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744 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 745

as a result of increased absorption is seen even in patients with infre- As discussed earlier in “Etiology and Pathogenesis,” a few attempts
quent transfusions (Chap. 43). Iron overload results in frequent diabetes have been made to correlate the genotype with the phenotype of hemo-
and endocrine disturbances, typically by fourth decade of life. A high globin H disease. In general, as expected, patients with a nondeletion
incidence of pigment gallstones, skeletal deformities, bone and joint form of α-thalassemia affecting the predominant α gene interacting
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0
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disease, leg ulcers, and thrombotic tendency, particularly after splenec- with an α -thalassemia determinant α α/– –, or α ConstantSpring α/– –, for
tomy, is observed. 7 example, have higher hemoglobin H levels, a greater degree of ane-
Hematologists should be aware that in patients heterozygous for mia, and a more severe clinical course than patients with the – –/–α
rare forms of β-thalassemia, a phenotype of thalassemia intermedia genotype. 212–215
that results in the clinical constellation of autosomal dominant thalas-
semia (discussed in “Pathophysiology” above) is encountered on rare Milder Forms of α-Thalassemia
occasions. Because two α-globin genes exist per haploid genome, a wide spectrum
of different conditions with overlapping phenotypes result from their
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various interactions. The carrier states for the deletion and nondeletion
β-THALASSEMIA MINOR forms of α-thalassemia, –α/αα and α α/αα, are symptomless. Similarly,
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The heterozygous state for β-thalassemia is usually identified during the homozygous states for the deletion forms of α -thalassemia, –α/–α,
0
family studies of patients with more severe forms of β-thalassemia, and the heterozygous state for α -thalassemia, – –/αα, are symptomless,
population surveys, or, most frequently, by the chance finding of the although they are associated with mild anemia and red cell changes.
characteristic hematologic changes during a routine study. There is On the other hand, the homozygous states for the nondeletion forms
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an extensive literature on this condition, some of which suggests that of α-thalassemia, α α/α α, are associated with an extremely diverse
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affected individuals may have symptoms of anemia and, not infre- series of phenotypes. As mentioned in “Interactions of α-Thalassemia
quently, splenomegaly, while other studies suggest that the condition Haplotypes” above in “Etiology and Pathogenesis,” they sometimes
is completely symptomless and palpable splenomegaly does not occur. result in the clinical picture of hemoglobin H disease. In other patients,
7
Surprisingly, none of these studies have been controlled. A controlled they are associated with only mild hypochromic anemia. The homozy-
study reported that individuals with the β-thalassemia trait suffer from gous states for the chain termination mutants, notably hemoglobin
fatigue and other symptoms indistinguishable from those with mild Constant Spring, constitute a special case because they produce a par-
anemias from other causes. There was no difference in the frequency of ticularly characteristic phenotype. In this case, moderate hemolytic ane-
palpable splenomegaly between the thalassemic and control groups. mia with splenomegaly are seen. 7,216,217
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The trait not infrequently causes a moderately severe anemia of preg-
nancy, in some cases requiring transfusion. Some β-thalassemia carri- α-Thalassemia and Mental Retardation
ers have increased iron stores, although this is most often a result of The clinical phenotype of these conditions is heterogeneous. In cases
inappropriate iron therapy based on a misdiagnosis. In countries where associated with chromosomal deletion (tip of chromosome 16; ATR-16
there is a relatively high frequency of genetic determinants for hemo- [α-thalassemia chromosome 16-linked mental retardation syndrome]),
chromatosis, the possibility of their coinheritance should be borne in the clinical defects vary with the extent of chromosomal defect; only
157
mind if a patient with β-thalassemia trait with an unusually high plasma α-thalassemia and mental retardation are constant. To some extent
iron or serum ferritin level is encountered. this clinical variation is related to the length of the associated deletions;
those which extend for 2000 kb involve the genes that are involved in
tuberous sclerosis and polycystic kidney disease. In these cases the lat-
α-THALASSEMIAS ter dominate the clinical picture, but there mental retardation and α-
Hemoglobin Bart’s Hydrops Fetalis Syndrome thalassemia are also associated.
The clinical phenotype in the second group of these disorders,
This disorder is a frequent cause of stillbirth in Southeast Asia. Infants which are caused by mutations of ATR-X, includes skeletal abnormali-
either are stillborn between 34 and 40 weeks’ gestation or are born ties, dysmorphic face, neonatal hypotonus, genital abnormalities, and a
alive but die within the first few hours. 7,206 Pallor, edema, and hepato- variety of less-constant features, in addition to mental retardation and
splenomegaly are seen. The clinical picture resembles hydrops fetalis α-thalassemia. 158
as a result of Rh blood group incompatibility. Massive extramedullary
hemopoiesis and enlargement of the placenta are noted at autopsy. A εγδβ-Thalassemia
variety of congenital anomalies have been observed. The clinical picture varies with the stage of development. Neonates may
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The rescue of a few infants with this syndrome by prena- be significantly anemic and require transfusions. In contrast, children
tal detection and exchange transfusion has been reported. These and adults with this condition are asymptomatic. They have the clinical
babies have grown and developed normally, although they are blood and laboratory picture of heterozygous β-thalassemia, with the excep-
transfusion–dependent. 207,208 tion of a normal hemoglobin A level. The reason for this discrepancy of
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This condition is associated with a high incidence of maternal tox- developmental differences of the clinical phenotype has not been iden-
emia of pregnancy and difficulties at the time of delivery because of the tified. The homozygous state is assumed to be lethal.
massive placenta. The reason for placental hypertrophy is unknown,
206
although severe intrauterine hypoxia is suspected because a similar phe-
nomenon is observed in hydrops infants with Rh incompatibility. LABORATORY FEATURES
Hemoglobin H Disease β-THALASSEMIA MAJOR
Hemoglobin H disease was described independently in the United States Hemoglobin levels at presentation may range from 2 to 3 g/dL or even
and in Greece in 1956. 209,210 The clinical findings are variable. A few lower. The red cells show marked anisopoikilocytosis, with hypochro-
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patients are affected almost as severely as patients with β-thalassemia mia, target cell formation, and a variable degree of basophilic stippling
major, but most patients have a much milder course. 7,211 Lifelong anemia (Fig. 48–16). The appearance of the blood film varies, depending on
with variable splenomegaly occurs; bone changes are unusual. whether the spleen is intact. In nonsplenectomized patients, large

Kaushansky_chapter 48_p0725-0758.indd 745 9/18/15 2:58 PM