• Congenital Sideroblastic Anemia (CSA)

    Sideroblastic anemia - sideroblasts Bone marrow from a patient with congenital
    sideroblastic anemia; the blue spots are
    iron particles ‘ringing’ the nucleus of
    developing red blood cells. (Perls stain 50X)
    Sideroblastic anemia occurs when the bone marrow fails to produce a sufficient number of healthy red blood cells. Instead, it produces sideroblasts, abnormal red blood cell precursors (cells that normally mature into red blood cells) in which iron accumulates in the mitochondria. These iron loaded mitochondria surround the nucleus of the developing red blood cell and give the appearance of a ‘ring’.

    Because the iron is essentially stuck in the mitochondria, your child’s body cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently throughout the body. This defect in red blood cell production also can alter the iron balance within your child, often resulting in total body iron overload.

    Sideroblastic anemia can be either congenital (inherited) or acquired (not inherited). Both types have very different causes, treatments, and prognoses. This page is primarily focused on congenital sideroblastic anemia.

    Sideroblastic Anemia Treatment at Dana-Farber/Boston Children's

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

    What is congenital sideroblastic anemia?

    The sideroblastic anemias can be divided into congenital (inherited) forms and acquired forms. Acquired sideroblastic anemias (SAs) are more common and are seen almost exclusively in older adults. They usually are the result of acquired (not inherited) genetic mutations that occur only in the red blood cell precursors that lead to ringed sideroblasts. This form of sideroblastic anemia – refractory anemia with ringed sideroblasts (RARS) – is classified within a broader group of diseases called myelodysplastic syndromes (MDS) and can eventually lead to leukemia. In more than 75% of cases of RARS, the bone marrow cells have acquired a mutation in one particular gene called SF3B1. Acquired sideroblastic anemias can also be due to nutritional deficiencies, acquired metabolic diseases, or toxins.

    By contrast, the congenital sideroblastic anemias (CSAs) are inherited diseases caused by genetic mutations that are present at birth in all the cells. Importantly, even though the mutations are inherited and present at birth, anemia may not be present in infancy, and sometimes may not be recognized until adulthood. Thus, it is particularly important to distinguish late-onset CSA from an acquired SA because they have very different causes, treatments, and prognoses.

    What causes congenital sideroblastic anemia?

    The CSAs are the result of inborn abnormalities in one of three pathways that occur in mitochondria: heme biosynthesis, the synthesis of other iron containing compounds called iron sulfur clusters, and protein synthesis in general within mitochondria. Approximately two-thirds of patients with congenital sideroblastic anemias have inherited mutations in a known gene. However, the remainder do not yet have a genetic explanation and are a focus of our research. CSAs can be passed on in families in several different patterns including autosomal recessive, autosomal dominant, X-linked, and mitochondrial inheritance.

    What are the different types of congenital sideroblastic anemia?

    The CSAs are generally divided into those that affect only the blood system (non-syndromic) and those that also affect other tissues, such as the nervous system and muscles (syndromic). In some cases of syndromic sideroblastic anemia, the anemia may be an incidental problem – the major signs and symptoms of the disease may be in other tissues. In general, the CSAs that affect heme synthesis result in non-syndromic anemia with small red blood cells (microcytosis), whereas those that affect mitochondrial protein synthesis are syndromic and have large red blood cells (macrocytosis). Mutations in genes involved in iron-sulfur cluster synthesis generally have normal sized red blood cells (normocytic) and may be syndromic or non-syndromic.

    The currently recognized forms of CSA with the genes that cause them are described below:

    Gene mutations in congenital sideroblastic anemia

    What are the symptoms and signs of congenital sideroblastic anemia?

    The symptoms and signs of congenital sideroblastic anemia (CSA) in children are primarily related to the anemia and its severity:

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

    Some forms of CSA are associated with other symptoms or signs outside the blood system. These combinations of symptoms and signs are referred to as syndromic CSAs. The associated symptoms can include:

    • developmental delay
    • deafness
    • vision loss
    • muscle dysfunction (heart muscle and/or other muscles)
    • organ failure (e.g. kidney and/or liver)
    • immunodeficiency
    • fevers
    • acidosis

    How is congenital sideroblastic anemia diagnosed?

