Adult DISORDERED STEROIDOGENESIS medicine.medical_specialty Adolescent 030209 endocrinology & metabolism Biology Models Biological Genomic disorders and inherited multi-system disorders [IGMD 3] 03 medical and health sciences Young Adult Internal medicine medicine Adrenal insufficiency ABNORMAL STEROL Humans Congenital adrenal hyperplasia Multiplex ligation-dependent probe amplification Genitalia Allele Genetic Association Studies CYTOCHROME-P450 OXIDOREDUCTASE 030304 developmental biology NADPH-Ferrihemoprotein Reductase Adrenal Hyperplasia Congenital IDENTIFICATION MUTATIONS Hormonal regulation [IGMD 6] Biochemistry (medical) ANTLEY-BIXLER-SYNDROME medicine.disease GENE VASCULOGENESIS Multiplex Polymerase Chain Reaction Adrenal Insufficiency RETINOIC ACID HOMEOSTASIS |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism; Vol 97 Journal of Clinical Endocrinology and Metabolism, 97(2), E257-E267. ENDOCRINE SOC Journal of Clinical Endocrinology and Metabolism, 97, E257-67 Journal of Clinical Endocrinology and Metabolism, 97, 2, pp. E257-67 |
| ISSN: | 0021-972X |
| Popis: | Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17 alpha-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 1846, XX and seven of 1246,XY individuals. Homozygosity for p.A287P was invariably associated with 46, XX DSD but normal genitalia in 46, XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing. (J Clin Endocrinol Metab 97: E257-E267, 2012) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|