454.

9Thalassemia Syndromes

The thalassemias are the most common genetic disorder on a worldwide basis. The selective
pressures that have made the thalassemias so common are not known but are assumed to relate to
the geographic distribution of malaria. Children with thalassemia have a shorter red cell life, fetal
hemoglobin in their red cells until an older age than normal, and red cells that are more sensitive
to oxidative stress.

Epidemiology.

Although there are more than 200 mutations for β-thalassemia, most are rare. About 20 common
alleles constitute 80% of the known thalassemias worldwide; 3% of the world's population carry
genes for β-thalassemia, and in Southeast Asia 5–10% of the population carry genes for α-
thalassemia. In a particular area there are fewer common alleles.

Pathophysiology.

Mutations in β-thalassemia involve globin gene deletions, promoter region mutations,

termination mutations, splice site mutations, and other rare mutations. There are relatively few α-
thalassemia mutations; most are deletions. Selected features of the thalassemias can be seen in
Table 454–4 . The key feature is the fact that there is a globin chain imbalance. In the bone
marrow the thalassemic mutations disrupt the maturation of the red cell, resulting in ineffective
erythropoiesis; the marrow is hyperactive, but there are relatively few reticulocytes and severe
anemia. In β-thalassemias there is an excess of α-globin chains relative to β- and γ-globin chains;
α-globin tetramers (α4) are formed, and these inclusions interact with the red cell membrane and
shorten red cell survival, leading to anemia and increased erythroid production. The γ-globin
chains are produced in normal amounts, leading to an elevated Hb F (α2γ2). The δ-globin chains
are also produced in normal amounts, leading to an elevated Hb A2 (α2δ2) in β-thalassemia. In α-
thalassemia there are relatively fewer α-globin chains and an excess of β- and γ-globin chains.
These excess chains form Bart's hemoglobin (γ4) in fetal life and Hb H (β4) after birth. These
abnormal tetramers are not as lethal but lead to extravascular hemolysis.

Table 454-4 -- The Thalassemias

Thalassemia Globin Features Expression Hemoglobin
Genotype Electrophoresis
α-Thalassemia
1 gene deletion –,α / α, Normal Normal Newborn: Bart's
1–2%
2 gene deletion –, α/ –, α –, – Microcytosis, Normal, mild anemia Newborn: Bart's:
trait /α,α mild 5–10%
hypochromasia
3 gene deletion –,–/–,α Microcytosis, Mild anemia, transfusions Newborn: Bart's:
hemoglobin H hypochromic not required 20–30%
Thalassemia Globin Features Expression Hemoglobin
Genotype Electrophoresis
2 gene deletion –,–/ α,αConstant Microcytosis, Moderate to severe 2–3% Constant
Spring
+ Constant hypochromic anemia, transfusion, Spring, 10–15%
Spring splenectomy. hemoglobin H
4 gene deletion –,–/–,– Anisocytosis, Hydrops fetalis Newborn: 89–
poikilocytosis 90% Bart's with
Gower 1 and 2
and Portland
Nondeletional α,α/α,αvariant Microcytosis, Normal 1–2% variant
mild anemia hemoglobin
β-Thalassemia
β0or β0/A, β+/A Variable Normal Elevated A2,
β+heterozygote: microcytosis variable
trait elevation of F
β0-Thalassemia β0/β0,β+/β0,E/β0 Microcytosis, Transfusion dependent F 98% and A2
nucleated RCB 2%
E 30–40%
β+-Thalassemia β+/β+ Microcytosis Transfusion F 70–95%, A2
severe nucleated RBC dependent/thalassemia 2%, trace A
intermedia
Silent β+/A Microcytosis Normal with only A2 3.3–3.5%
microcytosis
β+/β+ Hypochromic, Mild to moderate anemia A2 2–5%, F 10–
microcytosis 30%
Dominant B0/A Microcytosis, Moderately severe Elevated F and
(rare) abnormal RBCs anemia, splenomegaly A2
δ-Thalassemia A/A Normal Normal A2 absent
(δβ)0- (δβ)0/A Hypochromic Mild anemia F 5–20%
Thalassemia
(δβ)+- βLepore/A Microcytosis Mild anemia Lepore 8–20%
Thalassemia
Lepore
Lepore βLepore/βLepore Microcytic, Thalassemia intermedia F 80%, Lepore
hypochromic 20%
γδβ- (γAδβ)0/A Microcytosis, Moderate anemia, Decreased F and
Thalassemia microcytic, Splenomegaly, A2 compared
hypochromic Homozygote:thalassemia with δβ-
intermedia thalassemia
Thalassemia Globin Features Expression Hemoglobin
Genotype Electrophoresis
γ-Thalassemia (γAγG)0/A Microcytosis Insignificant unless Decreased F
homozygote
Hereditary Persistence of Fetal Hemoglobin
Deletional A/A Microcytic Mild anemia F 100%
homozygotes
Nondeletional A/A Normal Normal F 20–40%

Homozygous β0- Thalassemia (Thalassemia Major, Cooley's Anemia)

Clinical Manifestations.

