Abstract

Hereditary iron overload is mainly due to mutations of the HFE gene, implicated in most cases of hereditary hemochromatosis. Non-HFE-related hereditary iron overload is rare. It includes hereditary hemochromatosis related to mutations of other genes, ferroportin disease (also known as hemochromatosis type 4), and entities associated with specific clinical manifestations. Four genes have been implicated in hereditary hemochromatosis: HFE and TFR2 (which codes for the second transferrin receptor), both involved in adult forms of hereditary hemochromatosis, and HAMP and HJV, which code for hepcidin and hemojuvelin, respectively, and are responsible for juvenile hemochromatosis. All types of hereditary hemochromatosis share common clinical and biological characteristics, including an autosomal recessive inheritance pattern, elevation of transferrin saturation as the initial manifestation, hepatic parenchymal iron overload, and sensitivity to therapeutic phlebotomy. They are due to hyperabsorption of dietary iron and are linked to a deficit of hepcidin, the principal iron regulator in the body. Ferroportin disease is a special dominantly inherited clinical form of iron overload due to mutations of the SLC40A1 gene. Its expression differs significantly from that of hereditary hemochromatosis, and its mechanism is related to impairment of iron release from reticuloendothelial cells. Other causes of non-HFE-related hereditary iron overload are usually associated with recognizable clinical manifestations, such as anemia or neurological disorders.