• Iron-refractory Iron Deficiency Anemia (IRIDA)

    Iron-refractory iron deficiency anemia (IRIDA) is a rare, inherited form of iron deficiency anemia. Iron deficiency anemia occurs when red blood cell counts are low due to a lack of iron.

    • While iron deficiency anemia is generally an acquired disease and due to insufficient iron in the child’s diet or chronic blood loss, children with IRIDA are born with a gene mutation that causes iron deficiency.
    • Common forms of acquired iron deficiency anemia are usually easily treated by oral iron supplements or intravenous (IV) iron infusions, but children with IRIDA will not respond fully to those treatments.
    • Children with IRIDA typically start to experience symptoms in infancy or early childhood.

    IRIDA Treatment at Dana-Farber/Boston Children's

    Dana-Farber/Boston Children's is an international leader in the diagnosis and management of rare iron disorders. Through our Rare Anemias and Iron Disorders Program, children and families with rare iron disorders such as IRIDA have access to world-renown multidisciplinary teams of hematologists, pathologists and researchers.

    What are the causes of IRIDA?

    IRIDA is caused by mutations in the gene TMPRSS6. It is inherited as an autosomal recessive disorder, which means both parents must have a copy of the gene mutation and pass it on to their child. Therefore it may be seen in several of the child’s family members. The TMPRSS6 gene encodes a particular liver protein that regulates the production of hepcidin, an iron regulatory hormone. In children with IRIDA, the TMPRSS6 mutation causes elevated levels of hepcidin, which ultimately impairs the body’s ability to both absorb and use iron. There is some evidence that relatives that carry one abnormal copy of TMPRSS6 (e.g., parents) are more susceptible to acquired iron deficiency.

    What are the symptoms of IRIDA?

    The symptoms of iron-refractory iron deficiency anemia (IRIDA) in children are similar to the symptoms of all forms of anemia and iron deficiency.

    Typical anemia symptoms include:

    • Fatigue, weakness
    • Irritability
    • Exercise/feeding intolerance
    • Exertional dyspnea
    • Headache, vertigo
    • Pale skin

    Symptoms of iron deficiency include:

    • Pica (craving of non-food items – such as clay, dirt, paper, ice, baby powder, starch)
    • Poor sleep or restless leg syndrome
    • Angular cheilitis (sore lesions at the corners of the mouth)

    In rare cases, children with iron deficiency anemia may also experience:

    • Nail changes (koilonychia or spoon nails)
    • Alopecia (hair loss) is rarely experienced
    • Atrophic glossitis (tongue swelling/pain or dry mouth)
    • Dysphagia (difficuly swallowing) 

    How is IRIDA diagnosed?

    The first step in treating your child is providing an accurate and complete diagnosis. General iron deficiency anemia can be identified through a complete blood count, an analysis that involves measuring the size, number and maturity of different blood cells within a set volume of blood.

    If your child is determined to have iron deficiency anemia, doctors will want to rule out possible causes of acquired iron deficiency (such as gastrointestinal blood loss), causes of small red blood cells (microcytosis), such as thalassemias or lead toxicity, or chronic inflammatory disorders or intestinal malabsorption, such as celiac disease (“sprue”).

    In order to distinguish IRIDA from other, more common forms of iron deficiency anemia, doctors will look for these key features:

    • lifelong anemia (hemoglobin 6-9 g/dL)
    • very low red blood cell size (microcytic), with a mean corpuscular volume (MCV) of 45-65 fL
    • very low iron levels in the blood (transferrin saturation <5%)
    • abnormal oral iron absorption – no response to oral iron supplements or failure of an “oral iron challenge” (see below)
    • abnormal iron utilization – a slow, incomplete, and transient response to parenteral iron (iron injected intravenously)
    • other affected family members with an autosomal recessive inheritance pattern

    If your child has most or all of these features, doctors can confirm the diagnosis by measuring the blood level of the hepcidin hormone in your child.

    You may also choose to have your child participate in a research protocol at Dana-Farber/Boston Children’s, in which your child’s TMPRSS6 gene is sequenced. The gene sequencing can confirm an IRIDA diagnosis, and over time this research may help reveal opportunities to improve treatment. In addition, if mutations in TMPRSS6 are not found, the research team is actively looking for other causes of inherited iron deficiency.

    What is the oral iron challenge?
    The oral iron challenge is an easy test provided in a doctor’s office. First, your child will have a blood test to check anemia and iron levels. This will be followed by a dose of oral iron. About 90 minutes later, your child will receive a second blood test to check iron levels again. The iron level in the blood should rise significantly. If the iron level does not rise, it suggests either a problem with the small bowel or IRIDA.

    How is IRIDA treated?

    Because the iron deficiency of IRIDA is refractory (does not respond) to oral iron supplementation and usually is only partially responsive to parenteral iron, your child may receive repeated infusions of intravenous iron. These repeated iron infusions can improve the anemia, microcytosis and iron stores (ferritin). However, the serum iron and transferrin saturation generally do not improve to the normal range, and if your child stops receiving regular intravenous iron infusions, the previous low iron levels and microcytic anemia almost certainly will appear again.

    What is the latest IRIDA research?

    IRIDA was first identified in 2008, when researchers at Dana-Farber/Boston Children’s discovered that most children and adults with a type of iron deficiency anemia that doesn’t respond to iron supplementation seemed to harbor mutations in the TMPRSS6 gene. This research led to the recognition of a new clinical entity: iron-refractory iron deficiency anemia (IRIDA). Since that time, Dana-Farber/Boston Children’s researchers continue to lead the way in research and treatment of IRIDA – including building our understanding of the clinical features of IRIDA and performing genetic studies of IRIDA.

    If you, your child, or other family members have the key features of IRIDA as described in the diagnosis section above, we invite you to contact us for an evaluation or to learn more about our research. We have an open research protocol that is helping to build our understanding of the key features and genetic underpinnings of IRIDA. Through this protocol, children and adults who choose to participate will agree to provide blood and urine samples. Our researchers will then use those samples to assess iron proteins in the blood, hepcidin level in the blood and urine, and to sequence the TMPRSS6 gene. In ongoing work, the team is working toward identifying other genes responsible for IRIDA and is using a novel test for hepcidin to discriminate patients with IRIDA from patients with complicated acquired iron deficiency. This testing is being performed primarily to increase scientific knowledge. However, if an individual’s test reveals information that could be of clinical benefit, those results will be returned to you and your doctor so that they can be confirmed in a certified diagnostic laboratory – as long as you indicate an interest in the results when signing up for the study.

    To learn more about the study, contact Mark D. Fleming, MD, DPhil at 617-919-2664.

    Our Published Research

    What is the long-term outlook for patients with IRIDA?

    Because IRIDA is rare, there is very limited information on the long-term treatment and effects of IRIDA. However, although IRIDA is lifelong, the severity and symptoms appear to decrease somewhat in adulthood.
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