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Pediatric Thalassemia
Updated: Oct 11, 2015
Author: Hassan M Yaish, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...

OVERVIEW

Practice Essentials
The thalassemias are inherited disorders of hemoglobin (Hb) synthesis. Their clinical severity
widely varies, ranging from asymptomatic forms to severe (see the image below) or even fatal
entities.

Peripheral blood film in Cooley anemia.

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Signs and symptoms

The clinical picture of the thalassemias varies widely, depending on the severity of the condition
and the age at diagnosis. In the more severe forms of the disease (eg, -thalassemia major),
symptoms vary from extremely debilitating in patients who are not receiving transfusions to mild
and almost asymptomatic in those receiving regular transfusion regimens and closely monitored
chelation therapy.

Signs and symptoms of different types of thalassemia include the following:

More severe forms: Some pallor, slight scleral icterus, enlarged abdomen
Rare types of -thalassemia trait: Severe hemolytic process requiring management, such as
thalassemia intermedia or thalassemia major
Hb E/ thalassemia: May have severe symptoms and clinical course identical to that of
-thalassemia major

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Heterozygous/homozygous Hb E: Usually slightly anemic and usually asymptomatic

-Thalassemia: Clearly evident hematologic abnormalities in newborns with mild or moderate
forms of the disease
-Thalassemia: Extreme pallor, swollen abdomen due to hepatosplenomegaly
Severe bony changes due to ineffective erythroid production (eg, frontal bossing, prominent
facial bones, dental malocclusion)
Hypermetabolism from ineffective erythropoiesis
Gout due to hyperuricemia (occasionally)
Iron overload: One of the major causes of morbidity in all patients with severe forms of
thalassemia
Growth retardation, failure to thrive
Metabolic symptoms that suggest diabetes, thyroid disorder, or other endocrinopathy
Neuropathy/paralysis in patients with severe anemia not receiving transfusion therapy

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of thalassemia is made through studies such as bone marrow examination,
hemoglobin electrophoresis, and iron count. The CBC count and peripheral blood film examination
results are usually sufficient to suspect the diagnosis. Hb evaluation confirms the diagnosis in
-thalassemia, Hb H disease, and Hb E/ thalassemia.

Classification of thalassemia

Although there are many types of thalassemic syndromes, each involves decreased production of
one globin chain or more, which form the different Hbs normally found in RBCs. In clinical practice,
the most important types affect either - or -chain synthesis.

The most common forms of -thalassemia are as follows:

Silent carrier -thalassemia: The diagnosis cannot be confirmed based on Hb electrophoresis

results, which are usually normal in all -thalassemia traits
-Thalassemia trait: Characterized by mild anemia and low RBC indices
Hb H disease: Represents -thalassemia intermedia, with mildly to moderately severe
anemia, splenomegaly, icterus, and abnormal RBC indices
-Thalassemia major: Results in the severe form of homozygous -thalassemia

Some of the more common forms of -thalassemia are as follows:

Silent carrier -thalassemia: Patients are asymptomatic, except for possible low RBC indices
-Thalassemia trait: Patients have mild anemia, abnormal RBC indices, and abnormal Hb
electrophoresis results with elevated levels of Hb A 2, Hb F, or both
Thalassemia intermedia: Patients have anemia of intermediate severity
-thalassemia associated with -chain structural variants: The most significant condition in
this group of thalassemic syndromes is the Hb E/ thalassemia
Thalassemia major (Cooley anemia): This condition is characterized by transfusion-
dependent anemia, massive splenomegaly, bone deformities, growth retardation, and peculiar
facies in untreated individuals, 80% of whom die within the first 5 years of life from
complications of anemia

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Staging

Stage I patients: Received fewer than 100 units of packed red blood cells; usually
asymptomatic
Stage II patients: Received 100-400 units of blood; may report slight fatigue
Stage III patients: Have symptoms ranging from palpitations to CHF

The Lucarelli classification is used for patients with severe disease who are candidates for
hematopoietic stem cell transplantation. [1]

Laboratory studies

CBC count
Hb electrophoresis
Peripheral blood smear
Iron studies (ie, levels of serum iron, serum ferritin)
Complete RBC phenotype
Hepatitis screen
Folic acid level
level of urinary excretion of iron after deferoxamine challenge
HLA typing before initiation of blood transfusion therapy
Renal function tests during chelation therapy

Imaging studies

Skeletal survey: Reveals classic bony changes in patients who are not regularly transfused
Chest radiography: To evaluate cardiac size and shape
MRI or CT scanning of affected areas: To diagnose complications (eg, bony deformities,
compression fractures)
R2 MRI: For noninvasive measurement of liver and cardiac iron overload and to monitor
response to iron chelation therapy (eg, FerriScan)
T2* MRI: Could evaluate both liver and cardiac iron load simultaneously [2]
ECG, echocardiography: To monitor cardiac function

Procedures

Bone marrow examination: To exclude other conditions that may manifest as thalassemia
major
Liver biopsy: To assess iron deposition and the degree of hemochromatosis

See Workup for more detail.

