Albertine Donker

Rare Inherited Iron and Heme-related Anemias 99 3 inheritance, anecdotal reports suggest that heterozygous pathogenic TMPRSS6 mutations might cause a mild IRIDA phenotype ( Supplement 1, online ). It is still unclear whether this can be explained by environmental factors, a combination with modulating polymorphisms or a low expressing allele, or whether the current Sanger sequencing strategy misses certain defects in the exons, introns of the gene or its regulatory regions, or whether defects in other genes are involved. Therefore, we conclude that IRIDA due to a TMPRSS6 defect can only be diagnosed with certainty when the patient is homozygous or compound heterozygous for a pathogenic mutation. Treatment Case reports indicate that the pathogenicity of the TMPRSS6 defect determines the response to oral iron. Severe TMPRSS6 defects usually lead to oral iron resistance. Only few cases (partially) respond to oral iron ( Supplement 1, online ). Ascorbic acid (3mg/d) supplementation along with oral ferrous sulfate has been reported to improve Hb and iron status in an infant resistant to oral iron supplementation only. 23 Case series show that repeated administration of intravenous iron (iron sucrose or iron gluconate) increase Hb and ferritin and to a lesser extent MCV and TSAT, although complete normalization of Hb is rarely achieved. Attempting to correct the Hb level into the reference range may place the patient at risk of iron overload. We found no evidence for a threshold of circulating ferritin levels above which the iron in the reticulo-endothelial (RE) macrophages becomes toxic on the long term. However, following guidelines for iron treatment in patients with chronic kidney disease, 24 we recommend monitoring serum ferritin levels and not exceed a concentration of 500 µg/L to avoid this risk, especially in children and adolescents. The role of erythropoietin (EPO) treatment in IRIDA is controversial. 25,26 Trials with novel hepcidin lowering compounds in these patients have not been performed. 27 1B. Ferroportin disease due defects in SLC40A1 Pathogenesis and epidemiology SLC40A1 (or ferroportin-1 , IREG1, MTP1, SLC11A3 ) (OMIM 606069) encodes the protein ferroportin, 28 the only known human cellular iron exporter ( Figure 1 ). 11,29 In 2000, ferroportin was identified in the zebrafish mutant weissherbst , as the defect gene responsible for the hypochromic anemia in these animals was ascribed to inadequate circulatory iron levels. 6 In man only heterozygous mutations in SLC40A1 are reported andmicrocytosis is not observed. The resulting hereditary hemochromatosis (HH) type