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Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

ABSTRACT: 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.The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.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.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?-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,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.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.

SUBMITTER: Krone N

PROVIDER: S-EPMC3380101 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

Krone Nils N Reisch Nicole N Idkowiak Jan J Dhir Vivek V Ivison Hannah E HE Hughes Beverly A BA Rose Ian T IT O'Neil Donna M DM Vijzelaar Raymon R Smith Matthew J MJ MacDonald Fiona F Cole Trevor R TR Adolphs Nicolai N Barton John S JS Blair Edward M EM Braddock Stephen R SR Collins Felicity F Cragun Deborah L DL Dattani Mehul T MT Day Ruth R Dougan Shelley S Feist Miriam M Gottschalk Michael E ME Gregory John W JW Haim Michaela M Harrison Rachel R Olney Ann Haskins AH Hauffa Berthold P BP Hindmarsh Peter C PC Hopkin Robert J RJ Jira Petr E PE Kempers Marlies M Kerstens Michiel N MN Khalifa Mohamed M MM Köhler Birgit B Maiter Dominique D Nielsen Shelly S O'Riordan Stephen M SM Roth Christian L CL Shane Kate P KP Silink Martin M Stikkelbroeck Nike M M L NM Sweeney Elizabeth E Szarras-Czapnik Maria M Waterson John R JR Williamson Lori L Hartmann Michaela F MF Taylor Norman F NF Wudy Stefan A SA Malunowicz Ewa M EM Shackleton Cedric H L CH Arlt Wiebke W

The Journal of clinical endocrinology and metabolism 20111207 2

<h4>Context</h4>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.<h4>Objective</h4>The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.<h4>Design</h4>The design of the study was the clinical, biochemical, and ge ...[more]

PMID: 22162478

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Project description:In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking.The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH.We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort.CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups.In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

Dataset Information

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

Publications

Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

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