Management

Patients with thalassemia traits do not require medical or follow-up care after the initial diagnosis is
made. Do not initiate iron therapy unless a definite deficiency is confirmed.

Patients with severe thalassemia require medical treatment. Regular blood transfusion combined
with well-monitored chelation therapy is the standard therapy.

Pharmacotherapy

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Antipyretics, analgesics (eg, acetaminophen)

Antihistamines (eg, diphenhydramine)
Chelating agents (eg, deferoxamine, deferasirox)
Corticosteroids (eg, hydrocortisone)
Antibacterial combinations (eg, TMP/SMX, gentamicin, penicillin V)
Vitamins (eg, ascorbic acid, alpha-tocopherol, folic acid)
Vaccines (eg, polyvalent pneumococcal; 7-valent pneumococcal conjugated; H influenzae
type B; meningitis group A, C, Y, and W-135)
Antineoplastics (eg, hydroxyurea)
Growth hormone (eg, somatropin)

The FDA has expanded the approved use of deferasirox to treat children aged 10 years and older
with chronic iron overload due to nontransfusion-dependent thalassemia (NTDT). The agency
recommends administration of deferasirox in such children who have a hepatic iron concentration
of at least 5 mg of iron per gram of dry liver weight. Previously, deferasirox was approved for
managing chronic iron overload due to blood transfusions in patients ages 2 years and older. [3, 4]

Surgical options

Splenectomy: Principal surgical procedure for many patients with thalassemia

Placement of central line: For the ease and convenience of administering blood transfusions,
chelation therapy, or both in patients with severe thalassemia on transfusion therapy

See Treatment and Medication for more detail.

Background
The thalassemias are inherited disorders of hemoglobin (Hb) synthesis. Their clinical severity
widely varies, ranging from asymptomatic forms to severe or even fatal entities. The name
Mediterranean anemia, which Whipple introduced, is misleading because the condition can be
found in any part of the world. As described below, different types of thalassemia are more endemic
to certain geographic regions.

In 1925, Thomas Cooley, a Detroit pediatrician, described a severe type of anemia in children of
Italian origin. He noted abundant nucleated red blood cells (RBCs) in the peripheral blood, which
he initially thought was erythroblastic anemia, an entity that von Jaksh described earlier. Before
long, Cooley realized that erythroblastemia is neither specific nor essential in this disorder and that
the term erythroblastic anemia was nothing but a diagnostic catchall. Although Cooley was aware
of the genetic nature of the disorder, he failed to investigate the apparently healthy parents of the
affected children.

In Europe, Riette described Italian children with unexplained mild hypochromic and microcytic
anemia in the same year Cooley reported the severe form of anemia later named after him. In
addition, Wintrobe and coworkers in the United States reported a mild anemia in both parents of a
child with Cooley anemia. This anemia was similar to the one that Riette described in Italy. Only
then was Cooley's severe anemia recognized as the homozygous form of the mild hypochromic
and microcytic anemia that Riette and Wintrobe described. This severe form was then labeled as
thalassemia major and the mild form as thalassemia minor. The word thalassemia is a Greek term
derived from thalassa, which means "the sea" (referring to the Mediterranean), and emia, which
means "related to blood."

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These initial patients are now recognized to have been afflicted with thalassemia. In the following
few years, different types of thalassemia that involved polypeptide chains other than chains were
recognized and described in detail.

In recent years, the molecular biology and genetics of the thalassemia syndromes have been
described in detail, revealing the wide range of mutations encountered in each type of thalassemia,
depicted in the image below.

Various mutations in the beta gene that result in beta thalassemia.

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thalassemia alone can arise from any of more than 150 mutations.

Pathophysiology
The thalassemias are inherited disorders of Hb synthesis that result from an alteration in the rate of
globin chain production. A decrease in the rate of production of a certain globin chain or chains (,
, , ) impedes Hb synthesis and creates an imbalance with the other, normally produced globin
chains.

Because 2 types of chains ( and non-) pair with each other at a ratio close to 1:1 to form normal
Hbs, an excess of the normally produced type is present and accumulates in the cell as an
unstable product, leading to the destruction of the cell. This imbalance is the hallmark of all forms of
thalassemia. For this reason, most thalassemias are not considered hemoglobinopathies because
the globin chains are normal in structure and because the defect is limited to a decreased rate of
production of these normal chains. However, thalassemic hemoglobinopathies are recognized, as
discussed below.

