Albertine Donker

Rare Inherited Iron and Heme-related Anemias 103 3 DISORDERS DUE TO DEFECTS IN IRON ACQUISITION BY THE ERYTHROID PRECURSORS 2A. Hypotransferrinemia due to defects in TF Pathogenesis and epidemiology Genetic hypotransferrinemia is a rare autosomal recessive disease due to a defect in TF (OMIM 19000). 48 Transferrin deficiency leads to low concentrations of transferrin bound iron with iron deficient erythropoiesis and high concentrations of non- transferrin bound iron with subsequent iron overload in non-hematopoietic tissues. Functional studies in a limited number of patients indicate that the intestinal iron absorption is increased with augmented plasma iron clearance and reduced red cell iron utilization. 49,50 The increased intestinal iron absorption results from the strongly reduced hepatic hepcidin production ascribed to iron deficient erythropoiesis and low transferrin concentration. 51,52 Since 1961 at least 13 cases in 11 families with of hypotransferrinemia are reported worldwide, 49,50,53-56 Underlying molecular defects in TF are recognized in six patients ( Supplement 1, online ). Clinical presentation and diagnosis Patients present in early life with microcytic and hypochromic anemia. The anemia is characterized by low serum iron and high ferritin levels. The transferrin level varies between below limits of detection to 20 % of normal and is fully saturated. Serum hepcidin levels are low. The iron content in the bone marrow is reduced with a decreased myeloid to erythroid ratio in most cases. 49,50, 53-56 Affected children may show a failure to thrive with occasionally retardation in the mental development. There are signs of widespread iron overload with hepatomegaly and strikingly early endocrinopathy, skin iron deposition, and sometimes fatal, cardiomyopathy. Some patients have osteoporosis. 55,56 The diagnosis is confirmed by molecular analysis of TF . Heterozygous relatives have decreased transferrin concentrations, without anemia or systemic iron loading.