title: Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene.
abstract: METHODS
  Hereditary hemochromatosis in adults is usually characterized by mutations in the HFE gene on the short arm of chromosome 6. Most patients have a substitution of tyrosine for cysteine at position 282 (C282Y). We studied a large family from Italy that includes persons who have a hereditary iron-overload condition indistinguishable from hemochromatosis but without apparent pathogenic mutations in the HFE gene. We performed biochemical, histologic, and genetic studies of 53 living members of the family, including microsatellite analysis of chromosome 6 and direct sequencing of the HFE gene.
  
  
  RESULTS
  Of the 53 family members, 15 had abnormal serum ferritin levels, values for transferrin saturation that were higher than 50 percent, or both. Thirteen of the 15 had elevated body iron levels, diagnosed on the basis of the clinical evaluation and liver biopsy, and underwent iron-removal therapy. The other two, both children, did not undergo liver biopsy or iron-removal therapy. None of the 15 members had the C282Y mutation of the HFE gene; 5 of the 15 (as well as 5 healthy relatives) had another mutation of this gene, a substitution of aspartate for histidine at position 63, but none were homozygous for it. No other mutations were found after sequencing of the entire HFE gene for all family members. Microsatellite analysis showed no linkage of the hemochromatosis phenotype with the short arm of chromosome 6, the site of the HFE gene.
  
  
  CONCLUSIONS
  Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene.
authors.affiliation: Department of Internal Medicine, Università di Modena, Italy. pietra@unimo.it
authors.forename: A
authors.initials: A
authors.lastname: Pietrangelo
authors.forename: G
authors.initials: G
authors.lastname: Montosi
authors.forename: A
authors.initials: A
authors.lastname: Totaro
authors.forename: C
authors.initials: C
authors.lastname: Garuti
authors.forename: D
authors.initials: D
authors.lastname: Conte
authors.forename: S
authors.initials: S
authors.lastname: Cassanelli
authors.forename: M
authors.initials: M
authors.lastname: Fraquelli
authors.forename: C
authors.initials: C
authors.lastname: Sardini
authors.forename: F
authors.initials: F
authors.lastname: Vasta
authors.forename: P
authors.initials: P
authors.lastname: Gasparini
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D005293:Ferritins / Q000097:blood; D008040:Genetic Linkage; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000032:analysis; D007558:Italy; D008099:Liver / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; 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; D007501:Iron