title: Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 17α-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.
  
  
  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.
authors.affiliation: Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
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authors.lastname: Szarras-Czapnik
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mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000652:urine; D000309:Adrenal Insufficiency / Q000235:genetics / Q000378:metabolism / Q000652:urine; D000328:Adult; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D012734:Disorders of Sex Development; D005260:Female; D056726:Genetic Association Studies; D005835:Genitalia / Q000002:abnormalities; D012739:Gonadal Steroid Hormones / Q000652:urine; D006801:Humans; D008297:Male; D055442:Metabolome; D008954:Models, Biological; D008958:Models, Molecular; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D012739:Gonadal Steroid Hormones; D009251:NADPH-Ferrihemoprotein Reductase