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The following case study focuses on a 35-year-old male who was evaluated for microcytic anemia shown on a routine CBC. Test your knowledge by reading the background information below and making the proper selection.

CBC showed WBC 4.5 x 109/L, Hgb 10.2 g/dl, PLT 350 x 109/L with MCV of 76 fl. Lactate dehydrogenase (LDH) was normal at 150 µ/L. Peripheral smear showed hypochromic, microcytic RBCs. Patient has no history of GI symptoms, and endoscopic exams were unremarkable. Iron panel showed Fe of 15, transferrin saturation of 5 percent. He was diagnosed with iron-deficiency anemia and given oral iron supplementation. No significant improvement in Hgb was shown two months later, and IV iron supplementation was given with subsequent improvement in Hgb. Of note, he has two cousins who were diagnosed with iron-deficiency anemia during their first year of life, and they have required intermittent infusion of intravenous iron in the past.

What is the likely cause of his iron-deficiency anemia?

1. Parvovirus-induced pure red cell aplasia
2. Tmprss6 mutation
3. Diamond-Blackfan anemia
4. X-linked sideroblastic anemia

Answer

2. Tmprss6 mutation

Explanation

The most likely diagnosis is congenital iron deficiency. Rarely, families with iron-deficiency anemia unresponsive to oral iron therapy but partially responsive to parenteral iron have been reported. Hepcidin, encoded by the gene Hamp, plays a key regulatory role in iron absorption.¹ It lowers plasma iron level by binding ferroportin, an iron efflux channel, and causes subsequent degradation of the channel. As a result, efflux of iron from macrophages or intestinal cells into the plasma is prevented. Several factors, including hemochromatosis protein, transferrin receptor 2, hemojuvelin, and transcription factor SMAD4, have been shown to regulate body iron levels by promoting expression of Hamp.^2-7 Furthermore, Hamp is up-regulated in response to the inflammatory cytokines, IL-6 and IL-1, and bone morphogenetic proteins, BMP2, BMP4, and BMP9.^8-11

Recently reported was the discovery of a gene, Tmprss6, which has been shown to negatively regulate Hamp gene and, therefore, decrease hepcidin expression to promote iron uptake.¹²Tmprss6 encodes the transmembrane serine protease matriptase-2 (MT2). It is highly expressed in the liver and participates in a transmembrane signaling pathway triggered by iron deficiency and suppresses hepcidin expression by cleaving membrane-bound hemojuvelin (mHJV) to increase iron absorption.¹³

Genome-wide scanning by microsatellites and single nucleotide polymorphisms analysis of a Sardinian family with iron deficiency due to defective iron absorption located Tmprss6 (also known as matriptase-2) as the candidate gene responsible for the condition. Sequence analysis of these individuals showed homozygous G->C substitution at the +1 position of intron 6, within the 5’-splice donor site in all the affected subjects.¹⁴

Missense mutations in the second class A low-density lipoprotein receptor (LDLRA) domain of Tmprss6 have also been reported and functional studies showed that these mutations led to defective cleavage of mHJV.¹⁵ Two nonsense mutations also have been identified, which have been predicted to delete the serine protease domain of matriptase-2.¹⁶ Other studies showed that Tmprss6-dependent pathway may predominate over all known Hamp-activating pathways, since overexpression of Tmprss6 could override the hepcidin-inducing effects of hemojuvelin, BMP2/4/9, SMAD1, IL-1, and IL-6.¹²

References

1. Nemeth E, Ganz T. Annu Rev Nutr. 2006;26:323-42.
2. Nemeth E, Tuttle MS, Powelson J, et al. Science. 2004;306:2090-3.
3. Nicolas G, Bennoun M, Porteu A, et al. Proc Natl Acad Sci USA. 2002;99:4596-601.
4. Ahmad KA, Ahmann JR, Migas MC, et al. Blood Cells Mol Dis. 2002;29:361-66.
5. Kawabata H, Fleming RE, Gui D, et al. Blood. 2005;105:376-81.
6. Papanikolaou G, Samuels ME, Ludwig EH, et al. Nat Genet. 2004;36:77-82.
7. Wang RH, Li C, Xu X, et al. Cell Metab. 2005;52:399-409.
8. Nemeth E et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2002;110:1037-44.
9. Lee P, Peng H, Gelbart T, et al. Proc Natl Acad Sci USA. 2005;102:1906-10.
10. Roy CN, Andrews NC. . Curr Opin Hematol. 2005;12:107-11.
11. Truksa J, Peng H, Lee P, et al. Proc Natl Acad Sci USA. 2006;103:10289-93.
12. Du X, She E, Gelbart T, et al. Science. 2008;320:1088-92.
13. Silvestri L, Pagani A, Nai A, et al. Cell Metab. 2008;8:502-11.
14. Melis M, Pagani A, Nai A, et al. Haematologica. 2008;93:14737-9.
15. Silvestri L, Guillem F, Pagani A, et al. Blood. 2009;113:5605-8.
16. Guillem F, Lawson S, Kannengiesser C, et al. Blood. 2008;112:2089-91.

Case study submitted by Jenny J. Kim, MD, MS, Cleveland Clinic Taussig Cancer Institute.