Rare types of genetic hemochromatosis

Most types of genetic hemochromatosis are due to mutations in the HFE gene, although similar iron overload and organ damage can also result from mutations in genes other than HFE in rare types of hemochromatosis. Non-HFE hemochromatoses have been divided into two subgroups with distinctive features. The first includes juvenile and TFR2-related hemochromatoses that, similar to HFE hemochromatosis, show recessive inheritance, increased transferrin saturation, iron storage in hepatocytes and responsiveness to phlebotomy. Disorders in this subgroup, although differing regarding the severity of iron overload and/or the age at presentation, are all either due to hepcidin deficiency or to the inability to increase hepcidin levels according to iron stores. The second subgroup of hemochromatosis is caused by autosomal dominant mutations in the SLC40A1 gene encoding the iron exporter ferroportin with distinctive features. Iron loading of Kupffer cells and normal transferrin saturation characterize the so-called 'ferroportin disease'. In contrast, few mutations in SLC40A1 that cause hepcidin resistance lead to a hemochromatosis-like phenotype with dominant inheritance. The precise diagnosis of the genetic type of hemochromatosis is relevant for the follow-up, treatment, and for family counseling.