title: Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory.
abstract: TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Albertine E
authors.initials: AE
authors.lastname: Donker
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Charlotte C M
authors.initials: CC
authors.lastname: Schaap
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Vera M J
authors.initials: VM
authors.lastname: Novotny
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tessa M A
authors.initials: TM
authors.lastname: Peters
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bert L P
authors.initials: BL
authors.lastname: van den Heuvel
authors.affiliation: Department of Pediatric Hematology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Raphael
authors.affiliation: Department of Hematology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Anita W
authors.initials: AW
authors.lastname: Rijneveld
authors.affiliation: Department of Pediatric Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Inge M
authors.initials: IM
authors.lastname: Appel
authors.affiliation: Department of Internal Medicine, Rijnstate Hospital Arnhem, Arnhem, The Netherlands.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Vlot
authors.affiliation: Department of Pediatric Hematology, University Medical Center, Utrecht, The Netherlands.
authors.forename: A Birgitta
authors.initials: AB
authors.lastname: Versluijs
authors.affiliation: Department of Hematology, Maastricht UMC, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: van Gelder
authors.affiliation: Department of Pediatrics, Maastricht UMC, Maastricht, The Netherlands.
authors.forename: Bernd
authors.initials: B
authors.lastname: Granzen
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mirian C H
authors.initials: MC
authors.lastname: Janssen
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alexander J M
authors.initials: AJ
authors.lastname: Rennings
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Pediatric Hemato-Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Paul P T
authors.initials: PP
authors.lastname: Brons
authors.affiliation: Department of Laboratory Medicine, Máxima Medical Center, Veldhoven, Eindhoven, The Netherlands.
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Bakkeren
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Hemato-Oncology, Máxima Medical Center, Veldhoven, Eindhoven, The Netherlands.
authors.forename: Marten R
authors.initials: MR
authors.lastname: Nijziel
authors.affiliation: Department of Internal Medicine, Bronovo Hospital, The Hague, The Netherlands.
authors.forename: L Thom
authors.initials: LT
authors.lastname: Vlasveld
authors.affiliation: Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center, Nijmegen, The Netherlands.|Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
mesh_terms: D000293:Adolescent; D000328:Adult; D018798:Anemia, Iron-Deficiency; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D055815:Young Adult