Albertine Donker

IRIDA: a Heterogeneous Disease 151 4 h Patient 4 was diagnosed with anemia refractory to oral iron as a child for which he temporarily received intravenous iron. IRIDA was diagnosed after screening for this disorder because of pregnancy of his wife. No data are available on Hb and iron parameters at time of presentation of anemia; i Hb and iron parameters of patient 11 at referral, after oral iron supplementation had been given; j Deletion 118 kb in intron 2, knocking out exon 3-18 of TMPRSS6 gene. Also other genes were deleted; RefSeq genes TEX33, MPST, TST and KCTD17 k Multiplex Ligation dependent Probe Amplification (MLPA) confirmed heterozygosity; l This substitution is predicted to introduce a new and more efficient acceptor splice site 4 bases downstream from the original acceptor splice site in intron 2 leading to a frameshift in the open reading frame. Not proven on RNA or protein level. (http://www.interactive-biosoftware.com/doc/alamut- visual/2.7/splicing.html), accessed on July 14 2016. m This substitution is located in the donor splice site of intron 7. The consequence of this change is not predictable, but a skip of exon 7 is very likely resulting in the loss of a classical splice site. Not proven on mRNA or protein level (http://www.interactive-biosoftware.com/doc/alamut-visual/2.7/splicing.html) , accessed on July 14 2016. Abbreviations: Hb denotes hemoglobin; MCV, mean corpuscular volume; TSAT, transferrin saturation; F, female; M, male; iv, intravenous; po, per os; im, intramuscular; BloodTx, blood transfusion; np, not provided; Wt, Wild-type In patient 8 (ferritin 924 µg/L) MRI of the liver showed only moderate signs of iron overload (60 µmol (or 3.35 mg) Fe dry weight tissue). Since no genotyping of the known hemochromatosis genes was performed for our patients, we cannot exclude ferroportin disease due to a variant of SLC40A1 for this woman. Dose of intravenous iron, treatment regimen and duration of treatment was highly variable in our small population, with a tendency to a reduction of intravenous iron requirements with increasing age. None of our patients was treated with erythropoietin (EPO). We conclude that only a minority of both bi-allelic and mono- allelic affected patients was responsive to oral iron and that most patients needed parenteral iron to increase their Hb levels. Genotypic and phenotypic family screening was performed in 27 relatives of 12 out of 21 probands; in 20 out of these 27 relatives a TSAT/hepcidin ratio was available. Four wild-type relatives and 20 relatives with a mono-allelic TMPRSS6 defect had no IRIDA phenotype. Two relatives with a bi-allelic TMPRSS6 defect (brother of patient 9 and sister of patient 11) had no complaints since their Hb was normal (MCV and TSAT