Albertine Donker

Chapter 3 112 Table 1. Recommendations Part 1: Anemia due to low iron bioavailability for erythropoiesis 1A. Iron refractory iron deficiency anemia (IRIDA) due to defects TMPRSS6 Clinical presentation and diagnostics • In patients with unexplained microcytic anemia with low transferrin saturation (TSAT) and normal or reduced serum ferritin concentration, not or partially responding to oral iron and (partially) responsive to intravenous iron supplementation, Iron Refractory Iron Deficiency Anemia (IRIDA) due to a TMPRSS6 defect should be considered. Determination of serum hepcidin is recommended in case the diagnosis IRIDA is suspected. • Increased serum hepcidin in relation to TSAT (hepcidin/TSAT ratio > p.97.5 of local reference value) is suggestive of IRIDA. TMPRSS6 mutation analysis is recommended. • In case of a homozygous or compound heterozygous TMPRSS6 defect, IRIDA due to a dysfunctional matriptase 2 protein should be diagnosed. • No recommendation can be made on the clinical significance of heterozygous TMRSS6 defects with or without concomitant polymorphisms, because of lack of evidence. Treatment • In a patient with iron deficiency anemia due to pathogenic TMRPSS6 defects initial treatment with oral iron or oral iron combined with ascorbic acid should be considered. • Patients, for whom this initial treatment does not result in acceptable Hb levels, should be treated with intravenous iron supplementation. • In IRIDA patients, the choice of the chemical form of intravenous iron should be based on its registration for the specific age group OR a proven good safety profile in adults during several years of post-marketing surveillance. • The total intravenous iron cumulative doses should be calculated based on formulas of the deficit on body iron allowing for the correction of the Hb deficit and rebuilding the iron stores. Doses should be repeated every 3-7 days until the total dose is administered. Single doses should not exceed the maximum single dose. • Serum ferritin levels should be monitored and preferably not exceed 500 µg/L to avoid toxicity of iron overload, especially in children and adolescents. • No recommendation can be made on the efficacy of the combination of iv supplementation and erythropoietin (EPO) treatment in IRIDA patients, because of low evidence. This combination therapy might prevent toxic iron loading in some patients. Family screening* • The proband should be informed about the mostly autosomal recessive inheritance pattern of IRIDA. We recommend to screen relatives of the proband for the IRIDA phenotype: siblings and spouse in case of consanguinity and reproductive age. If the proband is diagnosed at young age, and his/her parents are of reproductive age, phenotyping of the parents is recommended. In case of a clinical IRIDA phenotype in the above-mentioned relatives, mutation analysis is recommended. • Children of the proband should only be phenotyped and, in case of an IRIDA phenotype, genotyped in case of consanguinity of the proband and his/her spouse or in case of proven carrier ship of both proband and his/her spouse. • Because of the complex genotype-phenotype correlation in IRIDA, we recommend referral to a clinical geneticist in case of an IRIDA phenotype and a pathogenic heterozygous TMRSS6 defect.