Genetical diagnosis of hemochromatosis

Classical hemochromatosis (HFE1) is known as a progressive iron overload disease, inherited in an autosomal recessive pattern, affecting subjects of Caucasian descent. In Northern Europe 90 % of cases are related to homozygosity for the C282Y mutation of the HFE1 gene. Classical clinical features of hemochromatosis: diffuse hyperpigmentation (melanodermia), hepatomegaly, diabetes and cardiopathy are rarely observed. Most of the time, the diagnosis is suspected on earlier signs and symptoms like asthenia, arthropathy, aminotransferase elevation and biochemical abnormalities of iron metabolism. Increased transferrin saturation is the most sensitive single test for phenotypic detection of the disease. The discovery of the HFE1 gene has provided a powerful genetic blood test: the presence of the mutation C282Y at the homozygous state permits, in most cases, to establish the diagnosis in a non invasive way (i.e. without a liver biopsy). Besides this classical entity several other rare forms of hereditary iron overload have been described: HFE2 or juvenile hemochromatosis due to mutations in two different genes, hemojuvelin (HFE2A) and hepcidin (HFE2B), HFE3 related to mutations in the transferrin receptor 2 gene (TfR2), HFE4 due to mutations in SLC40A1 coding ferroportin, and lastly an hereditary form involving the H ferritin gene.