A child with severe iron-deficiency anemia and a complex TMPRSS6 genotype

Hematology. 2017 Oct;22(9):559-564. doi: 10.1080/10245332.2017.1317990. Epub 2017 Apr 27.


Objectives: We report a case of a 7-year-old girl with severe hypochromic microcytic anemia, who was unresponsive to classical iron supplements. We suspected IRIDA, iron-refractory iron-deficiency anemia, a genetic iron metabolism disorder, caused by TMPRSS6 variations. TMPRSS6 encodes matriptase-2, a negative regulator of hepcidin, and its pathological variants are related to normal to high levels of hepcidin. We analyzed the TMPRSS6 gene and we improved clinical management of the patient, selecting the appropriate supplementation therapy. Intervention & Technique: The parenteral iron therapy was started, but the patient was only partially responsive and the anemia persisted. To confirm the diagnosis, the TMPRSS6 gene sequence was analyzed by DNA sequencing and other relevant biochemical parameters were evaluated.

Results: The TMPRSS6 sequence analysis showed a complex genotype with a rare heterozygous missense variant, in addition to other common polymorphisms. The serum hepcidin value was normal. We unexpectedly observed a normalization of patient's hemoglobin (Hb) levels only after liposomal iron treatment.

Discussion and conclusion: The proband was symptomatic for IRIDA during a critical phase of growth and development, but we did not find a clearly causative genotype. A long-term result, improving stably patient's Hb levels, was obtained only after liposomal iron supplementation. Children may be at greater risk for iron deficiency and the degree of anemia as well as the response to the iron supplements varies markedly patient to patient. Here, we show the importance of comprehensive study of these patients in order to collect useful information about genotype-phenotype association of genes involved in iron metabolism.

Keywords: Hypochromic microcytic anemia; IRIDA; TMPRSS6; iron deficiency; iron metabolism; iron supplementation; liposomal iron.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Substitution
  • Anemia, Hypochromic / diagnosis
  • Anemia, Hypochromic / genetics
  • Anemia, Hypochromic / therapy
  • Anemia, Iron-Deficiency / diagnosis*
  • Anemia, Iron-Deficiency / genetics*
  • Anemia, Iron-Deficiency / therapy
  • Biomarkers
  • Child
  • Erythrocyte Indices
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype*
  • Humans
  • Membrane Proteins / genetics*
  • Mutation
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA
  • Serine Endopeptidases / genetics*
  • Severity of Illness Index


  • Biomarkers
  • Membrane Proteins
  • Serine Endopeptidases
  • TMPRSS6 protein, human

Supplementary concepts

  • Anemia, hypochromic microcytic