ASK THE HEMATOLOGIST
Sylvia S. Bottomley, MD
Dr. Bottomley is Professor Emeritus of Medicine at the University of Oklahoma
College of Medicine and Staff Physician at the Oklahoma City Veterans Affairs
Medical Center.
THE PATIENT
A three-year-old Caucasian boy with normal growth and development was noted
to have microcytic, hypochromic anemia at the age of nine months, prior to a
minor surgical procedure. Hemoglobin thereafter ranged from 5.9 to 7.2 g/dL,
MCV 44 to 52 fL, and RDW 28 to 32 percent; hemoglobin electrophoresis showed
normal values of Hb A, A2, and F, and iron supplement was prescribed. At age
two, blood iron studies revealed serum iron of 212 µg/dL, TIBC 210 µg/dL,
and ferritin of 1053 µg/L without change in the hemogram. The iron therapy
was discontinued and blood was submitted for research studies of "iron-related
genes." The parents had requested a second opinion, and this hematologist
discovered ring sideroblasts in the bone marrow aspirate. On subsequent pyridoxine
supplementation there was no effect on the anemia. The blood count values of
the parents and an older sister are normal. Mutation analysis of the erythroid
5-aminolevulinate synthase (ALAS2) gene is pending.
WHAT IS THE CLUE FOR PROMPTER DIAGNOSIS OF CONGENITAL SIDEROBLASLTIC
ANEMIA IN THIS CASE?
Once iron deficiency or iron-deficient erythropoiesis (i.e., from chronic infection
or inflammation) and a thalassemic phenotype have been excluded, congenital
sideroblastic anemia is the third most common cause of microcytic anemia. To
establish the diagnosis of the latter, appropriate iron staining of the bone
marrow aspirate is essential.
WHAT IS THE DIFFERENTIAL DIAGNOSIS OF CONGENITAL SIDEROBLASTIC ANEMIA?
X-linked sideroblastic anemia (XLSA) typically exhibits microcytic anemia in
males. Severity as well as any response to pyridoxine is generally dictated
by the nature of the mutation in the ALAS2 gene affecting the function
of the ALAS2 enzyme, and the disorder may be discovered at any age. When an
ALAS2 mutation is not found, the anemia can be attributed to an as-yet-undefined
autosomal defect(s), with dominant or recessive inheritance, or it may be sporadic.
All other diagnostic considerations involve sideroblastic anemia as a component
of genetic syndromes. In the very rare syndrome of X-linked sideroblastic anemia
with ataxia (XLSA/A), microcytic anemia has been mild in three reported families.
The others, namely thiamine-responsive megaloblastic anemia, myopathy with lactic
acidosis, and sideroblastic anemia (MLASA) and Pearson syndrome, have normal
or macrocytic erythrocyte indices.
WHY MUST CAUTION BE EXERCISED TO ATTRIBUTE A SIDEROBLASTIC ANEMIA TO
A MYELODYSPLASTIC SYNDROME (MDS)?
While isolated congenital or inherited sideroblastic anemia in males is almost
always characterized by microcytic morphology, which essentially excludes MDS,
XLSA expressed in females is usually normocytic or macrocytic. Most women carrying
an ALAS2 mutation who develop the disorder in adulthood do so due to age-related
nonrandom X-inactivation in hematopoietic tissue, with preferential inactivation
of the normal X chromosome, and very rarely because of constitutive skewed X-inactivation.
Thus examination of the X-inactivation status is useful for screening females
with sideroblastic anemia caused by mutations in the ALAS2 gene. The
lack of microcytosis in affected women is attributable to a markedly defective
or non-functional mutant ALAS2 enzyme in apoptotic erythroid precursors, and
the peripheral erythrocytes represent essentially only progeny of the residual
normal clone that are released at an accelerated rate from the marrow.
Once a genetic basis for the sideroblastic anemia is established, the family
or patient can be advised that there is no known increased risk for leukemia
or the like in the disorder. It is also advisable to screen family members for
silent disease.
HOW SHOULD THE PATIENT AND OTHERS WITH ISOLATED HERITABLE OR CONGENITAL
SIDEROBLASTIC ANEMIA BE MANAGED?
The DNA analysis should establish whether the child has XLSA due to an ALAS2
mutation. Analysis of how an ALAS2 mutation affects the structure
and function of the ALAS2 protein can predict a clinical response to supplements
of its cofactor pyridoxine. Up to two-thirds of cases respond variably to pyridoxine
supplementation, but the hemoglobin normalizes in only about one-third of responders.
The vitamin is ineffective in all other forms of sideroblastic anemia.
Otherwise, treatments remain largely supportive. They can provide normal survival
in many cases and are aimed at control of symptoms of anemia and prevention
of organ damage from the associated iron overload. Red cell transfusion should
be kept to a minimum. Phlebotomy or iron chelation therapy is generally instituted
when serum ferritin is above 500 µg/L.
Cure of congential sideroblastic anemia when not associated with a genetic
syndrome can only be achieved with hematopoietic stem cell transplantation save
for the attendant risks of the procedure.
FURTHER READING
- Bottomley SS. Congenital sideroblastic anemias. Curr Hematol
Rep 2006;5:41-49.
- Aivado M, Gattermann N, Rong A, et al. X- linked sideroblastic anemia associated
with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation
patterns. Blood Cells Mol Dis 2006 (in press).
- Fleming MD. The genetics of sideroblastic anemias. Semin Hematol 2002;39:270-281.
- Bottomley SS. Secondary iron overload disorders. Semin Hematol 1998; 35:77-86.
- Bottomley SS. Causes, pathophysiology, diagnosis and treatment of sideroblastic
anemias. In UpToDate, version 14.1 (www.uptodate.com),
Waltham, MA; 2006.
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