Albertine Donker

Chapter 1 32 To date, 69 different TMPRSS6 defects have been identified in 65 IRIDA families with 94 patients of different ethnic origin. 108,116,117 Despite this increasing number of IRIDA cases that are being reported, many questions remain concerning the mode of inheritance, the genotype–phenotype correlation, the diagnostic workup, and the optimal treatment. Until now, IRIDA has been considered as a disorder with an autosomal recessive mode of inheritance but anecdotal data are available of phenotypically affected IRIDA patients in whom only a heterozygous TMPRSS6 variant was found. 37,38,107,118,119 Concerning the genotype–phenotype relationship, there is a tendency towards lower hemoglobin, MCV and TSAT in patients with two nonsense mutations. 117 The influence of high frequency TMPRSS6 variants, other still unrecognized genes and environmental factors in the phenotypic expression of the disease still needs clarification. Furthermore, diagnosing IRIDA is challenging because of the highly variable phenotype 108,117 and the unclear genotype–phenotype relation. In addition, serum hepcidin measurements procedures have not been standardized nor harmonized until now. This hampers comparability of results obtained from different laboratory assays, whereas effective care for IRIDA patients and clinical research on IRIDA and other genetic and acquired disorders of ironmetabolism require comparability of laboratory results independent of time, place, and measurement procedure. Failure to recognize that results are standardized nor harmonized may lead to erroneous medical decisions or misinterpretation of research data. As a first step, harmonization ensures traceability to a reference system agreed on by convention. The next step is standardization, ensuring traceability to the International System of Units. 120,121 Standardization but at least harmonization is paramount regarding serum hepcidin measurements procedures. For children >3-18 years, no reference values of serum hepcidin levels and its concentration relative to TSAT levels are available, hampering the diagnosis of IRIDA in this age group. 122 Also, unsolved questions remain regarding the optimal oral and/or intravenous iron treatment of IRIDA. As the acronym IRIDA implies, patients with TMPRSS6 defects are usually unresponsive to oral iron. However, anecdotal data suggest that in some IRIDA patients with both mono-allelic and bi-allelic TMPRSS6 defects hemoglobin levels increase to a clinically acceptable level with prolonged oral iron supplementation, or with a combination of oral iron and vitamin C. 123 Nevertheless, most IRIDA patients require parenteral iron in order