The type of thalassemia usually carries the name of the underproduced chain or chains. The
reduction varies from a slight decrease to a complete absence of production. For example, when
chains are produced at a lower rate, the thalassemia is termed +, whereas -0 thalassemia
indicates a complete absence of production of chains from the involved allele.

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The consequences of impaired production of globin chains ultimately result in the deposition of less
Hb into each RBC, leading to hypochromasia. The Hb deficiency causes RBCs to be smaller,
leading to the classic hypochromic and microcytic picture of thalassemia. This is true in almost all
anemias caused by impairment in production of either of the 2 main components of Hb: heme or
globin. However, this does not occur in the silent carrier state, since both Hb level and RBC indices
remain normal.

In the most common type of thalassemia trait, the level of Hb A2 (2/2) is usually elevated. This
is due to the increased use of chains by the excessive free chains, which results from a lack of
adequate chains with which to pair. The gene, unlike and genes, is known to have a
physiologic limitation in its ability to produce adequate chains; by pairing with the chains,
chains produce Hb A2 (approximately 2.5-3% of the total Hb).

Some, but not all, of the excessive chains are used to form Hb A2 with the chains, whereas the
remaining chains precipitate in the cells, reacting with cell membranes, intervening with normal
cell division, and acting as foreign bodies, leading to destruction of RBCs. The degree of toxicity
caused by the excessive chains varies according to the type of such chains (eg, the toxicity of
chains in thalassemia is more prominent than the toxicity of chains in thalassemia).

thalassemia is mostly related to a point mutation in the globin gene. However, large deletions
that may involve the entire gene, or even extend to delete the neighboring gene, have been
previously reported. Four new such mutations were identified in French patients. In 3 of these
mutations, the deletion has extended to involve the gene, resulting in failure to produce any Hb
A2. In such cases, the / thalassemia is to be differentiated from the phenotypically similar
condition known as hereditary persistence of fetal hemoglobin (HPFH). The importance of
differentiating the conditions is reflected in prenatal and newborn screening for hemoglobinopathy.
[5]

In the severe forms, such as thalassemia major or Cooley anemia, the same pathophysiology
applies with substantial exaggeration. The significant excess of free chains caused by the
deficiency of chains causes destruction of the RBC precursors in the bone marrow (ie, ineffective
erythropoiesis).

Globin chain production

To understand the genetic changes that result in thalassemia, one should be familiar with the
physiologic process of globin chain production in the healthy individual. The globin chain as a unit
is a major building block for Hb: together with heme, it produces the Hb molecule (heme plus globin
equals Hb). Two different pairs of globin chains form a tetrameric structure with a heme moiety in
the center. All normal Hbs are formed from 2 -like chains and 2 non- chains. Various types of Hb
are formed, depending on the types of chains pairing together. Such Hbs exhibit different oxygen-
binding characteristics, normally related to the oxygen delivery requirement at different
developmental stages in human life.

In embryonic life, chains (-like chains) combine with chains to produce Hb Portland (2/2) and
with chains to produce Hb Gower-1 (2/2).

Subsequently, when chains are produced, they form Hb Gower-2, pairing with chains (2/2).
Fetal Hb is composed of 2/2 and the primary adult Hb (Hb A) of 2/2. A third physiologic Hb,

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known as Hb A2, is formed by 2/2 chains, as in the image below.

Alpha chain genes in duplication on chromosome 16 pairing with non-alpha chains to produce various normal
hemoglobins.
View Media Gallery

Genetic changes

All the genes that control the production of globin chains lie within 1 of 2 clusters located on 2
different chromosomes. Chromosome 11 is the site of 5 functional b-like globin genes arranged in a
link cluster over 60 kilobases (kb). From left to right (5'-3'), they are /-G/-A//. -G and -A
differ by only one amino acid (alanine vs glycine).

A critical control region of the d-globin gene (promoter) is known to be defective; it inhibits
messenger RNA (mRNA) processing, resulting in only a small amount of Hb A2 (2/2) production,
which thus accounts for less than 3% of total Hb in adult RBCs.

The -like globin gene cluster is located on chromosome 16 and consists of 3 functional genes.
From left to right (5'-3'), the genes are /2/1.

Understanding the structure of the globin genes, how they are regulated to produce globin chains,
and how the chains pair together to produce the various Hbs is critical for appreciating the different
pathologic changes of this process that result in thalassemia.

Molecular biology

Each globin gene consists of a string of nucleotide bases divided into 3 coding sequences, termed
exons, and 2 noncoding regions, known as introns or intervening sequences (IVS). See the image
below.

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Alpha and beta globin genes (chromosomes 16 and 11, respectively).

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Three other regions, known as regulatory regions, are also present in the 5' noncoding or flanking
region of each globin gene.

