{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:25:24Z","timestamp":1790033124067,"version":"4.0.1"},"reference-count":54,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T00:00:00Z","timestamp":1479254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:p><jats:italic>TMPRSS6<\/jats:italic> variants that affect protein function result in impaired matriptase\u20102 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\u2013phenotype correlation, and optimal clinical management. We describe 14 different <jats:italic>TMPRSS6<\/jats:italic> 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 <jats:italic>TMPRSS6<\/jats:italic> variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar <jats:italic>TMPRSS6<\/jats:italic> genotypes. Mono\u2010allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi\u2010allelic 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\u2013E490, 2016. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.24561","type":"journal-article","created":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T23:42:38Z","timestamp":1474328558000},"source":"Crossref","is-referenced-by-count":35,"title":["Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory"],"prefix":"10.1002","volume":"91","author":[{"given":"Albertine E.","family":"Donker","sequence":"first","affiliation":[{"name":"Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center Nijmegen, The Netherlands"},{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Center Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte C.M.","family":"Schaap","sequence":"additional","affiliation":[{"name":"Radboudumc Expert Center for Iron Disorders, Radboud University Medical Center Nijmegen, The Netherlands"},{"name":"Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Center Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera M. 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