title: Lack of correlation between phenotype and genotype in untreated 21-hydroxylase-deficient Indonesian patients.
abstract: BACKGROUND
  Mutations in CYP21A2 lead to deficiency of 21-hydroxylase and can have either severe or moderate effects on phenotype, which can be prevented by early treatment. We studied long-term effects of this deficiency on phenotype in patients who had not been treated for prolonged periods and correlated these phenotypes with the mutations found in our patients.
  
  
  OBJECTIVE
  To assess the correlation between genotype and phenotype in untreated patients with 21-hydroxylase deficiency.
  
  
  METHODS
  Subjects with 21-hydroxylase deficiency were selected from a large population of Indonesian patients with disorders of sexual differentiation. CYP21A2 mutations in these patients were correlated with their phenotype in terms of genital development and steroid hormone levels.
  
  
  METHODS
  Fifteen 46,XX patients with ages between 1 and 33 years, of whom 12 had never been treated before.
  
  
  METHODS
  Mutations in CYP21A2, genital phenotype and steroid hormone levels.
  
  
  RESULTS
  We found in all patients CYP21A2 mutations which affect enzyme activity, with a relatively high allele frequency of R356W (40%), I172N (20%) and IVS2 - 1A > G (13%). Clitoris length was directly correlated with levels of testosterone, but not with age. The phenotype was not always concordant with the genotype: different phenotypes (mild to severe virilization) were found in sibling pairs with the mutations IVS2 - 13A > G or I172N. The high frequency of homozygous mutants for R356W in patients aged from 1 to 11 years old is remarkable, as this mutation has been described only in salt-wasting patients. In our study, this mutation caused a urogenital sinus in three out of seven cases, whereas in the remaining cases the labia were at least partially fused. This mutation caused severe virilization with remarkably high serum levels of renin. We found one novel substitution in intron 2 (IVS2 - 37A > G), containing the branch site, which is likely to affect the CYP21-enzyme. Two additional intron 2 substitutions were discovered, which are supposed to affect the 21-hydroxylase (i.e. IVS2 + 33A > C and IVS2 + 67C > T).
  
  
  CONCLUSIONS
  We conclude that a correlation exists between the concentration of androgens and the extent of virilization. However, there was no clear correlation between genotype and phenotype, except for the mutation R356W.
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Kristel
authors.initials: K
authors.lastname: Goossens
authors.forename: Achmad Z
authors.initials: AZ
authors.lastname: Juniarto
authors.forename: Marianna A
authors.initials: MA
authors.lastname: Timmerman
authors.forename: Sultana M H
authors.initials: SM
authors.lastname: Faradz
authors.forename: Katja P
authors.initials: KP
authors.lastname: Wolffenbuttel
authors.forename: Stenvert L S
authors.initials: SL
authors.lastname: Drop
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002987:Clitoris / Q000033:anatomy & histology / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007214:Indonesia; D007223:Infant; D007621:Karyotyping; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D014770:Virilism / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase