Albertine Donker

Chapter 3 98 DISORDERS DUE TO LOW IRON AVAILABILITY FOR ERYTHROPOIESIS 1A. Iron refractory iron deficiency anemia (IRIDA) due to defects in TMPRSS6 Pathogenesis and epidemiology TMPRSS6 (OMIM 609862) encodes matriptase 2 (a type II plasma membrane serine protease), that senses iron deficiency and blocks hepcidin transcription by cleaving hemojuvelin (HJV). Consequently, pathogenic TMPRSS6 defects result in uninhibited hepcidin production, causing iron refractory iron deficiency anemia (IRIDA). 14-16 At the population level Genome Wide Association Studies (GWAS) show that TMPRSS6 is polymorphic with a relatively large amount of high frequency polymorphisms of which some (particularly p.Ala736Val) are associated with significant decrease of the concentrations of iron, hemoglobin (Hb) and Mean Cellular Volume (MCV) of the red blood cell. 17,18 The prevalence of pathogenic mutations leading to IRIDA is unknown, but under-diagnosis seems likely. IRIDA patients due to a suspected homozygous or compound heterozygous TMPRSS6 defect are described in 61 cases in 39 families. Since functional studies are not always performed, it is unclear whether all thesemutations are pathogenic. A few cases with microcytic anemia, low TSAT, and low-normal ferritin are reported to be heterozygous for TMPRSS6 defects ( Supplement 1 , online ). Clinical presentation and diagnosis Most IRIDA patients present in childhood with a microcytic anemia, which tends to become less severe with increasing age, 19 in combination with a remarkably low TSAT and – if untreated- a low to normal ferritin. Most patients fail to respond to oral iron (see below), but since this feature is also observed in iron deficient anemic patients with autoimmune atrophic gastritis, Helicobacter pylori infection and celiac disease, these (non-genetic) disorders should be considered in the diagnostic work up. 20 In IRIDA, serum hepcidin is inappropriately high given the low body iron status. Consequently, the hepcidin/TSAT ratio is high. 21 In the absence of inflammation, an increased hepcidin/TSAT ratio is specific for IRIDA, whereas a low hepcidin/ferritin ratio is characteristic for many genetic iron loading disorders. In affected children, growth, development and intellectual performances are normal. 22 Although the pedigree structure of most IRIDA patients shows an autosomal recessive