A "Constant" Problem
Carlo Brugnara, MD
Department of Laboratory Medicine
The Children's Hospital
Boston, Massachusetts, USA
The patient is a 7 year old girl from Cambodia who is being followed by our hematology service. Her disease was diagnosed at 5 years of age following an admission for abdominal pain, fatigue and anemia. Six months after diagnosis she had a second admission for viral flu-like symptoms with low WBC count and low Hct. These symptoms resolved without the need for blood transfusion.
The patient complains of intermittent dizziness and fatigue. Her only medication is folic acid. Physical examination is noteworthy for the presence of a systolic ejection murmur at the left upper sternal border and splenomegaly (6 cm below the costal margin). Results from the CBC are presented below.
Histograms for red cell volume and hemoglobin concentration are presented in Figure 1.
Figure 1. Histograms for red cell volume and hemoglobin concentration
Peripheral smear is presented in Figure 2.
Figure 2. Peripheral smear
Hb electrophoresis is presented in lane 3 of Figure 3.
Figure 3. Hb electrophoresis
LDH and AST were mildly elevated (298 and 57 U/mL, respectively).
Total bilirubin was 3.5 mg/dL with 0.2 mg/dL conjugated. Lead was less than 5 m.
Table 1
Red Cell Parameters
Hb (g/dL) 7.3
Hct (%) 28.2
RBC (106/m>L) 3.810
MCV (fL) 74
RDW (%) 28
CHCM (g/dL) 25.4
HDW (g/dL) 4.1
MCH (pg) 19.2
% Microcytic RBCs 26.5
% Hypochromic RBCs 78.3
Reticulocyte Parameters
% reticulocytes 7.9
Absolute Ret. (109/liter) 301
MCVr (fL) 95.8
CHr (pg) 19.2
Diagnosis and Discussion
Hb Constant Spring is characterized by a base substitution in the normal a chain termination codon UAA to CAA, leading to synthesis of Gln and of an elongated a chain with 31 additional amino acids. Due to mRNA instability, this abnormal Hb is only present in very low amounts, and is therefore functionally equivalent to a thalassemia.
Flow cytometric studies have been shown to be particularly useful in the differential diagnosis of various forms of a and b thalassemia (1,2). In this patient, the microcytosis and elevated RDW are associated with a characteristic decrease of the CHCM and increased HDW, with reduced MCH. Hypochromia (> 35%) is a distinguishing feature of Hb H/CS versus Hb H disease, whereas microcytosis is more pronounced in Hb H disease and is usually less than 35% in Hb H/CS disease (1). In addition, the ratio of HYPO/MICRO is greater than 2.5 in most of the patients with Hb H/CS, while it is less than 2.5 in the majority of patients with Hb H.
Similar abnormalities are present in the reticulocyte analysis which shows an increased number of reticulocytes that are microcytic and hypochromic when compared with normal controls(3).
References
1) Bunyaratvej A, Butthep P, Fucharoen S, Saw D. Erythrocyte volume and haemoglobin concentration in hemoglobin H disease: Discrimination between the two genotypes. Acta Haematol 1992; 87:1-5.
2) Bunyaratvej A, Fucharoen S, Greenbaum A, Mohandas N. Hydration of red cells in and ß thalassemias differs: A useful approach to distinguishing between these red cell phenotypes. Am J Clin Pathol 1994; 102:217-222.
3) Khuhapinant A, Bunyaratvej A, Tatsumi N, Pribwai M, Fucharoen S. Number and maturation of reticulocytes in various genotypes of thalassemia as assessed by flow cytometry. Acta Haematol 1994; 91:119-125.
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