The first is the promoter, which plays a major role in the transcription of the structural genes. The
second region is the enhancer, which has an important role in promoting erythroid-specific gene
expression, as well as in coordinating the changes in globin gene activity at different stages of
development (embryonal, fetal, adult). Enhancers can influence gene expression, despite being
located some distance away from the gene itself, and, unlike the promoter, they can stimulate
transcription irrespective of their orientation relative to the transcription start site. Finally, master
regulatory sequences, known as locus control regions (in the -globin gene family) and HS40 (in
the gene complex), are responsible for activating the genes in erythroid cells.

Each of these regulatory sequences has a modular structure that consists of short nucleotide motifs
that act as binding sites for transcriptional activator or suppressor molecules. Such molecules
activate or suppress gene expression in different cell types at different stages of development. A
certain gene is transcribed by an initiation complex formed of certain proteins and a number of
transcription factors, which interact with binding sites on the promoters and other regulatory
sequences of the relevant genes.

When a gene is transcribed, mRNA is synthesized from one of the gene's DNA strands by the
action of RNA polymerase. The initial product is a large mRNA precursor. Both exons and introns
are initially present on this mRNA precursor; the introns are ultimately subsequently eliminated, and
the exons are spliced together in the nucleus. At this stage, the mRNA, which has also been
modified at both 5' and 3' ends, moves to the cytoplasm to act as a template for the production of
globin chains.

Carrier molecules (transfer RNA [tRNA]) transport amino acids to the mRNA template. Each amino
acid has a specific tRNA, which also contains 3 bases (anticodon), complimentary to the mRNA
codons for that amino acid. The position of each amino acid in the globin chain is thus established
by its corresponding triplet code (codon) in the globin gene. The cytidine, uridine, and guanosine
(CUG) codon, for example, encodes the amino acid leucine, while the adenosine, adenosine, and
adenosine (AAA) codon encodes lysine. When a tRNA molecule carries the initial amino acid to the
template, directed by codon-anticodon base pairing, globin chain synthesis begins.

Once the first tRNA is in place, a complex is formed between several protein initiation factors and
the subunit of the ribosome that is to hold the growing peptide chains together on the mRNA as it is
translated. A second tRNA moves in alongside, and a new amino acid is bound to the first with a
peptide bond, resulting in a peptide chain 2 amino acids long. This process continues from left to
right until a specific codon for termination is reached. At this point, the completed peptide chain
drops off the ribosome-mRNA complex and the ribosomal subunits are recycled. The globin chain
is now ready to join a heme molecule and 3 other globin chains to form an Hb molecule.

The developmental switches from embryonic to fetal and then to adult Hb production are
synchronized throughout the different organs of hematopoiesis (yolk sack, liver, bone marrow),

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which function at various stages of development. Even though the mechanism of such switches is
not clearly understood, the globin gene promoter is known to contain information that specifies
developmental stages of transcription.

Molecular pathology

To date, more than 1000 inherited mutations that affect either the structure or synthesis of the -
and -globin chains are known. Mutations that result in or thalassemia are similar in principle
but different in their patterns. Presently, more than 200 molecular defects known to downregulate
the expression of globin have been characterized. Such defects result in various types of
thalassemia.

Major deletions in thalassemia are unusual (in contrast to thalassemia), and most of the
encountered mutations are single base changes, small deletions, or insertions of 1-2 bases at a
critical site along the gene, as in the image below.

Various mutations in the beta gene that result in beta thalassemia.

View Media Gallery

These mutations occur in both exons and introns. For example, in a nonsense mutation, a single
base change in the exon generates a stop codon in the coding region of the mRNA, resulting in
premature termination of globin chain synthesis. This termination leads to the production of short,
nonviable chains.

Conversely, in the frame shift mutation, one or more bases on the exon are lost or inserted,
resulting in a change in the reading frame of the genetic code or the production of a new stop
codon.

RNA-splicing mutations are fairly common and represent a large portion of all mutations that result
in thalassemia. These mutations corrupt the splicing process. The importance of precise splicing
in the quantitative production of stable functional mRNA cannot be overemphasized.

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Slippage by even one nucleotide changes the reading frame of the mRNA. Both ends of the RNA
introns (at the junction with the exons) have specific consensus sequences; these motifs include
GT in the 5' (left end or donor site) consensus sequence and AG in the 3' (right end or acceptor
site) consensus sequence. Such sequences are obligatory for correct splicing, and a single
substitution at the invariant GT or AG sequence prevents splicing altogether and results in -0 or
-0 thalassemia. Mutations in the other members of the consensus sequences, although still highly
conserved, result in variable degrees of ineffective -globin production, causing milder types of
thalassemia.

