title: Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors: Nils
authors: N
authors: Krone
authors: Ian T
authors: IT
authors: Rose
authors: Debbie S
authors: DS
authors: Willis
authors: James
authors: J
authors: Hodson
authors: Sarah H
authors: SH
authors: Wild
authors: Emma J
authors: EJ
authors: Doherty
authors: Stefanie
authors: S
authors: Hahner
authors: Silvia
authors: S
authors: Parajes
authors: Roland H
authors: RH
authors: Stimson
authors: Thang S
authors: TS
authors: Han
authors: Paul V
authors: PV
authors: Carroll
authors: Gerry S
authors: GS
authors: Conway
authors: Brian R
authors: BR
authors: Walker
authors: Fiona
authors: F
authors: MacDonald
authors: Richard J
authors: RJ
authors: Ross
authors: Wiebke
authors: W
authors: Arlt
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D006113:United Kingdom
chemical_list: D013255:Steroid 21-Hydroxylase