Albertine Donker

Chapter 10 338 family screening of the index patient. We presented evidence-based, multidisciplinary guidelines on the diagnosis, the management and the recommended family screening of 12 disorders of microcytic anemia due to defects in 13 different genes involved in iron metabolism and heme synthesis. In order to help the clinician in discriminating this diseases from the fare more common hemoglobinopathies and acquired iron deficiency anemias, we added a flow chart with a step-by-step plan supporting the diagnostic process and a table summarizing the key features characterizing these disorders. We recommended the collaboration between centers of excellence with special expertise of these particular disorders join in order to enlarge pathophysiological insights and to ultimately improve the diagnostic workup and treatment. In Chapter 4 we retrospectively described a case series of 21 Dutch patients diagnosed with Iron Refractory Iron Deficiency Anemia (IRIDA) due to 14 different TMPRSS6 defects, resulting in decreased matriptase 2 activity with inappropriately increased hepcidin levels relative to body iron parameters. In fourteen patients we found a homozygous or compound heterozygous TMPRSS6 defect. Interestingly, in the other 7 patients we only found a heterozygous TMPRSS6 defect after both DNA sequencing and multiplex ligation dependent probe amplification (MLPA), challenging the idea of IRIDA being a disease with an autosomal recessive inheritance pattern. Nine out of 14 TMPRSS6 defects in our population had not been described earlier. We assessed pathogenicity of the TMPRSS6 variants in our patients by review on the literature on previous reports and functional studies in case of known defects, and by considering the association of the TMPRSS6 variants with the phenotype within a family and by bio-informatic tools in case of novel defects. We explored genotype-phenotype correlation, age of presentation, disease severity and response to oral and parenteral iron treatment. We observed that most patients were dependent of parenteral iron. However, a severe genotype did not preclude responsiveness to oral iron. We found that the transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA patients than in healthy relatives, suggesting that the TSAT/ hepcidin ratio is a promising diagnostic tool for discriminating IRIDA from the far more common acquired iron deficiency anemias (we expanded upon this issue in Chapter 8 ). Since we found a noticeable discrepancy between the phenotypes of probands and of relatives with the same genotype, we suggest that a complex interplay between genetic and environmental factors plays a role in the pathogenesis or IRIDA.