Mutations in exon sequences may activate a cryptic splice site. For example, in exon 1 of the
-globin gene, a consensus sequence that resembles a sequence in IVS-1 has been identified as
the site for several distinct mutations, resulting in a gene that carries the features of both
thalassemia and hemoglobinopathy simultaneously (quantitatively and qualitatively abnormal Hb
production). This type of mutation represents a clear link between the thalassemias and the
hemoglobinopathies, and, accordingly, these are labeled thalassemic hemoglobinopathies.

Thus, mutations at codon 19 (A to G), 26 (G to A), and 27 (G to T)all in exon 1result in reduced
production of mRNA (thalassemia) because of inefficient splicing and an amino acid substitution
encoded by the mRNA that is spliced and translated (albeit inefficiently) into protein. The resulting
abnormal Hbs are Malay, E, and Knossos, respectively.

The flanking regions of the -globin gene are also sites for various mutations. A single base
substitution that involves the promoter element, for example, can downregulate -globin gene
transcription, resulting in a mild form of thalassemia. Conversely, a mutation that affects the 3'
end of the -globin mRNA can interfere with its processing, resulting in a severe form of
thalassemia.

Clearly, many different thalassemia mutations exist, and compound heterozygosity is frequently
encountered. The resulting laboratory findings may lead to confusion. An example is the patient
who manifests symptoms of thalassemia major without an elevated Hb A2 level. The explanation
for such a situation is often co-inheritance of and thalassemia. / thalassemia further is
divided into /+ or /-0.

In the first type, a misalignment in the / genes during meiosis results in the production of fused
/ genes, a process responsible for the production of an Hb variant termed Hb Lepore.

The fused / gene is under the control of a -globin gene promoter region (the gene promoter is
deleted in the process). Because the gene promoter carries mutations that lead to ineffective
transcription, the fused / chains are produced in limited amounts, resulting in thalassemia. This is
in addition to the hemoglobinopathy.

Conversely, in d/-0 thalassemia, a large deletion occurs in the -globin gene cluster, removing
both the and the genes, which can also extend to involve all globin genes on chromosome 11,
thus producing , , , and -0 thalassemia.

Cellular pathophysiology

The basic defect in all types of thalassemia is imbalanced globin chain synthesis. However, the
consequences of accumulation of the excessive globin chains in the various types of thalassemia
are different. In thalassemia, excessive chains, unable to form Hb tetramers, precipitate in the

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RBC precursors and, in one way or another, produce most of the manifestations encountered in all
of the thalassemia syndromes; this is not the situation in thalassemia.

The excessive chains in thalassemia are chains earlier in life and chains later in life. Because
such chains are relatively soluble, they are able to form homotetramers that, although relatively
unstable, nevertheless remain viable and able to produce soluble Hb molecules such as Hb Bart (4
chains) and Hb H (4 chains). These basic differences in the 2 main types of thalassemia are
responsible for the major differences in their clinical manifestations and severity.

chains that accumulate in the RBC precursors are insoluble, precipitate in the cell, interact with
the membrane (causing significant damage), and interfere with cell division. This leads to excessive
intramedullary destruction of the RBC precursors. In addition, the surviving cells that arrive in the
peripheral blood with intracellular inclusion bodies (excess chains) are subject to hemolysis; this
means that both hemolysis and ineffective erythropoiesis cause anemia in the person with
thalassemia.

The ability of some RBCs to maintain the production of chains, which are capable of pairing with
some of the excessive chains to produce Hb F, is advantageous. Binding some of the excess a
chains undoubtedly reduces the symptoms of the disease and provides additional Hb with oxygen-
carrying ability.

Furthermore, increased production of Hb F, in response to severe anemia, adds another

mechanism to protect the RBCs in persons with thalassemia. The elevated Hb F level increases
oxygen affinity, leading to hypoxia, which, together with the profound anemia, stimulates the
production of erythropoietin. As a result, severe expansion of the ineffective erythroid mass leads to
severe bone expansion and deformities. Both iron absorption and metabolic rate increase, adding
more symptoms to the clinical and laboratory manifestations of the disease. The large numbers of
abnormal RBCs processed by the spleen, together with its hematopoietic response to the anemia if
untreated, results in massive splenomegaly, leading to manifestations of hypersplenism.

If the chronic anemia in these patients is corrected with regular blood transfusions, the severe
expansion of the ineffective marrow is reversed. Adding a second source of iron would theoretically
result in more harm to the patient. However, this is not the case because iron absorption is
regulated by 2 major factors: ineffective erythropoiesis and iron status in the patient.

Ineffective erythropoiesis results in increased absorption of iron because of downregulation of the

HAMP gene, which produces a liver hormone called hepcidin. Hepcidin regulates dietary iron
absorption, plasma iron concentration, and tissue iron distribution and is the major regulator of iron.
It acts by causing degradation of its receptor, the cellular iron exporter ferroportin. When ferroportin
is degraded, it decreases iron flow into the plasma from the gut, from macrophages, and from
hepatocytes, leading to a low plasma iron concentration. In severe hepcidin deficiency, iron
absorption is increased and macrophages are usually iron depleted, such as is observed in patients
with thalassemia intermedia.

Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of different anemias, such as
is seen in thalassemia, anemia of inflammation, and chronic renal diseases. Improvement and
availability of hepcidin assays facilitates diagnosis of such conditions. The development of hepcidin
agonists and antagonists may enhance the treatment of such anemias. [6]

By administering blood transfusions, the ineffective erythropoiesis is reversed, and the hepcidin

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level is increased; thus, iron absorption is decreased and macrophages retain iron.

Iron status is another important factor that influences iron absorption. In patients with iron overload
(eg, hemochromatosis), the iron absorption decreases because of an increased hepcidin level.
However, this is not the case in patients with severe thalassemia because a putative plasma
factor overrides such mechanisms and prevents the production of hepcidin. Thus, iron absorption
continues despite the iron overload status.

As mentioned above, the effect of hepcidin on iron recycling is carried through its receptor
"ferroportin," which exports iron from enterocytes and macrophages to the plasma and exports iron
from the placenta to the fetus. Ferroportin is upregulated by iron stores and downregulated by
hepcidin. This relationship may also explain why patients with thalassemia who have similar iron
loads have different ferritin levels based on whether or not they receive regular blood transfusions.

For example, patients with thalassemia intermedia who are not receiving blood transfusions have
lower ferritin levels than those with thalassemia major who are receiving regular transfusion
regimens, despite a similar iron overload. In the latter group, hepcidin allows recycling of the iron
from the macrophages, releasing high amounts of ferritin. In patients with thalassemia intermedia,
in whom the macrophages are depleted despite iron overload, lower amounts of ferritin are
released, resulting in a lower ferritin level.

Most nonheme iron in healthy individuals is bound tightly to its carrier protein, transferrin. In iron
overload conditions, such as severe thalassemia, the transferrin becomes saturated, and free iron
is found in the plasma. This iron is harmful since it provides the material for the production of
hydroxyl radicals and additionally accumulates in various organs, such as the heart, endocrine
glands, and liver, resulting in significant damage to these organs.

By understanding the etiology of the symptoms in thalassemia, one can appreciate that certain
modifiers may result in the development of milder types of thalassemia. Factors that may reduce
the degree of globin chain imbalance are expected to modify the severity of the symptoms; co-
inheritance of thalassemia, the presence of higher Hb F level, or the presence of a milder
thalassemia mutation all typically ameliorate the symptoms of thalassemia.

Malaria hypothesis

In 1949, Haldane suggested a selective advantage for survival in individuals with the thalassemia
trait in regions where malaria is endemic. He argued that lethal RBC disorders such as
thalassemia, sickle cell disease, and G-6-PD deficiency are present almost exclusively in tropical
and subtropical regions of the world. The incidence of these genetic mutations in a certain
population thus reflects the balance between the premature death of homozygotes and the
increased fitness of heterozygotes.

For instance, in thalassemia, the frequency of the gene is greater than 1% in the Mediterranean
Basin, India, Southeast Asia, North Africa, and Indonesia; it is very uncommon in other parts of the
world. thalassemia may be the most common single gene disorder in the world (5-10% in the
Mediterranean, 20-30% in West Africa, approximately 68% in the South Pacific); however, the gene
prevalence in Northern Europe and Japan is less than 1%.

The mechanism of protection against malaria is not clear. Hb F in cells has been demonstrated to
retard the growth of the malaria parasite, and, by virtue of its high level in infants with thalassemia

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trait, the fatal cerebral malaria known to kill infants in these areas may be prevented. The RBCs of
patients with Hb H disease have also shown a suppressive effect on the growth of the parasites.
This effect is not observed in thalassemia trait.

Classification of thalassemia

A large number of thalassemic syndromes are currently known; each involves decreased
production of one globin chain or more, which form the different Hbs normally found in RBCs. The
most important types in clinical practice are those that affect either or chain synthesis.

thalassemia

Several forms of thalassemia are known in clinical practice. The most common forms are as
follows:

Silent carrier thalassemia

This is a fairly common type of subclinical thalassemia, usually found by chance among
various ethnic populations, particularly African American, while the child is being
evaluated for some other condition. As pointed out above, 2 genes are located on
each chromosome 16, giving thalassemia the unique feature of gene duplication, see
the image below. This duplication is in contrast to only one -globin gene on
chromosome 11.

Alpha and beta globin genes (chromosomes 16 and 11, respectively).

