A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria

Background/Aims: The HFE gene is a crucial candidate gene for hemochromatos is. The aims of this study were to assess the HFE genotypic profile in a la rge series of unrelated probands diagnosed as having phenotypic hemochromat osis, to characterize the subgroup of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE -identical siblings. Methods: In 217 patients, the phenotypic diagnosis of hemochromatosis was b ased on strict bioclinical and/ or histological criteria, and their genotyp ic profile (C282Y and H63D mutations) was determined. Results: 1) 209 of the 217 probands were C282Y+/ +. In 33 cases, an HFE-ide ntical sibling was identified, Two of them had neither a clinical nor a bio chemical phenotypic profile of hemochromatosis in the absence of any extern al factor which might have attenuated this expression. 2) Fight patients (s even males) were not C282Y+/+. Their genotypic profiles were: (C282Y+/-): s ix cases (four were H63D+/- and two H63D-/-); (C282Y-/-): two cases (one wa s H63D+/+, one H63D+/-). Phenotypic expression consisted of six cases of mi ld liver siderosis (among whom were the four compound heterozygotes and one case of alcoholic cirrhosis) and two severe cases of hepatic iron overload tone with alcoholic cirrhosis). Three HFE-identical siblings were identifi ed, none of them presenting with iron excess. Conclusions: In our population: 1) The classical phenotypic criteria fitted , in 96.3% of cases, with a homogeneous genotypic entity defined by homozyg osity for the C282Y mutation. Incomplete penetrance of the homozygous statu s was shown by the absence of the hemochromatosis phenotypic profile in 6% of the HFE-identical siblings. 2) A minority (3.7%) were not homozygous for C282Y. These were essentially men with mild iron overload, and might prese nt with distinct iron overload entity(ies) as suggested by the presence in three of an HFE-identical sibling with absence of iron overload.