These children usually become symptomatic from progressive hemolytic anemia with profound
weakness and cardiac decompensation during the second 6 mo of life if not treated. Depending
on the mutation and degree of fetal hemoglobin production, transfusions in thalassemia major are
necessary in the second month of life or the second year of life but rarely later. The decision to
transfuse depends on the child's ability to compensate for the degree of anemia. Most infants and
children have cardiac decompensation at hemoglobins of 4 g/dL or less. Generally, fatigue, poor
appetite, and lethargy are late findings of severe anemia in an infant or child. These were
common before transfusions were standard therapy. The classic presentation of children with
severe thalassemic facies, pathologic fractures, marked hepatosplenomegaly, and cachexia is still
seen in some developing countries. The spleen may become so enlarged that it causes
mechanical discomfort and secondary hypersplenism. These are features of ineffective
erythropoiesis ( Fig. 454–3 ): expanded medullary spaces (with massive expansion of the marrow
of the face and skull), extramedullary hematopoiesis, and a huge caloric need. The
hepatosplenomegaly may interfere with nutritional support. Pallor, hemosiderosis, and jaundice
may combine to produce a greenish brown complexion. Because of the anemia there is also an
increase in iron absorption, with toxicity leading to further complications, if the child survives
long enough to develop them. Many of these features became less severe and infrequent with
transfusion therapy, but transfusional hemosiderosis is a consequent complication. Many of the
complications of thalassemia seen in developed countries today are the result of iron overload: in
the liver, fibrosis and cirrhosis; in the beta cells of the pancreas, diabetes mellitus; in the
pituitary, testis, and ovaries, growth retardation and hypogonadotropic hypogonadism; in the
parathyroid, hypocalcemia and osteoporosis; and in the heart, arrhythmias, myocarditis, and
intractable cardiac failure. Most, if not all, of these complications can be avoided by the
consistent use of an iron chelator. However, chelation therapy also has associated complications.

Figure 454-3 Ineffective erythropoiesis in untransfused 3-year-old patient with thalassemia major. Massive widening of the diploic
spaces of the skull on MRI, radiographic appearance of trabeculae seen on plain radiograph, and obliteration of the maxillary
sinuses with hematopoietic tissue as seen on computed tomography.
Laboratory Findings.

The infant is born only with Hb F or, in some cases, Hb F and Hb E (heterozygosity for β0-
thalassemia). Eventually in β0-thalassemia there is severe anemia, few reticulocytes, numerous
nucleated red cells, and microcytosis with almost no normal-appearing red cells on the smear
(see Fig. 454–2E ). The hemoglobin level falls progressively to lower than 5 g/dL unless
transfusions are given. The unconjugated serum bilirubin level is usually elevated, but other
chemistries may be normal at an early stage. Even if untransfused, eventually there is iron
accumulation with an elevated serum ferritin and saturation of the transferrin. Bone marrow
hyperplasia can be seen on radiographs (see Fig. 454–3 ).

Treatment.

Before initiating chronic transfusions, the diagnosis of β0-thalassemia should be confirmed and
the parents counseled concerning this life-long therapy. Beginning transfusion and chelation
therapy are difficult challenges for parents to face early in their child's life. Before beginning
transfusion therapy, a red cell phenotype is obtained; blood products that are leukoreduced and
phenotypically matched for the Rh and Kell antigens are required for transfusion. If there is the
possibility of a bone marrow transplant, the blood should be negative for cytomegalovirus and
irradiated. Transfusion therapy promotes general health and well-being and avoids the
consequences of ineffective erythropoiesis. Iron overload is inevitable, and “hyper”-transfusion
should be avoided. A post-transfusion hemoglobin level of 9.5 g/dL is the goal. Banked blood in
developed countries is generally safe. Designated donors are not encouraged; some blood centers
have “partner” programs, pairing donors and recipients, which decreases the exposure to multiple
red cell antigens. As a child grows, more donors will be needed.

Transfusional hemosiderosis causes many of the complications of thalassemia major.

