Alternative titles; symbols
SNOMEDCT: 722005000; ORPHA: 209981; DO: 11252;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q12.3 | Iron-refractory iron deficiency anemia | 206200 | Autosomal recessive | 3 | TMPRSS6 | 609862 |
A number sign (#) is used with this entry because of evidence that iron-refractory iron deficiency anemia (IRIDA) can be caused by homozygous or compound heterozygous mutation in the TMPRSS6 gene (609862) on chromosome 22q12.
Variation in the TMPRSS gene has been associated with hemoglobin levels as a quantitative trait; see HCHGQ3, 613284.
Finberg et al. (2008) referred to this phenotype as iron-refractory iron deficiency anemia (IRIDA) and reviewed the key features: a congenital hypochromic, microcytic anemia; a very low mean corpuscular erythrocyte volume; a low transferrin saturation; abnormal iron absorption characterized by no hematologic improvement following treatment with oral iron; and abnormal iron utilization characterized by a sluggish, incomplete response to parenteral iron. The authors noted that although urinary levels of hepcidin (606464) are typically undetectable in individuals with iron deficiency, in 5 individuals with IRIDA urinary hepcidin/creatinine ratios were within or above the normal range.
Buchanan and Sheehan (1981) described 2 brothers and a sister with microcytic anemia but no evidence of reduced iron intake or blood loss. The anemia failed to respond to oral iron therapy, and malabsorption of oral medicinal iron was demonstrated. There was a partial but incomplete response to intramuscular iron dextran treatment. No evidence was found for other well-defined causes of hypochromic microcytic anemia or for a generalized disorder of intestinal absorption.
Brown et al. (1988) reported 2 sisters with apparent familial hypochromic microcytic anemia unresponsive to oral iron or pyridoxine therapy; 1 sister had a partial response to parenteral iron. As both parents were hematologically normal, the authors suspected a recessively inherited disorder. Cultured bone marrow cells from both patients grew adequate numbers of erythroid colonies (CFU-E and BFU-E) in the presence of erythropoietin, and small numbers of endogenous CFU-E were seen in 7-day cultures. Assays on bone marrow cells from both patients revealed a 6- to 7-fold reduction in baseline delta-aminolevulinate synthase (125290) activity, with an increase to normal levels upon exposure to pyridoxal phosphate (PLP). Ferrochetalase (612386) and ALAD (125270) activities were normal in both patients. There were no significant differences in bone marrow heme oxygenase (see 141250) between patients and controls in the presence or absence of PLP, but heme synthesis by patients' bone marrow was less than controls. Brown et al. (1988) concluded that bone marrow cells from patients with this disorder have some disturbances in heme metabolism, but erythropoiesis appears to be normal in the presence of adequate nutrients in vitro.
Hartman and Barker (1996) described an African American brother and sister who had severe hypoproliferative microcytic anemia with decreased serum iron and ferritin despite prolonged treatment with oral iron. An iron challenge study with 2 mg/kg of ferrous sulfate revealed iron malabsorption; treatment with intravenous iron dextran did not result in the expected reticulocytosis, and serum iron and TIBC remained decreased although serum ferritin increased, with only a partial correction of hemoglobin, hematocrit, and microcytosis. The bone marrow was hypocellular with abnormal iron incorporation into erythroid precursor cells. The father had borderline microcytosis, and the maternal grandmother and a maternal aunt had documented iron deficiency anemia as adults despite oral iron therapy; the maternal aunt also had a poor response to an oral iron challenge test in the presence of serologic iron deficiency. The authors concluded that this represented a rare form of inherited anemia characterized by iron malabsorption and disordered iron metabolism that only partially corrects after the administration of parenteral iron, and noted that these features resemble those found in the microcytic (mk/mk) mouse.
Andrews (1997) reported a well-appearing 18-month-old boy with profound hypochromic microcytic anemia unresponsive to oral iron and partially responsive to intravenous iron therapy, in whom anemia persisted after total body iron stores were repleted. The author noted that the red cell morphology was consistent with severe iron deficiency, but his RBC count was surprisingly high, a feature that is also seen in mk mice. No family members had microcytosis or significant anemia; he had a healthy older brother.
Pearson and Lukens (1999) reported a 15-year study of 2 sisters with severe microcytic anemia and iron malabsorption who had only a partial response to parenteral iron. At 16 and 14 years of age, respectively, both sisters had normal growth, development, and intellectual performance. Their unrelated parents, of northern European descent, and a younger brother had normal blood parameters. Ferrokinetic studies in 1 sister were characteristic of iron deficient erythropoiesis, with rapid plasma clearance of (59)Fe complexed with the patient's own transferrin followed by rapid, complete incorporation into erythrocytes; the authors noted that these ferrokinetics differ from those of the mk/mk mouse. Pearson and Lukens (1999) concluded that the defect in these sisters appeared to be an undefined, novel abnormality involving mobilization of iron into plasma from both intestinal mucosa and reticuloendothelial cells.
Mayo and Samuel (2001) reported an 11-year-old Caucasian girl and her 15-year-old brother who were both discovered to be anemic on routine screening during their first year of life and who were unresponsive to oral iron therapy; both had only a partial response to intravenous iron, indicating that abnormal gastrointestinal iron absorption was only part of the iron metabolism disorder. Neither parent had been diagnosed with anemia, but the maternal grandmother had received regular intramuscular injections of iron throughout her adult life.
Finberg et al. (2008) noted that autosomal recessive IRIDA had been mapped to chromosome 22q12-q13 in a Sardinian kindred. Finberg et al. (2008) performed haplotype analysis in 5 kindreds with IRIDA, which supported linkage to 22q12-q13.
