Albertine Donker

IRIDA: a Heterogeneous Disease 141 4 INTRODUCTION Matriptase 2, encoded by TMPRSS6 , plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Pathogenic TMPRSS6 mutations result in uninhibited hepcidin production, causing Iron Refractory Iron Deficiency Anemia (IRIDA), a disease characterized by a microcytic, hypochromic anemia due to serum hepcidin values that are inappropriately high for the body iron levels. 1-6 IRIDA patients typically present in childhood with microcytic anemia not responding to oral iron, in combination with remarkably low transferrin saturation (TSAT), which tends to become less severe with increasing age. 7 Serum ferritin levels are generally within the low-normal range, and increase following intravenous iron treatment. 5 Only a few patients with elevated ferritin concentrations have been described before intravenous iron treatment had been given. 8 To date, 69 different TMPRSS6 defects have been identified in 65 IRIDA families with 94 patients of different ethnic origin. 4,5,9.10 At the population level, Genome Wide Association Studies (GWAS) show that TMPRSS6 is polymorphic with a relatively large amount of polymorphisms of which the non-synonymous c.2207C>T (p.Ala736Val) is associated with a significant decrease of the concentrations of iron, hemoglobin (Hb), hematocrit (Ht), Mean Corpuscular Volume (MCV), Mean Cellular Hemoglobin (MCH) and red blood cells. 11,12 These findings are corroborated by functional studies, which show that the 736Ala variant inhibits hepcidin production more efficiently. 13 The increasing number of IRIDA cases that are being reported, generate more knowledge on the disease, but many questions remain concerning the mode of inheritance, the genotype-phenotype correlation, the diagnostic workup and the optimal treatment. Since usually bi-allelic TMPRSS6 variants are found in IRIDA patients, the disease is considered as recessive. However, anecdotal data are available of phenotypically affected IRIDA patients in which only a heterozygous TMPRSS6 variant was found. 3,14-17