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In the silent carrier state, one of the genes is usually absent, leaving only 3 of 4 genes
(aa/ao). Patients are hematologically healthy, except for occasional low RBC indices.
In this form, the diagnosis cannot be confirmed based on Hb electrophoresis results,
which are usually normal in all thalassemia traits. More sophisticated tests are
necessary to confirm the diagnosis. One may look for hematologic abnormalities in
family members (eg, parents) to support the diagnosis. A CBC count in one parent that
demonstrates hypochromia and microcytosis in the absence of any explanation is
frequently adequate evidence for the presence of thalassemia.
thalassemia trait: This trait is characterized by mild anemia and low RBC indices. This
condition is typically caused by the deletion of 2 (a) genes on one chromosome 16 (aa/oo)
or one from each chromosome (ao/ao). This condition is encountered mainly in Southeast
Asia, the Indian subcontinent, and some parts of the Middle East. The ao/ao form is much
more common in black populations because the doubly deleted (oo) form of chromosome 16

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is rare in this ethnic group.

Hb H disease: This condition, which results from the deletion or inactivation of 3 globin
genes (oo/ao), represents thalassemia intermedia, with mildly to moderately severe anemia,
splenomegaly, icterus, and abnormal RBC indices. When peripheral blood films stained with
supravital stain or reticulocyte preparations are examined, unique inclusions in the RBCs are
usually observed. These inclusions represent b chain tetramers (Hb H), which are unstable
and precipitate in the RBC, giving it the appearance of a golf ball. These inclusions are
termed Heinz bodies, depicted below.

Supra vital stain in hemoglobin H disease that reveals Heinz bodies (golf ball appearance).
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thalassemia major: This condition is the result of complete deletion of the a gene cluster on
both copies of chromosome 16 (oo/oo), leading to the severe form of homozygous
thalassemia, which is usually incompatible with life and results in hydrops fetalis unless
intrauterine blood transfusion is given.

thalassemia

Similar to thalassemia, several clinical forms of thalassemia are recognized; some of the more
common forms are as follows:

Silent carrier thalassemia: Similar to patients who silently carry thalassemia, these
patients have no symptoms, except for possible low RBC indices. The mutation that causes
the thalassemia is very mild and represents a + thalassemia.
thalassemia trait: Patients have mild anemia, abnormal RBC indices, and abnormal Hb
electrophoresis results with elevated levels of Hb A 2, Hb F, or both. Peripheral blood film
examination usually reveals marked hypochromia and microcytosis (without the anisocytosis
usually encountered in iron deficiency anemia), target cells, and faint basophilic stippling, as
depicted below. The production of chains from the abnormal allele varies from complete
absence to variable degrees of deficiency.

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Peripheral blood film in thalassemia minor.

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Thalassemia intermedia: This condition is usually due to a compound heterozygous state,
resulting in anemia of intermediate severity, which typically does not require regular blood
transfusions.
thalassemia associated with chain structural variants: The most significant condition in
this group of thalassemic syndromes is the Hb E/ thalassemia, which may vary in its clinical
severity from as mild as thalassemia intermedia to as severe as thalassemia major.
Thalassemia major (Cooley anemia): This condition is characterized by transfusion-
dependent anemia, massive splenomegaly, bone deformities, growth retardation, and peculiar
facies in untreated individuals, 80% of whom die within the first 5 years of life from
complications of anemia. Examination of a peripheral blood preparation in such patients
reveals severe hypochromia and microcytosis, marked anisocytosis, fragmented RBCs,
hypochromic macrocytes, polychromasia, nucleated RBCs, and, on occasion, immature
leukocytes, as shown below.

Peripheral blood film in Cooley anemia.

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Frequency
United States

Because of immigration to the United States from all parts of the world and the intermarriages that
have taken place over the years, all types of thalassemia occur in any given part of the country.
However, until recently, the number of patients with severe forms of both and thalassemia has
been very limited. For this reason, finding more than 2-5 patients with the very severe forms in any
pediatric hematology center is unusual (except for in the few referral centers in the United States).

However, this situation is changing rapidly in certain parts of the country. In the last 10 years, Asian

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immigration has been steadily increasing. According to the Federal Census Bureau, in 1990, 6.9
million Asians were in the United States, twice that reported in the 1980 Census count. The
prevalence of various thalassemia syndromes in this population is very high. and thalassemia,
as well as Hb E/ thalassemia, are currently on the rise in the state of California as a result of the
large concentration of Asian immigrants in that part of the country.

The interaction between Hb E (a chain variant) and thalassemia (both very common among
Southeast Asians) has created the Hb E/ thalassemia entity, which is now believed to be the most
common thalassemia disorder in many regions of the world, including coastal North America, thus
replacing thalassemia major in frequency. For this reason, the cord-blood screening program for
detection of hemoglobinopathy in California has been modified to include the detection of Hb H
disease. In California alone, 10-14 new cases of thalassemia major and Hb E/ thalassemia and
40 cases of neonatal Hb H disease are detected annually.