The transmission pattern of IRIDA in the patients reported by Finberg et al. (2008) was consistent with autosomal recessive inheritance.
To determine the genetic basis of IRIDA, Finberg et al. (2008) selected the TMPRSS6 gene (609862), located in the critical linkage interval and encoding a type II transmembrane serine protease expressed primarily in liver, as a candidate gene. That a recessive mutation in the mouse ortholog leads to anemia as a result of defective dietary iron uptake made TMPRSS6 a particularly attractive candidate. In 3 of 4 IRIDA kindreds in which the phase of chromosomal segregation was known, Finberg et al. (2008) identified biallelic mutations (609862.0001-609862.0008). In the fourth family, they found a mutation only on the paternal allele; however, they did not exclude the presence of other types of mutations, such as large deletions, that were not detectable by sequencing. In a fifth kindred for which DNA was available only from affected sibs, a nonconservative missense mutation was found in both. To explain inappropriately elevated hepcidin levels, Finberg et al. (2008) suggested that normal TMPRSS6 may cleave a protein that acts in or on hepatocytes to negatively regulate hepcidin production, secretion, or clearance. Studies in the Tmprss6 mouse mutant suggested that TMPRSS6 is a negative regulator of hepcidin transcription.
Guillem et al. (2008) found compound heterozygosity for 2 nonsense mutations in the TMPRSS6 gene (609862.0009 and 609862.0010) in a patient with IRIDA, confirming the findings of Finberg et al. (2008). Hepcidin levels were inappropriately normal in the patient reported by Guillem et al. (2008), suggesting defective hepcidin downregulation.
Buchanan and Sheehan (1981) suggested that this disorder may be analogous to the recessively inherited microcytic anemia of the mk-mk mouse (Bannerman, 1981), first described at the Jackson Laboratory (Nash et al., 1964; Russell et al., 1970), in which there is a generalized impairment in cellular uptake of iron (Bannerman et al., 1972; Edwards and Hoke (1972, 1975)).
Andrews, N. C. Iron deficiency: lessons from anemic mice. Yale J. Biol. Med. 70: 219-226, 1997. [PubMed: 9544492]
Bannerman, R. M., Edwards, J. A., Kreimer-Birnbaum, M., McFarland, E., Russell, E. S. Hereditary microcytic anaemia in the mouse; studies in iron distribution and metabolism. Brit. J. Haemat. 23: 235-245, 1972. [PubMed: 5070129] [Full Text: https://doi.org/10.1111/j.1365-2141.1972.tb03476.x]
Bannerman, R. M. Of mice and men and microcytes. J. Pediat. 98: 760-762, 1981. [PubMed: 7194903] [Full Text: https://doi.org/10.1016/s0022-3476(81)80838-4]
Brown, A. C., Lutton, J. D., Pearson, H. A., Nelson, J. C., Levere, R. D., Abraham, N. G. Heme metabolism and in vitro erythropoiesis in anemia associated with hypochromic microcytosis. Am. J. Hemat. 27: 1-6, 1988. [PubMed: 3354554] [Full Text: https://doi.org/10.1002/ajh.2830270102]
Buchanan, G. R., Sheehan, R. G. Malabsorption and defective utilization of iron in three siblings. J. Pediat. 98: 723-728, 1981. [PubMed: 7229750] [Full Text: https://doi.org/10.1016/s0022-3476(81)80831-1]
Edwards, J. A., Hoke, J. E. Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia. Proc. Soc. Exp. Biol. Med. 141: 81-84, 1972. [PubMed: 5082324] [Full Text: https://doi.org/10.3181/00379727-141-36720]
Edwards, J. A., Hoke, J. E. Red cell iron uptake in hereditary microcytic anemia. Blood 46: 381-388, 1975. [PubMed: 807277]
Finberg, K. E., Heeney, M. M., Campagna, D. R., Aydinok, Y., Pearson, H. A., Hartman, K. R., Mayo, M. M., Samuel, S. M., Strouse, J. J., Markianos, K., Andrews, N. C., Fleming, M. D. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nature Genet. 40: 569-571, 2008. [PubMed: 18408718] [Full Text: https://doi.org/10.1038/ng.130]
Guillem, F., Lawson, S., Kannengiesser, C., Westerman, M., Beaumont, C., Grandchamp. B. Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood 112: 2089-2091, 2008. [PubMed: 18596229] [Full Text: https://doi.org/10.1182/blood-2008-05-154740]
Hartman, K. R., Barker, J. A. Microcytic anemia with iron malabsorption: an inherited disorder of iron metabolism. Am. J. Hemat. 51: 269-275, 1996. [PubMed: 8602626] [Full Text: https://doi.org/10.1002/(SICI)1096-8652(199604)51:4<269::AID-AJH4>3.0.CO;2-U]
Mayo, M. M., Samuel, S. M. Iron deficiency anemia due to a defect in iron metabolism: a case report. Clin. Lab. Sci. 14: 135-138, 2001. [PubMed: 11517621]
Nash, D. J., Kent, E., Dickie, M. M., Russell, E. S. The inheritance of 'mick,' a new anemia in the house mouse. Am. Zoologist 14: 404-405, 1964.
Pearson, H. A., Lukens, J. N. Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J. Pediat. Hemat. Oncol. 21: 412-417, 1999. [PubMed: 10524456] [Full Text: https://doi.org/10.1097/00043426-199909000-00014]
Russell, E. S., Nash, D. J., Bernstein, S. E., Kent, E. L., McFarland, E. C., Matthews, S. M., Norwood, M. S. Characterization and genetic studies of microcytic anemia in house mice. Blood 35: 838-850, 1970. [PubMed: 5427253]