Congenital Sideroblastic Anemia

Congenital sideroblastic anemia (CSA) occurs when the bone marrow fails to produce a sufficient number of healthy red blood cells. Instead, it produces sideroblasts (abnormal red blood 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 stuck in the mitochondria, the 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.

Acquired anemia

Sideroblastic anemias can be divided into congenital and acquired forms. Acquired anemias are more common and are seen almost exclusively in older adults. They usually are the result of acquired non-inherited genetic mutations that occur only in the red blood cell precursors leading 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.

Anemia from a genetic mutation

By contrast, the congenital sideroblastic anemias are inherited diseases caused by genetic mutations that are present at birth in all the cells. 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. Therefore, it is particularly important to distinguish late-onset CSA from an acquired sideroblastic anemia, because they have very different causes, treatments, and prognoses.

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

• Fatigue
• Jaundice
• Irritability
• Exercise/feeding intolerance
• Exertional dyspnea
• Headache, vertigo

Some forms of CSA are associated with other symptoms or signs outside the blood system. These 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

Each of the CSA types require testing to isolate. It is important to understand that some symptoms of CSA may resemble those of other more common medical problems or other blood disorders. Because some of these symptoms can also point to other conditions and because anemia itself can be a symptom of another medical problem, it’s important to have your child evaluated by a qualified medical professional for an accurate diagnosis and prompt treatment.

The specific CSA diagnosis relies on an experienced clinician trained to recognize 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.)

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

Depending on the specific type of a child’s CSA and the severity of the condition, a hematologist may recommend a variety of different treatments.

Medical therapy

X-linked sideroblastic anemia (XLSA) can sometimes respond very favorably to treatment with vitamin B6. Unfortunately, none of the other CSAs are known to respond to vitamins 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. Children who have repeated red blood cell transfusions or require chronic transfusions can also quickly become iron overloaded. Without removal of this iron, through chelators, it can build up and become toxic to several vital organs. 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 from another person (donor) to your child. 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 children with a compatible full-sibling donor meet with a pediatric stem cell doctors to learn more about the process.

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.

Children and adolescents with CSA are treated at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center through our Rare Anemias and Iron Disorders Program. Our Rare Anemias and Iron Disorders Program provides comprehensive care for children with all types of rare anemias and iron disorders, as well as ongoing medical management and access to new treatment approaches through our clinical research. Learn about our anemias and iron disorders research study.