International

Worldwide, 15 million people have clinically apparent thalassemic disorders. Reportedly, disorders
worldwide, and people who carry thalassemia in India alone number approximately 30 million.
These facts confirm that thalassemias are among the most common genetic disorders in humans;
they are encountered among all ethnic groups and in almost every country around the world.

Certain types of thalassemia are more common in specific parts of the world. thalassemia is
much more common in Mediterranean countries such as Greece, Italy, and Spain. Many
Mediterranean islands, including Cyprus, Sardinia, and Malta, have a significantly high incidence of
severe thalassemia, constituting a major public health problem. For instance, in Cyprus, 1 in 7
individuals carries the gene, which translates into 1 in 49 marriages between carriers and 1 in 158
newborns expected to have thalassemia major. As a result, preventive measures established and
enforced by public health authorities have been very effective in decreasing the incidence among
their populations. thalassemia is also common in North Africa, the Middle East, India, and
Eastern Europe. Conversely, thalassemia is more common in Southeast Asia, India, the Middle
East, and Africa.

Mortality/Morbidity
thalassemia major is a mortal disease, and virtually all affected fetuses are born with hydrops
fetalis as a result of severe anemia. Several reports describe newborns with thalassemia major
who survived after receiving intrauterine blood transfusions. Such patients require extensive
medical care thereafter, including regular blood transfusions and chelation therapy, similar to
patients with thalassemia major. Morbidity and mortality remain high among such patients. In the
rare reports of newborns with thalassemia major born without hydrops fetalis who survived
without intrauterine transfusion, high level of Hb Portland, which is a normally functioning
embryonic Hb, is thought to be the cause for the unusual clinical course.

Patients with Hb H disease also require close monitoring. They may require frequent or only
occasional blood transfusions, depending on the severity of the condition. Some patients may
require splenectomy. Morbidity is usually related to the anemia, complications of blood
transfusions, massive splenomegaly in some patients, or the complications of splenectomy in
others.

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In patients with various types of thalassemia, mortality and morbidity vary according to the
severity of the disease and the quality of care provided. [7, 8, 9] Severe cases of thalassemia major
are fatal if not treated. Heart failure due to severe anemia or iron overload is a common cause of
death in affected persons. Liver disease, fulminating infection, or other complications precipitated
by the disease or by its treatment are some of the causes of morbidity and mortality in the severe
forms of thalassemia. [10]

Morbidity and mortality are not limited to untreated persons; those receiving well-designed
treatment regimens also may be susceptible to the various complications of the disease. Organ
damage due to iron overload, chronic serious infections precipitated by blood transfusions, or
complications of chelation therapy, such as cataracts, deafness, or infections with unusual
microorganisms (eg, Yersinia enterocolitica), are all considered potential complications.

Race

Although thalassemia occurs in all races and ethnic groups, certain types of thalassemia are more
common in some ethnic groups than in others (see Frequency). thalassemia is common in
southern Europe, the Middle East, India, and Africa. thalassemia is more common in Southeast
Asia; nevertheless, it is also seen in other parts of the world. Furthermore, specific mutations of the
same type of thalassemia are more common among certain ethnic groups than others; this
facilitates the screening and diagnostic processes because certain probes for the more common
mutations in a particular region are usually readily available.

The thalassemia trait in Africa is usually not of the cis deletion on chromosome 16, unlike the
condition in Southeast Asia, which is associated with complete absence of the gene on one
chromosome. When both parents have the cis deletion, the fetus may develop hydrops fetalis. For
this reason, hydrops fetalis is not a risk in the African population, although it remains a risk for
Southeast Asian population.

Sex

Both sexes are equally affected with thalassemia.

Age

Despite thalassemia's inherited nature, age at onset of symptoms varies significantly. In

thalassemia, clinical abnormalities in patients with severe cases and hematologic findings in
carriers are evident at birth. Unexplained hypochromia and microcytosis in a neonate, depicted
below, are highly suggestive of the diagnosis.

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Peripheral blood film in hemoglobin H disease in a newborn.

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However, in the severe forms of thalassemia, symptoms may not be evident until the second half
of the first year of life; until that time, the production of -globin chains and their incorporation into
fetal Hb can mask the condition.

Milder forms of thalassemia are frequently discovered by chance and at various ages. Many
patients with an apparent homozygous thalassemia condition (ie, hypochromasia, microcytosis,
electrophoresis negative for Hb A, evidence that both parents are affected) may show no significant
symptoms or anemia for several years. Almost all such patients' conditions are categorized as
thalassemia intermedia during the course of their disease. This situation usually results when the
patient has a milder form of the mutation, is a compound heterozygote for + and -0 thalassemia,
or has other compound heterozygosity.

Clinical Presentation

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