Assessment of iron overloading is best achieved by liver biopsy, supplemented by ferritometry
and the measurement of serum ferritin. Liver biopsy is the only method that is reproducible and
should be available in centers caring for thalassemic patients. There are few available
ferritometers. Ferritin can only provide an assessment of the trend of the iron status for a
particular patient.

Transfusional hemosiderosis can be prevented by the use of deferoxamine (Desferal).

Deferoxamine chelates iron and some other divalent cations, allowing their excretion in the urine
and the stool. If used appropriately, a negative iron balance can be achieved. Deferoxamine is
given subcutaneously over 10–12 hr, 5–6 days a week. It should be used cautiously in young
children. The side effects include ototoxicity with high-frequency hearing loss, retinal changes,
and bone dysplasia with truncal shortening. Oral iron chelators (deferiprone: L-1) have not been
as effective as deferoxamine and there is a concern about their causing neutropenia, arthritis, and
hepatic fibrosis. Other iron chelators are being studied for oral and subcutaneous use.

Splenectomy may be indicated for patients with thalassemia intermedia who have a falling
steady-state hemoglobin and for transfused patients with a rising transfusion requirement.
However, splenectomy may have serious infectious consequences. Because of the increased risk
of infection after splenectomy, all patients should be fully immunized against encapsulated
bacteria before splenectomy, and they subsequently should be on long-term penicillin
prophylaxis. Preliminary evidence that splenectomy may lead to pulmonary hypertension has led
to anticoagulation being considered for some splenectomized patients.

Bone marrow transplantation has successfully cured over a thousand patients who have
thalassemia major. Most success has been in children younger than 15 yr of age without iron
overload and hepatomegaly who have HLA-matched siblings. All children who have an HLA-
matched sibling should be offered the option of bone marrow transplantation.

Other β-Thalassemia Syndromes

The β-thalassemia syndromes are broken into six groups: β-thalassemias, δβ-thalassemias, γ-
thalassemias, δ-thalassemias, εγδβ-thalassemias, and the HPFH syndrome (see Chapter 454.8 ).
Most of these thalassemias are relatively rare, some being found only in family groups. The β-
thalassemias can also be classified clinically as thalassemia trait, minima, minor, intermediate,
and major, reflecting the degree of anemia. The genetic classification does not necessarily define
the phenotype, and the degree of anemia does not always predict the genetic classification.

Thalassemia intermedia can be any combination of β-thalassemia mutations (β0/β+, β0/βvariant, E/β0),
which will lead to a phenotype of microcytic anemia with hemoglobin of about 7 g/dL. There is
controversy about whether to transfuse these children. They will certainly develop a degree of
medullary hyperplasia, nutritional hemosiderosis perhaps requiring chelation, splenomegaly, and
other complications of thalassemia and iron overload. Extramedullary hematopoiesis can occur
in the vertebral canal, compressing the spinal cord and causing neurologic symptoms; the latter is
a medical emergency requiring immediate local radiation therapy to halt erythropoiesis.
Transfusion will alleviate the thalassemic manifestations and hasten the need for chelation. A
splenectomy puts the child at risk for infection and pulmonary hypertension.

The thalassemias classified as minima and minor are usually heterozygotes (β0/β, β+/β+) having a
phenotype more severe than trait but not as severe as intermedia. These children should be
investigated for their genotype and monitored for iron accumulation. The β-thalassemias are
influenced by the presence of α-thalassemia: α-thalassemia trait leading to less severe anemia
and duplicated α genes (ααα/αα(leading to more severe thalassemia. Frequently, individuals who
are in these groups require transfusions in adolescence or adulthood; some may be candidates for
chemotherapy such as hydroxyurea.

Thalassemia trait is frequently misdiagnosed as iron deficiency in children because the two are
similar hematologically and iron deficiency is much more prevalent. A short course of iron and
re-evaluation is all that is required to separate those children who will need further evaluation.
Children who have β-thalassemia trait will have a persistent red cell distribution width, and on
hemoglobin electrophoresis they will have an elevated Hb F and diagnostically elevated Hb A2.
There are “silent” forms of thalassemia trait, and if the family history is suggestive, further
studies may be indicated.

