Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene

Background and Methods Hereditary hemochromatosis in adults is usually char acterized by mutations in the hemochromatosis (HFE) gene on the short arm o f 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 fr om hemochromatosis but without apparent pathogenic mutations in the HFE gen e. We performed biochemical, histologic, and genetic studies of 53 living m embers 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, va lues 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 thera py. The other two, both children, did not undergo liver biopsy or iron-remo val 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 we re 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. (N Engl J Med 1999;341:72 5-32,) (C)1999, Massachusetts Medical Society.