    The recognition of the specific CSA diagnosis relies on an experienced clinician recognizing the characteristics of the anemia (e.g., red blood cell size: microcytic, normocytic, or macrocytic), the age of child (or adult) when symptoms are first noticed, and other potential symptoms (such as muscle weakness).

    CSAs are usually diagnosed with:

    • Blood tests, including a complete blood count
    • Bone marrow examination
    • Body iron measurements (by laboratory testing, radiology/imaging and/or biopsy of the liver)
    • Molecular testing (gene sequencing, protein studies, etc). Increasingly, genetic diagnostics provide the definitive diagnosis.

    After all tests are completed, the hematologist will be able to outline the best treatment options.

    How is congenital sideroblastic anemia treated?

    Treatment for CSA depends on the exact type and severity of the disorder. Depending on the specific type of a child’s CSA, a hematologist may recommend a variety of different treatments, including:

    Medical therapy

    • X-linked sideroblastic anemia (XLSA) can sometimes respond very favorably to treatment with vitamin B6 (pyridoxine). Thiamine-responsive megaloblastic anemia (TRMA) is often partially responsive to treatment with thiamine (vitamin B1). Unfortunately, none of the other CSAs are known to respond to vitamin or other medical therapies.

    Transfusion therapy

    • Blood transfusions may be given to treat severe anemia.
    • Some children with CSAs may receive repeated blood transfusions to keep their hemoglobin level high enough to perform routine activities. 

    Iron chelators

    • CSAs can result in gradual iron overload related to increased daily iron absorption from the gut.
    • CSA patients who have repeated intermittent red blood cell transfusions or require chronic transfusions can also quickly become iron overloaded.
    • Without removal of this iron by, it can build up and become toxic to several vital organs.
    • Iron can be removed from the body by medications called chelators.
    • Children may take chelators orally or by injection in order to remove excess iron from the body.

    Stem cell transplant

    Right now, the only cure for some CSAs is a stem cell transplant– the transplantation of normal blood stem cells from another person (‘donor’) to your child. In CSA, the best transplant outcomes are almost always when the donor is a healthy sibling with compatible stem cells. The stem cells replace the diseased stem cells and restore normal blood production. In the syndromic sideroblastic anemias, disease manifestations unrelated to the bone marrow disease do not get better after bone marrow transplantation.

    Because stem cell transplant also carries risk, it is recommended that patients with a compatible full-sibling donor meet with our pediatric stem cell doctors to learn more about the process. Dana-Farber/Boston Children's has one of the largest pediatric stem cell transplant programs in the United States. Our Stem Cell Transplant Center is at the forefront of new, improved protocols for stem cell transplantation for blood-related disorders, including CSA.

    What is the latest congenital sideroblastic anemia research?

    Scientists at Boston Children’s Hospital and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center are the international leaders in research into the molecular underpinnings and identification of different sub-types of CSA. Our researchers have made key discoveries of the specific gene mutations and proteins involved in both syndromic and non-syndromic congenital sideroblastic anemias, and we have an open research protocol that is helping us to reach our ultimate goal of understanding the genetic basis of all types of CSAs.

    By building this scientific knowledge into the variability of CSAs, we are better able to identify potential therapeutic options for each sub-type of the disease. Some day we may be able to offer treatment options that directly impact the genetic causes of CSA to cure the disease.

    Research Study for Patients with CSA

    If you, your child, or other family members have the key features of congenital sideroblastic anemia, 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 CSA. 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 the blood cells, iron proteins and to conduct genetic testing that will sequence all the known CSA genes. 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 CSA Research

    What is the long-term outlook for patients with congenital sideroblastic anemia?

    The long-term outlook for children with CSA depends heavily on the specific type of CSA. A child with CSA will need regular follow-up care by a hematologist.

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