Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory

Albertine E Donker, Charlotte C M Schaap, Vera M J Novotny, Roel Smeets, Tessa M A Peters, Bert L P van den Heuvel, Martine F Raphael, Anita W Rijneveld, Inge M Appel, Andre J Vlot, A Birgitta Versluijs, Michel van Gelder, Bernd Granzen, Mirian C H Janssen, Alexander J M Rennings, Frank L van de Veerdonk, Paul P T Brons, Dirk L Bakkeren, Marten R Nijziel, L Thom Vlasveld & 1 others Dorine W Swinkels

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)E482-E490
JournalAmerican Journal of Hematology
Volume91
Issue number12
DOIs
Publication statusPublished - Dec 2016

Cite this

Donker, A. E., Schaap, C. C. M., Novotny, V. M. J., Smeets, R., Peters, T. M. A., van den Heuvel, B. L. P., ... Swinkels, D. W. (2016). Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory. American Journal of Hematology, 91(12), E482-E490. https://doi.org/10.1002/ajh.24561
Donker, Albertine E ; Schaap, Charlotte C M ; Novotny, Vera M J ; Smeets, Roel ; Peters, Tessa M A ; van den Heuvel, Bert L P ; Raphael, Martine F ; Rijneveld, Anita W ; Appel, Inge M ; Vlot, Andre J ; Versluijs, A Birgitta ; van Gelder, Michel ; Granzen, Bernd ; Janssen, Mirian C H ; Rennings, Alexander J M ; van de Veerdonk, Frank L ; Brons, Paul P T ; Bakkeren, Dirk L ; Nijziel, Marten R ; Vlasveld, L Thom ; Swinkels, Dorine W. / Iron refractory iron deficiency anemia : a heterogeneous disease that is not always iron refractory. In: American Journal of Hematology. 2016 ; Vol. 91, No. 12. pp. E482-E490.
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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. {\circledC} 2016 Wiley Periodicals, Inc.",
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Donker, AE, Schaap, CCM, Novotny, VMJ, Smeets, R, Peters, TMA, van den Heuvel, BLP, Raphael, MF, Rijneveld, AW, Appel, IM, Vlot, AJ, Versluijs, AB, van Gelder, M, Granzen, B, Janssen, MCH, Rennings, AJM, van de Veerdonk, FL, Brons, PPT, Bakkeren, DL, Nijziel, MR, Vlasveld, LT & Swinkels, DW 2016, 'Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory' American Journal of Hematology, vol. 91, no. 12, pp. E482-E490. https://doi.org/10.1002/ajh.24561

Iron refractory iron deficiency anemia : a heterogeneous disease that is not always iron refractory. / Donker, Albertine E; Schaap, Charlotte C M; Novotny, Vera M J; Smeets, Roel; Peters, Tessa M A; van den Heuvel, Bert L P; Raphael, Martine F; Rijneveld, Anita W; Appel, Inge M; Vlot, Andre J; Versluijs, A Birgitta; van Gelder, Michel; Granzen, Bernd; Janssen, Mirian C H; Rennings, Alexander J M; van de Veerdonk, Frank L; Brons, Paul P T; Bakkeren, Dirk L; Nijziel, Marten R; Vlasveld, L Thom; Swinkels, Dorine W.

In: American Journal of Hematology, Vol. 91, No. 12, 12.2016, p. E482-E490.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Iron refractory iron deficiency anemia

T2 - a heterogeneous disease that is not always iron refractory

AU - Donker, Albertine E

AU - Schaap, Charlotte C M

AU - Novotny, Vera M J

AU - Smeets, Roel

AU - Peters, Tessa M A

AU - van den Heuvel, Bert L P

AU - Raphael, Martine F

AU - Rijneveld, Anita W

AU - Appel, Inge M

AU - Vlot, Andre J

AU - Versluijs, A Birgitta

AU - van Gelder, Michel

AU - Granzen, Bernd

AU - Janssen, Mirian C H

AU - Rennings, Alexander J M

AU - van de Veerdonk, Frank L

AU - Brons, Paul P T

AU - Bakkeren, Dirk L

AU - Nijziel, Marten R

AU - Vlasveld, L Thom

AU - Swinkels, Dorine W

N1 - © 2016 Wiley Periodicals, Inc.

PY - 2016/12

Y1 - 2016/12

N2 - 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.

AB - 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.

U2 - 10.1002/ajh.24561

DO - 10.1002/ajh.24561

M3 - Article

VL - 91

SP - E482-E490

JO - American Journal of Hematology

JF - American Journal of Hematology

SN - 0361-8609

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Donker AE, Schaap CCM, Novotny VMJ, Smeets R, Peters TMA, van den Heuvel BLP et al. Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory. American Journal of Hematology. 2016 Dec;91(12):E482-E490. https://doi.org/10.1002/ajh.24561