α-Thalassemia
The same evolutionary pressures that produced the β-thalassemia and sickle hemoglobinopathies
produced α-thalassemia. Infants are identified in the newborn period by the increased production
of Bart's hemoglobin (γ4) during fetal life and its presence at birth. Although these thalassemias
occur in all malarious areas, they are most common in Southeast Asia. Deletion mutations are
common in the α-thalassemias and rare in β-thalassemia. The variety of phenotypes seen in β-
thalassemia are lacking in α-thalassemia. There are four α-globin genes and four deletional α-
thalassemia phenotypes. There are five common α0-thalassemia mutations, -FIL, -MED, -THAI, -SEA, and -
(α)20.5
deletions, and two α+-thalassemia mutations, -α3.7 and -α4.2. They can be identified by
polymerase chain reaction analysis. Most of these deletions, with the exception of the SEA
deletion, common in Southeast Asia, include the ζ-globin gene and are not compatible with life
in the homozygous state. In addition to these deletional mutations there are also nondeletional α-
globin gene mutations, the most common being Constant Spring (αCSα); these mutations cause a
more severe anemia and clinical course than the deletional mutations.

The deletion of one α-globin gene (silent trait) is not identifiable hematologically; individuals
with this deletion are usually diagnosed after the birth of a child with a two gene deletion or Hb
H (β4). This deletion is common in African-Americans.

The deletion of two α-globin genes results in α-thalassemia trait. The globin genes can be lost in
trans, -α/-α or cist, such as α,α/-SEA. The cist or α0 mutations combined with other mutations can
lead to Hb H or α-thalassemia major. The α-thalassemia traits present as a microcytic anemia that
can be mistaken for iron-deficiency anemia (see Fig. 454–2F ). The hemoglobin electrophoresis
is normal. The diagnosis of iron deficiency must be eliminated and the diagnosis presumed or
confirmed by DNA testing.

The deletion of three α-globin genes leads to the diagnosis of Hb H disease. This form of α-
thalassemia is significant for a marked microcytosis and anemia; it is identified by hemoglobin
electrophoresis. Although there have been few studies of this hemoglobinopathy, it is generally
asymptomatic with a moderate anemia and mild splenomegaly, and, occasionally, scleral icterus
or cholelithiasis is present. Although brilliant cresyl blue can stain Hb H, it is rarely used for
diagnosis. Transfusion is not usually necessary for treatment of the anemia.

The deletion of all four α-globin genes causes profound anemia during fetal life, resulting in
hydrops fetalis; the ζ-globin gene must be present for fetal survival. There are no normal
hemoglobins present at birth (primarily Bart's, with hemoglobins Gower 1, Gower 2, and
Portland). If the fetus survives, immediate exchange transfusion is indicated. These infants with
α-thalassemia major are transfusion dependent. There have been at least two successful bone
marrow transplants that cured this disease.

The presence of a nondeletional α-globin mutation with a two-gene deletion results in a more
severe anemia, increased hepatosplenomegaly, increased jaundice, and a much more severe
clinical course than Hb H disease. Hb H Constant Spring is the most common form (-α/α,αCS).

Treatment of the α-thalassemia deletion syndromes consists of folate supplementation, possible

splenectomy (with the attendant risks), intermittent transfusion during severe anemia for the
nondeletion Hb H diseases, and chronic transfusion therapy or bone marrow transplant for
survivors of hydrops fetalis. These children also should not be exposed to oxidant medications.

Iron Overload Disorders

The disorders leading to iron overload are not disorders of hemoglobin. Hereditary
hemochromatosis (HH) is a disorder of iron absorption leading to toxicity in the fourth to fifth
decades of life. Iron absorption is primarily in the liver, heart, and pancreas leading to hepatic
cirrhosis and liver failure. It has a prevalence of 1:250 in white Northern Europeans. There are
two alleles of the HFE gene: 845 G➙A (C282Y) and 187 C➙G (H63D). These alleles have
been associated with hereditary hemtochomatosis. Expression of the C282Y gene is homozygous
in 84–100% of individuals with HH (type 1). A second mutation, H63D, is found in combination
with C282Y in 2–7% of HH. There are individuals with HH who have neither mutation (type 3).
Diagnosis can be made by evaluation of transferrin saturation and ferritin. Treatment is
phlebotomy.

There are three pediatric forms of iron overload. Juvenile hemochromatosis (type 2),
atransferrinemia/hypotransferrinemia, and neonatal hemochromatosis. Juvenile
hemochromatosis differs from HH in that the iron loading is primarily in the heart and
endocrine system with associated morbidity (i.e., cardiac arrhythmias and failure, diabetes
mellitus). Without phlebotomy, death occurs in the third decade. There is no genetic determinant.
Infants born with atransferrinemia have a disorder similar to HH but also have anemia owing to
the lack of transferrin. Neonatal hemochromatosis is a rare disease that presents as hepatic iron
overload leading to liver dysfunction and failure in the neonatal period. It is sometimes
associated with neonatal giant cell hepatitis.