Albertine Donker

Chapter 4 160 Up to now, 94 IRIDA patients of different ethnic origin with 69 different homozygous or compound heterozygous TMPRSS6 defects have been described in 65 families. 4,5,9,10 Our case series of 21 patients adds nine new mutations, spread throughout the entire matriptase 2 protein and illustrates a geographical distribution of TMPRSS6 defects with different mutations in the patients from Dutch versus Turkish descent. However, haplotype analysis could not prove common ancestry of all patients with identical defects. Since the cardinal feature of IRIDA is a discrepantly high serum hepcidin in relation to the low iron body status, we hypothesized that the TSAT/hepcidin ratio as first mentioned by Heeney 38 could be a useful diagnostic tool. In our population, consisting of clinically presenting patients and their relatives, TSAT/hepcidin ratio was able to discriminate between bi-allelic and mono-allelic IRIDA patients, and between mono-allelic IRIDA patients and their phenotypically unaffected relatives with the same heterozygous TMPRSS6 defect, even after iron supplementation had been given, provided that inflammation was absent. However, before its introduction as a diagnostic test in the work up of iron deficient microcytic anemic patients suspected for the presence of IRIDA, the ratio needs confirmation in phenotypically and genotypically proven IRIDA patients versus patients presenting with an iron deficient microcytic anemia because of other reasons, e.g. inadequate intake, blood loss or other forms of refractory IDA, such as celiac disease, autoimmune gastritis and Helicobacter pylori. In five of our patients an OIAT test was performed. 31,31 Results were abnormal but since quantitative results did not correlate with the severity of the phenotype and response to oral iron therapy, we concluded that the diagnostic value of this test is limited in the work up of patients suspected or diagnosed with IRIDA. As the acronym IRIDA implies, patients with TMPRSS6 defects are usually unresponsive to oral iron. However, as shown by our case series and also by others in some IRIDA patients with both mono-allelic and bi-allelic TMPRSS6 defects it is possible to increase the Hb to a clinically acceptable level with only oral iron, or with a combination of oral iron and vitamin C. 39 Nevertheless, most IRIDA patients require parenteral iron in order to correct the anemia. According to the literature and to our data, there is a tendency to a reduction of intravenous iron requirements with increasing age. To our knowledge, no studies are available on the optimal dose