title: Underdiagnosis of hereditary haemochromatosis: lack of presentation or penetration?
abstract: BACKGROUND
  The majority of hereditary haemochromatosis (HH) patients are homozygous for the C282Y mutation in the HFE gene. We have demonstrated a homozygote frequency of 1 in 83 for the C282Y mutation in a retrospective analysis of Irish neonates. However, a fully developed phenotype is not observed at the same frequency clinically, suggesting that a large proportion of Irish HH patients may remain undiagnosed.
  
  
  OBJECTIVE
  To determine whether underdiagnosis of HH results from the non-specific nature of early symptoms or incomplete penetrance of the C282Y mutation.
  
  
  METHODS
  Seventy nine C282Y homozygous individuals identified from family screening for HH and 30 HH probands were investigated. Non-specific symptoms (fatigue, arthropathy, and impotence) and their association with iron indices (transferrin saturation and serum ferritin) and hepatic iron deposition were analysed.
  
  
  RESULTS
  We found that 78% of men (mean age 42 years) and 36% of women (mean age 39 years) who were identified as C282Y homozygotes following family screening had iron overload, as defined by a transferrin saturation >or=52% combined with a serum ferritin >or=300 microg/l for men and >or=200 microg/l for women. The frequency of reports of non-specific symptoms in those individuals with iron overload was not significantly different from those who did not have iron overload.
  
  
  CONCLUSIONS
  Our findings indicate that underdiagnosis of HH may be due to the non-specific nature of early symptoms and less frequently to the incomplete penetrance of the C282Y mutation.
authors.affiliation: Centre for Liver Disease, Mater Misericordiae Hospital, Dublin 7, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Ryan
authors.forename: V
authors.initials: V
authors.lastname: Byrnes
authors.forename: B
authors.initials: B
authors.lastname: Coughlan
authors.forename: A-M
authors.initials: AM
authors.lastname: Flanagan
authors.forename: S
authors.initials: S
authors.lastname: Barrett
authors.forename: J C
authors.initials: JC
authors.lastname: O'Keane
authors.forename: J
authors.initials: J
authors.lastname: Crowe
mesh_terms: D000328:Adult; D000368:Aged; D005221:Fatigue / Q000209:etiology; D005260:Female; D005293:Ferritins / Q000097:blood; D005820:Genetic Testing; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007592:Joint Diseases / Q000209:etiology; D008099:Liver / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D018709:Statistics, Nonparametric; D014168:Transferrin / Q000032:analysis
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins