Dental Management of Thalassemia Patients

Dental Management of
Thalassemia Patients

CLINICAL AND RADIOLOGICAL STUDY OF ORO-FACIAL
MANIFESTATIONS IN THALASSAEMIA
By
Dr. SHILPA PATIL
Dissertation submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
In partial fulfillment
of the requirements for the degree of
MASTER OF DENTAL SURGERY
In
ORAL MEDICINE AND RADIOLOGY
Under the Guidance of
Dr. ASHOK L. M.D.S.
Professor and Head
DEPARTMENT OF ORAL MEDICINE AND RADIOLOGY
BAPUJI DENTAL COLLEGE AND HOSPITAL
DAVANGERE, KARNATAKA, INDIA.
March - 2006

v
ACKNOWLEDGEMENT
My humble gratitude to the ALMIGHTY GOD, for the
blessing showered upon me.
People and events by their profound influence shape an
individuals personality, life and career. It is indeed a
privilege and pleasure to mention a few such names who have
moulded me into what I am today.
The individual most responsible for the completion of
this study is my Guide and Professor Dr.ASHOK L., M.D.S.,
Professor and Head, Department of Oral Medicine and
Radiology, Bapuji Dental College and Hospital, Davangere.
His tireless pursuit for academic excellence and
professional insight were a source of constant encouragement
and inspiration. I will be indebted to him for his
overwhelming help and kindness. To be like him one day will
be an ongoing task.
I would like to express my heartfelt gratitude and
deep appreciation to my esteemed teachers Dr.RAJESHWARI A.,
Professor, Dr.SUJATHA G.P., Associate Professor,
Dr.SHIVAPRASAD S., Associate Professor, Dr.ATUL P.S.,
Reader and Dr.SANJAY N.B., Reader, Department of Oral
Medicine and Radiology, Bapuji Dental College and Hospital,
Davangere. Their insistence on learning the basics,
thinking logically and working systematically have spurred
me to do the best that I could.
I also extend my sincere thanks to Dr.NAGABUSHAN D,
Dr.ANITHA, Dr.SHIVAKUMAR G.C., Assistant Professors, for
their help in my hour of need and thoughtful suggestions.
I express my sincere thanks to Dr.K. SADASHIVA SHETTY
Principal, Bapuji Dental College Hospital, Davangere, for

vi
providing excellent facilities to complete my post-
graduation course.
I am extremely grateful to my colleagues Dr.SARBJEET,
Dr.CEENA, Dr.HEMA, Dr.GURU, Dr.SANGAMESH, Dr.SHRUTI,
Dr.NAGARAJ, Dr. RANJANA, Dr.SHILPASHREE, Dr.SHILPA B.J., and
Dr.VIJAYA LAKSHMI. I would like to express my regards and
sense of indebtness to them because of their help,
constructive comments, suggestions and support, this study
has seen the light of this day.
My sincere thanks to Mr.D.K.SANGAM, Bio-Statistician,
for his service in carrying out the Statistical analysis.
I would like to thank Mr. Surendra of DYNA COMPUTERS,
for deciphering my writing and typing this thesis in time.
I am thankful to Mrs.VANDANA, Mrs.CHANDRAMMA,
Mr.HANUMANTHAPPA, Mr.BASAVANAGOWDA, Mr.SATISH &
Mr.SHIVAKUMAR, for their help during the course of my
study.
Acknowledgement is also due to my cherished friends
whose love, support and humour has indeed been life saving.
My FATHER and MOTHER and my wonderful brother
Dr.SANDEEP, have been a most important source of moral
support, and have always been there when I needed them, I am
forever indebted to them.
My MOTHER-IN-LAW, SISTER-IN-LAW and my NIECES have
been a constant source of encouragement.
My bundle of joy my daughter TANISHKA who has given me
so much at the time when she needed me the most. My friend
and Companion Dr.ASHWIN who initiatives make me what I am
today. I am indebted and incomplete without them.

vii
Last but not the least I thank my PATIENTS for their
kind co-operation inspite of their sufferings.
Date :
Place : Davangere. Dr.
SHILPA PATIL
LIST OF ABBREVIATIONS USED
ALT Alanine Amine Transferase
DMFT Decayed Missing Filled Teeth
DNA Deoxy Ribonucleic Acid
EMH Extra Medullary Hemopoiesis
gm/dl Gram per deciliter
GVHD Graft Versus Host Disease
Hb Hemoglobin
HbA Adult hemoglobin
HbA2 Adult hemoglobin 2
HbF Fetal Hemoglobin
HbH Hemoglobin H
IgA Immunoglobin A
IgG Immunoglobin G
IgM Immunoglobin M
IOPA Intraoral Periapical Radiograph
MCH Mean corpuscle hemoglobin
MCV Mean Corpuscles volume
OHI-S Oral Health Index Score
OPG Orthopantomograph
RBC’s Red Blood Cells
SNA Sella Nasion Point-A
TM Thalassaemia major

viii
WBC White Blood Count
α Alpha
β Beta
β+
Reduced rate of β chain formation
βo
Complete absence of production of beta chains
γ Gamma
δ Delta

ix
ABSTRACT
Background & Objectives : Thalassaemias are the most common single gene
disorder in the world and represent a major health burden. Oro-facial changes occur
during the disease process mainly because of marrow expansion to compensate for
anemia. The aim of this study was to evaluate the orofacial and radiological features
in thalassaemia and to co-relate them to the duration of the disease process. To also
find out if oro-facial manifestations could aid in early diagnosis and provide a clue to
the progress of the disease.
Methods : A group of 25 thalassaemia patients were evaluated for oral
manifestations by clinical examination and with radiographs (IOPA radiograph, OPG
and lateral cephalometric radiograph) for oro-facial changes. Lateral cephalometric
radiographs were traced using Steiner’s analysis to check for maxillary prognathism.
Results : 25 thalassaemia patients were in the age range of 3-28 years, with a male
predominance of 44% and maximum cases were β-thalassaemia major (88%). 18
(72%) patients were poorly built and nourished. All the patients showed pallorness,
icterus and frontal bossing with no changes in eyes, lips, parotid gland or on tongue.
A mean dmft of 1.8 (±2.3) was recorded with a female predominance. Angle’s Class
II molar relationship with increased overjet was present in 8% of cases. IOPA
findings were one case showed thin lamina dura, 3 cases had short roots and all cases
had enlarged marrow spaces. OPG showed altered trabeculae in 5 cases. Lateral
cephalometric radiograph showed widened dipolic space in 4 cases, hair on end
appearance in one case and maxillary prognathism in 3 cases with mean SNA angle
80.44o
.

x
Interpretation & Conclusion : The severity of the oro-facial changes depended on
the age, duration of illness, time of transfusion and spleenectomy. Thus they can help
to predict prognosis of the disease.
Keywords : Thalassaemia ; Oro-facial manifestations ; Marrow spaces ; Pallor ;
Steiner’s analysis ; OPG.

xi
CONTENTS
PAGE NO.
1. INTRODUCTION 01
2. AIMS AND OBJECTIVES 04
3. REVIEW OF LITERATURE 05
4. MATERIALS AND METHOD 65
5. RESULTS 83
6. DISCUSSION 95
7. CONCLUSION 105
8. SUMMARY 106
9. BIBLIOGRAPHY 108
10. ANNEXURES 119

xii
LIST OF TABLES
SL.NO. TITLE PAGE NO.
Table 1 Age Range and Mean Age 87
Table 2 Male and Female Incidence 87
Table 3 Types of thalassaemia in the study 87
Table 4 General Physical Examination Findings 87
Table 5 Extra Oral Findings 88
Table 6 Intra Oral Findings 88
Table 7 DMFT Index 88
Table 8 Molar Relationship 89
Table 9 Anterior Incisor Relationship 89
Table 10 IOPA Findings 89
Table 11 OPG Findings 90
Table 12 Lateral Cephalograph Findings 90

xiii
LIST OF GRAPHS
Graph 1 Graph Showing Sex Distribution 91
Graph 2 Graph Showing Type of Thalassaemia 91
Graph 3
Graph Showing Findings of General Physical
Examination
92
Graph 4 Graph Showing DMFT Index 92
Graph 5 Graph Showing Molar Relationship 93
Graph 6 Graph Showing Anterior Teeth Relationship 93
Graph 7 Graph Showing IOPA Radiograph Findings 94
Graph 8 Graph Showing OPG Findings 94
Graph 9 Graph Showing Lateral Cephalograph Findings 94

xiv
LIST OF PHOTOGRAPHS
Photograph 1 Armamentarium for Clinical Examination 77
Photograph 2 Armamentarium for IOPA Radiograph 77
Photograph 3 Armamentarium for OPG Radiograph 78
Photograph 4
Armamentarium for Lateral Cephalographic
Projection
78
Photograph 5 Patient positioning for IOPA Radiograph 79
Photograph 6 Patient positioning for OPG 79
Photograph 7
Patient positioning for lateral cephalometric
projection
80
Photograph 8 Chemicals for processing of radiographs 80
Photograph 9
Armamentarium for Lateral Cephalometric
Radiograph Tracing
80
Photograph 10 Frontal view of the patient 81
Photograph 11 Lateral view of the patient 81
Photograph 12 IOPA of Control Subjects 81
Photograph 13 IOPA of Thalassaemia Patient 81
Photograph 14 OPG of the Thalassaemia patient 82
Photograph 15
Lateral cephalometric projection of thalassaemia
patient
82
Photograph 16 Cephalometric Tracings on Acetate Sheet 82

1
INTRODUCTION
We are guilty of many errors and faults, but our worst crime is abandoning the children, neglecting the foundation
of life. Many things we need can wait. The child cannot. Right now is the time her bones are being formed, her
blood is being made and her senses are being developed. To her we cannot answer “Tomorrow”. Her name is
“Today”.
In this we have a crucial role to play.
- Gabriela Mitral
Tissue that connects and communicates is called connective tissue. One such
connective tissue is blood. The formed elements of the blood and its liquid portion
plays an extraordinary role in many physiologic mechanisms and processes in the
human body. The alteration of cells, serum or other components is a result of a
hereditary diathesis, nutritional deficiency or exposure to certain chemicals. Other
times, a focal or disseminated infection or a defect in one of the elements causes the
disturbance. When the disturbance of one of these constituents occurs, severe clinical
manifestations result.1
The various blood diseases present polymorphic clinical expressions, one of
which is the relatively constant involvement of oral structures. Oral manifestations of
blood disorders are clinically similar to those lesions which occur in the oral cavity as
a result of some local phenomenon, usually irritation or infection.1
Amongst various blood disorders Hereditary Hemolytic anaemias are of
considerable complexity which encompass a variety of clinical manifestations ranging
from benign conditions to complex disorders posing as public health problem.2
Hemolytic anaemias may be broadly classified depending upon whether the
abnormality is within or outside the erythrocyte into two groups.3

2
Extrinsic (extra corpuscular) hemolytic anaemias where the defect lies outside
the RBC, are usually acquired. Intrinsic (intra corpuscular) hemolytic anaemias
where the defect lies within RBC’s, can be either congenital or hereditary.
Thalassaemias are a group of inherited pathologic conditions characterized by
deficient synthesis of either α or β chains of globin in the adult hemoglobin molecule.
Thalassaemias pose a challenging problem mainly due to variable phenotypes
associated with these syndromes.
Thalassaemias produce a wide variety of signs and symptoms and
complications in those who inherit this disease. Clinicians may encounter patients
with α or β thalassaemia in their clinical practice. They should be aware of possible
oral manifestations of the condition, similarities to iron deficiency anemia, changes
reflected in dental radiographs and possible complications as a result of the disease
process or its treatment.
The dentists recognition or suspicion of a possible blood dyscrasia maybe
important from several different aspects4,5
:
1. The patient with such disease may be totally unaware of the condition, but
comes to his Dentist for periodic care, whereas he may see his physician only
sporadically.
2. The dentist is much more likely to take radiographs routinely than the
physician.
3. The patient may be aware of some oral changes related to his disease and thus
seek dental treatment.
4. The patient may be aware of his disease but still need routine or emergency
dental care.

3
5. The degree of cephalofacial deformities in this disease is closely related to the
severity of the disease and the time of institution of therapy, thus provide a
clue to the progress of disease.
Several of these haemoglobin disorders have been reported from our
population but the most prevalent seems to be the thalassaemias and to a lesser extent
structural hemoglobinopathies.6
Various reports of population surveys and case
reports from various parts of India prove that India is a rich reservoir of the
Thalassaemia gene.7
Early literature has been extensively reviewed by various
authors.8
From their review it can be inferred that the peculiarly heterogenous
population divided into different endogenous groups, the origin and evolution of
which are not traceable pose a difficult problem for the collection of data about these
abnormal hemoglobins and as a result data in this country are inadequate.
Taking the above aspects into consideration along with the available scattered
Indian reports and the scarcity of available data in the Karnataka region, the present
study is conducted to evaluate the oral manifestations in thalassaemia patients.

Aims & Objectives
4
AIMS AND OBJECTIVES
AIMS :
1) To evaluate the oro-facial manifestations in thalassaemia.
2) To evaluate the radiographic features of oro-facial structures in
thalassaemia.
3) To find out whether any co-relation exists between the duration of
thalassaemia and severity of oro-facial clinical and radiological
features.
OBJECTIVES :
1) To find out if oro-facial manifestations could aid in early diagnosis.
2) To find out whether oro-facial clinical and radiological features could provide
an indication to the progress of the disease.

Review of Literature
5
HISTORICAL REVIEW
In 1889, Von Jaksch described an anemia accompanied by splenomegaly and
leucocytosis which he thought was of specific nature and to which he gave the name
“Anaemia infantum pseudoleucaemica”. This was subsequently called “Jaksch-
Hayem-Luzet’s” anemia after the names of the authors who described it more fully.9
In 1925, Cooley TB and Lee P10
presented a brief report of five children with
anemia of the type generally described by Von Jacksch (1889), but which they set
apart because of peculiar mongoloid appearance caused by the enlargement of cranial
and facial bones combined with clinical features.
Cooley TB and Lee P (1923)9
were first to describe the typical mongoloid
facies in Thalassemia.
Rietti (1925)10
presented an account of primary hemolytic icterus.6
Cooley TB (1927, 1928)10
further refined his concepts of what he called
erythroblastic anemia.
Whipple and Bradford (1932)10
presented the first complete autopsy report
of patient with Cooley’s anemia in which they called attention to excessive pigment
deposition in many organs. They first suggested the term thalassemia.
Lehndroff H. (1936),9
was the first to propose that the condition was not only
familial, but inherited
Caminopetros (1938)10
proposed that the disorder was transmitted as a
mendelian recessive.

6
Gatto (1942)10
and Valentine & Neel (1944)10
suggested a mode of genetic
transmission of severe forms of Cooley’s anemia.
Valentine and Neel (1944)10
proposed the terms “thalassemia major” and
“thalassemia minor”.
Angelini (1937)9
and Caminopetros (1938)9
proposed the existence of
genetic carrier, as evidence by blood studies, fragility tests and mild roentgenographic
changes.
Caffey (1937)9
also had hypothesized that mild cases can reach adult life and
transmit the disease.
Thoma and Co-workers (1944) and Novak (1944)4
were among the first to
report in the dental literature on the radiographic changes associated with thalassemia.
Vecchio (1948)10
first described the presence of increased alkali resistant
hemoglobin in patients with thalassemia and demonstrated increased fetal hemoglobin
in thalassemia.
Hamilton, et al (1950), Kalpan and Zuelzar, (1950)10
demonstrated that the
erythrocytes of patients with thalassemia major and minor had a decreased survival
time.
Sturgeon, et al (1955)10
described intermediate types of thalassemia
clinically.
Kunkel and Wallenius (1955)10
described an increase in the percentage of A2
hemoglobin in thalassemia major.

7
Sturgeon and Finch (1957)10
demonstrated that patients with thalassemia
major, despite extreme erythroid hyperplasia of their bone marrow, were
characterized by ineffective delivery of erythrocytes to the circulation
Itano (1957)10
proposed thalassaemia may be caused by mutation interfering
with normal globin synthesis.
Sturgeon et al (1960)10
described α chain thalassaemia.
In the past 20 years, the two important forms of thalassemia α and β
Thalassemia have been recognized as the most common monogenic disease in
humans.
In recent years, the molecular biology and genetics of the thalassemia
syndromes have be described, revealing the wide range of mutations encountered in
each type of thalassemia. β thalassemia alone can arise from any of more than 150
mutations.

8
DEFINITION
S.F. Parkin (1968)11
defined thalassaemia as a hemolytic anemia, found
typically in peoples of Mediterranean origin and due to a dominant Mendelian
inherited abnormality of hemoglobin synthesis. The primary features of the disease
are the continued production of fetal hemoglobin (Hb-F) and the formation of
erythrocytes of aberrant structure which are low in hemoglobin content and which
have a drastically reduced life span.
Sandra F.Schnall and Edward J. Benz Jr. (2003)12
defined thalassaemia
syndromes as heterogenous inherited disorders that arise from mutations in the globin
genes that reduce or totally abolish synthesis of one or more of the globin chains.
They result in hypochromia and microcytosis and in the more severe forms, anemia.
As a group, they compromise the most single gene disorder.
Jon Aster (2003)13
defined thalassaemias as a heterogenous group of genetic
disorders of haemoglobin synthesis characterized by a lack of or decreased synthesis
of globin chains.

9
SYNONYMS
The word thalassaemia is derived from thalassa, which in the Greek word for
“Great sea”.11
Synonyms include Mediterranean anemia, Cooley’s anemia, hereditary
heptocytosis and target-oval cells syndrome.11
In its homozygous form it goes by the names, Cooley’s anemia or
thalassaemia major.
Whereas in its heterozygous form it goes by the names, thalassemia minor or
Rietti-Greppi-Micheli’s syndrome. Silverstonni and Bianco named it “Thalassaemia
minima when this hematological anomaly does not entail any clinical
manifestations.14

10
EPIDEMIOLOGY
Thalassaemia was first considered to affect people living in the central and
eastern Mediterranean regions and those who had emigrated (Eg. North American)
from these areas. Thus this disorder was considered to be frequently encountered in
Italy, Sardinia, Sicily and Greece and elsewhere in Mediterranean islands. Later it
came to be realized that thalassaemia was also to be found in many countries
throughout the world – commonly in some, but less frequently in others – and to
affect people of many races.15,16
α-thalassaemia are frequently seen in South East Asia, especially in Thailand.
It occurs with varying frequency in India.
β-thalassaemia is common in parts of India and Pakistan.
β and α - thalassaemias, although found world wide, differ in their incidence.
β-thalassaemia is particularly frequent in Italy, Sardinia and Sicily and in Greece. It
occurs less frequently in Eastern Mediterranean, through middle east to Pakistan and
India.
Chatterjee (1959)17
reported an incidence of 3.7% for heterozygous β-
thalassemia in the Bengalees in Calcutta.
Labie et al (1961)18
reported a high incidence of 14% to 17% in Madras,
South India.
Haemoglobin D or HbD- Punjab is a β chain variant and was first reported
from Poona in a Sikh soldier.
Saha and Banerjee (1965)19
surveyed in Punjab and reported, a high
incidence of heamoglobin-D in Sikhs.

11
ETIOLOGY
The etiology is obscure. It appears that both hereditary and inheritance are
involved, to a varying extent, the trait can be transmitted by genes from either
parents.11
Cooley, Witwer and Lee (1927)9
originally believed that the disorder was not
primarily hemolytic but rather a disorder of hematopoiesis due to a metabolic fault
which also affected bone maturation.
Wipple and Bradford (1932)9
offered the possibility of an inherited
metabolic disorder or a deficiency disease. They compared the lack of a vital factor to
that found in pernicious anemia.
Lehndorff (1936)9
suggested that the primary disturbance lay in a disturbed
bone marrow, which because of some hereditary or “mutational” influence was
creating defective red cells.
Nittis and Spiliopulos (1936)9
suggested that Mediterranean anemia may be a
peculiar form of malaria. Eight thalassemic children were treated with quinine.
Within 3 months after treatment, all had improved clinically and hematologically.
Caminopetros (1937)9
was of opinion that a coincidental malarial infection
in Mediterranean anemia was effective in relieving many of the symptoms.
Smith (1942)9
found no history of malaria in members of 16 families with
thalassaemia whom he studied.
Fawdry (1944)9
on the basis of his studies on conducted Greeks and on
Cyprus, concluded that malaria played no part in the causation of disease.

12
Damashek (1943)9
has suggested that a disturbance existed in the metabolism
of hemoglobin, particularly in development of a normal amount in the cytoplasm of
the nucleated red blood cells of the bone marrow.
Cooley (1945)9
postulated either a primary progressive abnormality of the
bone marrow or a hyperplasia due to long continued over stimulation. The
fundamental defect lies obviously in the production of red blood cells.
Valentine and Neel (1945)9
on the basis of their exhaustive original studies
and analysis of the recorded cases, concluded that Mediterranean anemia is due, not to
lack of extrinsic iron, but to an inherited inability of the body to utilize or synthesize
some substance essential to normal erythropoiesis. This deficiency being
quantitatively much greater in the fatal form of the disease than in the milder
genetically related variety.

13
PATHOPHYSIOLOGY OF THALASSEMIA
Thalassemias are inherited disorders of Hb synthesis resulting from an
alteration in the rate of globin chain production. A decrease in the rate of production
of a certain globin chain(s) (alpha, beta, gamma and delta) impedes Hb synthesis and
creates an imbalance with the other, normally produced globin chains. Since 2 types
of chains pair with each other 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.20
Bannerman Grioften and Moore (1959)21
were the first to report presence of
a possible defect in heme synthesis in thalassemia.
The type of thalassemia usually carries the name of the under produced
chain(s). The reduction varies from a slight decrease to complete absence of
production. For example, when β chains are produced at a lower rate, the thalassemia
is termed β+, whereas β-0 thalassemia indicates a complete absence of production of
beta chains from the involved allele.20
The consequences of impaired production of globin chains ultimately result in
less Hb being deposited in each RBC, leading to hypochromasis. The Hb deficiency
causes RBCs to be smaller, leading to the classic hypochromic and microcytic picture
of thalassemia.20
In the most common type of β thalassemia trait, the level of HbA2
(delta2/Alpha2) usually is elevated. This is due to the increased utilization of delta
chains by the excessive free α chains resulting from lack of adequate β chains with

14
which to pair. The delta gene, unlike β and α genes, is known to have a physiologic
limitation in its ability to produce adequate delta chains; by pairing with the α chains,
delta chains produce Hb A2 (approximately 2.5-3% of the total Hb). Some but not all
of the excessive α chains are used to form Hb A2 with the δ chains, while the
remaining α chains precipitate in the cells, reacting with cell membranes, intervening
with normal cell division, and acting as foreign bodies, leading to destruction of
RBCs.20
In other types of β thalassemia traits, the mutation is not limited to the β gene
but extends to the adjacent δ gene; thus, no elevation of Hb A2 is expected, and
instead, γ chains are activated resulting in elevation of HbF. Less common are the
types associated with elevation of both Hbs A2 and F.
In the severe forms, such as β thalassemia major or Cooley’s anemia, the same
pathophysiology applies with significant exaggeration. The significant excess of free
α chains brought about by the deficiency of β chains causes destruction of the RBC
precursors in the bone marrow.
Cellular Pathophysiology :
The consequences of accumulation of the excessive globin chains in the
various types of thalassemia are quite different. In β thalassemia, excessive α chains,
unable to form Hb tetramers, precipitate in the RBC precursors and, in one way or
another, produce most of the manifestations encountered in all of the β thalassemia
syndromes. This is not the situation in α thalassemia. The excessive chains in α
thalassemia are γ chains earlier in life and β chains later on. Both are able to form
homotetramers that, although relatively unstable, nevertheless remain viable and able

15
to produce soluble Hb molecules such as Bart (4 γ chains) and H (4 β chains). These
basic differences in the 2 main types of thalassemia are responsible for the major
differences in their clinical manifestations and severity.20
Alpha chains accumulating in the red cell 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 red cell
precursors. In addition, the surviving cells arriving 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 patient with β
Thalassemia. The ability of some red cells to maintain the production of γ chains,
which are capable of pairing with some of the excessive α chains to produce HbF, is
advantageous. Binding some of the excess α chains undoubtedly reduces the
symptoms of the disease.
Increased production of Hb F in response to severe anemia adds another
mechanism to protect the RBCs in patients with β thalassemia. The elevated HbF
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 red cells
processed by the spleen, together with its hematopoietic response to the anemia if
untreated, results in massive splenomegaly, leading to manifestations of
hypersplenism.

16
If one corrects the chronic anemia in these patients by giving regular blood
transfusions, the severe expansion of the ineffective marrow is reversed. However, by
doing so, another source of iron is added, which, together with the excessive iron
absorption normally present in such patients, leads to a state of iron overload. 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.
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 alpha
thalassemia, the presence of higher HbF level, or the presence of a milder thalassemia
mutation all typically ameliorate the symptoms of thalassemia.20

17
CLASSIFICATION
Sandra F.Schnall and Edward, Benz Jr. (2002).12
Classified thalassemia
based on the globin chain involved into ;
1. α-Thalassemia
- Reduced (α + Thalassemia) α globin synthesis
- Absent (αo
– Thalassemia) α globin synthesis
2. β-thalassemia
- Reduced β globin (β+
-Thalasemia) synthesis
- Absent β globin (βo
– Thalassemia) synthesis
3. δ β - Thalassemia – Both δ and β globin synthesis are reduced or absent.
4. Hereditary persistence of fetal hemoglobin.
In these conditions, synthesis of elevated amounts of fetal hemoglobin persists
in adult life.
Jon Aster (2003)13
gave clinical and genetic classification of thalassaemia.
Clinical and Genetic Classification :
Clinical
Nomenclature
Genotype Disease Molecular Genetics
β-Thalassemias
Thalassemia major Homozygous βo
Thalassemia (β0
/βo
);
homozygous β+
Thalassemia (β+
/ β+
)
Severe, requires blood
transfusions regularly
Rare gene deletions
in β0
/β0
Defects in
transcription process,
or translation of β-
globin messenger
RNA
Thalassemia minor β0
/ β Asymptomatic with
mild or no anemia ;
RBC abnormalities
seen
α-Thalassemia
Silent Carrier α / αα Asymptomatic; No
RBC abnormality
α-thalassemia trait α / αα (Asian) ; - α / -
α (black African)
Asymptomatic ; like
Thalassemia minor
HbH disease - / - α Severe anemia
tetramers of β-globin
(HbH) formed in RBCs
Hydrops fetalis - / - Lethal in utero
Gene deletions
mainly

18
ALPHA THALASSAEMIAS
Alpha thalassaemias are disorders in which there is a defective synthesis of
alpha globin chains resulting in depressed production of haemoglobins that contain α
chains i.e. HbA, HbA2 and HbF.
The molecular defects underlying α thalassaemias are extremely
heterogenous. α thalassaemias are categorized according to absence or presence of α
globin gene production as ;
Alpha-0 (αo
) Thalassemia-those with absent synthesis of α globin chains.
Alpha-+ (α+
) Thalassemia – Where there is reduced synthesis of α globin chains.
They are further subdivided according to molecular defects into deletional and
non-deletional types.22
There are normally four α-globin genes, the severity of the clinical syndromes
shows a great variation, depending on the number of affected α-globin genes. The
anemia stems both from lack of adequate hemoglobin and from the effects of
excessive unpaired non-α chains (β, γ, δ). However, the situation is somewhat
complicated by the fact that, normally different non α chains as synthesized at
different times of development. Thus, in the newborn with α-thalassemia, there is an
excess of unpaired γ-globin chains resulting in formation of γ4 –tetramers called
Bart’s hemoglobin, whereas in adults, the excess of unpaired β-globin chains
aggregate to from tetramers called hemoglobin H (HbH).
Since the non-α chains in general form more soluble and less toxic aggregates
than those derived from α-chains, the hemolytic anemia and ineffective erythropoiesis

19
tend to be less severe than with β-thalassemias of similar degree of chain imbalance.
A variety of molecular lesions have been detected in α-thalassemia.
The most common cause of reduced α-chain synthesis seems to be the
deletion of α-globin gene.
Non deletional forms of alpha thalassaemia affect the alpha2 gene (α2).23
The
gene is the dominant of the two alpha genes and the mutation of the α2 gene
ultimately determine the phenotype of the disease, which is of more severe type when
compared to the deletion mutants.22
It should be noted also that iron deficiency can induce a decrease in α globin
synthesis that mimics the decrease that occurs in α thalassaemia.24
Clinical Phenotypes of Alpha Thalassaemia :
The majority of normal individuals have 4 α globin genes (αα/αα) and 2% of
population have 5 α globin genes (ααα /αα). Rarely individuals have 6 α globin
genes (ααα/ααα) (αααα/αα), although the extra globin genes are functional these
individuals are no different from normal.22
α Thalassemia syndromes are classified on the basis of the number and
position of the α-globin genes deleted, which in turn determine the clinical syndrome.
α-globin genes occur in linked pairs on each of the two chromosomes 16. Each α-
globin gene normally contributes approximately 25% of the α-globin chains and may
be deleted independently.

20
Accordingly α thalassemias are22
;
1. One α-gene deletion : Single carrier state.
2. Two gene deletion : α-thalassemia trait.
3. Three α-gene deletion : HbH disease
4. Four α gene deletion : Hb Bart’s hydrops foetalis.
Single Carrier State :
This condition results due to an absence or abnormality of one α gene. This is
an asymptomatic condition difficult to diagnose and the diagnosis can be made only
from family studies of HbH cases or by the direct study of number and structure of α
genes.20
Some cases show a mild elevation of Hb barts in the range of (0.5 to 3%) at
birth, but characteristic RBC inclusions cannot be demonstrated. In most cases Hb
levels and RBC indices are within normal range. About 15% cases show slight
reduction in the mean corpuscles volume (MCV) and mean corpuscle hemoglobin
(MCH).
Alpha Thalassemia Trait :
In this condition there is lack of two alpha chain genes either on the same or
on the opposite chromosomes.20
Affected individuals are asymptomatic and have
normal or slightly reduced Hb levels, with low MCV and MCH and hypochromic red
cells. About 4-8% Hb barts may be present at birth.
When HbA2 levels are increased it is difficult to distinguish this condition
from high HbA2 β-thalassemia trait25
and when HbA2 is decreased it may be
difficult to distinguish it from iron deficiency anemia and sideroblastic anemias.26

21
This is because a relative deficiency of α globin synthesis is also noted in iron
deficiency and sideroblastic anemias.
Hemoglobin H disease (HbH disease) :
HbH disease is characterized by a chronic hemolytic anemia of variable
severity and a clinical picture of thalassaemia intermedia.22
It results when the total
output is equivalent to one functional alpha globin gene. It is seen most frequently in
south east Asian and the Mediterranean regions where it results with the interaction of
αo
and α+
Thalassemia. It may also result from homozygosity for non deletional
mutants affecting the dominant alpha2 globin gene.27
There seems to be a critical
threshold of α chain output below which the syndrome of HbH results.
HbH disease has also been described in individuals as an acquired defect with
myeloproliferative disorders.28
It is also associated with mental retardation and other
developmental disorders. Family studies show that neither of the parents are carriers
and that atleast one chromosome usually number 16 in the HbH case had a denova
mutation involving deletion of the entire α globin gene complex.
HbH can be diagnosed at birth by the finding of 19-27% of Hb Barts in cord
blood. But it usually diagnosed by the finding of 2-40% of HbH in peripheral blood
of older children and adults.20
Hepatosplenomegaly is seen in 70-80% cases and Hb levels vary between 8-
11 g/dl, but may be as low as 3-4 g/dl. Peripheral smear study shows microcytosis,
hypochromia as well as anisopoikilocytosis and target cells. Reticulocyte count is 4-
5%. In spleenectomized patients many red cells may contain one or more Heinz
bodies.

22
Hb Barts Hydrops Fetalis :
Thein and Weatherall (1988)22
stated that this condition is almost exclusively
seen in the South East Asia and Mediterranean countries. Where it was caused by the
interaction of 2 α0
determinants resulting in complete absence of alpha globin
synthesis.
Hb barts hydrops fetalis is incompatible with extra uterine life. The pregnancy
continues for 30 to 40 weeks and usually resulted in the still birth of the baby within
an hour after birth.20
Affected babies are pale, oedematous, have ascites, pleural and
pericardial effusions with spleenomegaly. Jaundice is not marked, there is presence
of extra medullary haemopoiesis in the liver, spleen and other sites. The Hb ranges
from 4-10g/dl and the blood film shows marked anisopoikilocytosis, microcytosis,
hypochromia, erythroblastosis and reticulocytosis. Hb barts (γ4) constitutes 80-90%
of the haemoglobin while 10% being embryonic Hb Portland and traces of HbH but
no HbA.
Oral Manifestations :
Willaim N.A. and William A. Bechtold (1977)29
reported a case of α
thalassaemia minor trait accompanied by clinical oral signs. They reported that the
patient demonstrated anterior maxillary protrusion, splaying of the anterior teeth and
severe generalized alveolar bone loss. In addition, there was an area of radiodensity
in the mandible similar to that found in sickle-cell anaemia, and was considered to be
an infarcted area of bone.

23
ABSENCE OF ALL α-GLOBIN GENES30
Decreased Hb Most Hb made is 10-20% of Hb made
Synthesis Hb Bart’s (γ4) Hb Portland ( γ2)
Unstable and Unable to deliver Capable of O2
forms O2 to tissues delivery to
precipitates tissues
Shortened red
Cell life span Keeps fetus alive
Till the third
Anemia Tissue hypoxia trimester
Massively enlarged Heart failure Interferes with Extramedullary
Placenta Organogenesis erythropoiesis
and development
Maternal complications Large Edema Congenital Large liver
- Pre-eclampsia heart Ascites anomalies, Large spleen
- Hypertension Pericardial Pleural including motor
- Hemorrhage effusion effusion and cognitive
- Retained placenta development

24
BETA THALASSAEMIA INTERMEDIA
CONCEPT :
Thalassaemia intermedia is an ill-defined clinical term use to describe patients
with phenotypes which are more severe than the usual asymptomatic thalassaemia
trait, but milder than transfusion dependent thalassaemia major.31
It encompasses a wide spectrum from patients presenting after the age of two
years and who are able to maintain a Haemoglobin level of 6 g/dl in childhood,
without transfusion, to transfusion independancey in adult life, with Hb levels
between of 10-12 g/dl. On the other hand, later on in life these patients are prone to
develop iron over load and its complications despite, minimal blood transfusions.22
PATHOPHYSIOLOGY OF THAL INTERMEDIA :
Weatherall and Clegg (1981)25
defined Βeta-thalassaemia intermedia as any
patient with the Hb level persistently below 9-10 g/dl, particularly if there is
associated splenomegaly. Many children go through life with these Hb levels but later
on may require transfusions, specially following complication such as hypersplenism,
or if the anaemia is worsened by folic acid deficiency, nutritional deficiency or
recurrent infections.
Therefore the same thalassaemia intermedia can cover a broad spectrum of
conditions ranging from complete health with no requirements of transfusion to
condition characterized by severe growth retardation and skeletal deformity requiring
transfusions.
The clinical and haematological manifestations of thalassaemia intermedia can
be explained on the basis of the 3 chief causes as discussed earlier.

25
1) There has been a mild defect in β globin chain synthesis which results in
relatively little globin chain imbalance and hence a less severe disorder. This
condition is characteristically seen in B+
homozygous Thalassemia of Negro
variety. The genotype is mild homozygous B+
Thalassaemia (B+
/B+
).
2) Co-inheritance of determinant for increased production of γ chains hence
increased production of HbF associated usually with homozygous Bo
-
thalassaemia.
3) Co-inheritance of the genes for α thalassaemia which has been known to
reduce the severity of the disorder, usually associated with homozygous B+
thalassaemia and to a lesser extent with B0
thalassaemia.
The reason for the mild clinical picture in case of homozygous could be due to
its ability to increase γ chain production sufficient enough to produce a mild
intermediate form. This type of intermediate Bo
thalassaemia seems to occur
frequently in individuals of middle east and Indian background.
It remains an enigma as to why patients with β-thalassaemia intermedia can
maintain reasonable Hb levels while that counterparts with homozygous
β-thalasaemia are not able to reasons could be ;
1) Presence of associated α thalassaemia gene which would reduce overall globin
chain imbalance usually associated with the homozygous B+
thalassaemia.
2) Inheritance of two mild B+
thalassaemia genes one from each parent hence a
milder degree of globin imbalance.
3) In cases where both parents have typical thalassaemia trait with no evidence of
associated α thalassaemia and their off spring had mild Bo
thalassaemia it

26
could be an ability to synthesis more γ chains related to some defect which is
not like the deletion observed in delta β-thalassaemia.
4) Double heterozygous conditions of β-thalassaemia with δ-β thalassaemia.32
Clinical Features of thalassaemia Intermedia :
Clinical features of thalassaemia intermedia are extremely variable. It may
present early in life with severe anaemia on one hand while it may not appear until
later in life when complication such as hypersplenism develops growth and
development maybe normal at one end of the spectrum or they maybe retardation of
growth and severe clinical features as in homozygous β thalassaemia at the other end
of the spectrum.
Major symptoms in early childhood are anemia and mild jaundice. There is
always some degree of hepatosplenomegaly, bone changes are variable and range
from none to severe deformity, identical to that seen in β-homozygous thalassaemia.
The course is that of a well compensated chronic anaemia, which may be exacerbated
during period of infection, folate deficiency or hypersplenism. While patients usually
require, no blood transfusions occasional transfusions may be required during periods
of increasing anaemia.
Haematology :
Blood Picture : There is a variable degree of anaemia with Hb levels in the range of 5
to 10 gms/dl. Red cells are typically thalassaemia, MCh and MCH are low, peripheral
smear shows moderate to marked abnormalities in shape and size of RBCs.
Reticulocyte counts are also elevated.

27
Oral Manifestations :
Ficarra et al (1987)5
reported a case of Thalassemia intermedia in which the
oro-facial deformities was the first sign of the disease, which prompted the
consultation. A 10 year old black girl visited her dentist for facial lineaments, large
maxillary bones. The OPG demonstrated ground glass appearance of maxilla and
mandible with obliteration of the maxillary sinuses. Subsequent skull radiographs
displayed sinus obliteration and parietal, frontal and occipital thickening.
He also discussed the other oral manifestations like Mongoloid features caused
by prominence of cheek bone, protrusion or flaring of maxillary anterior teeth and
depression of nose. The oral mucosa exhibited the characteristic anaemic pallor.
Radiographic features in skull were characteristic thickening of the dipole and
elongated trabeculae, giving a hair-on-end appearance, thinning of lamina dura and
circular radiolucencies in the alveolar site of mandibular bone. In general the jaws
exhibited mild osteoporosis with a peculiar trabecular pattern of the maxilla and
mandible was evident characterized by an apparent coarsening of some trabeculae and
disappearance of others resulting in a “salt and pepper effect”.
Thus they concluded that degree of cephalofacial deformities in this disease
was closely related to the severity of the disease and the time of institution of therapy.

28
β-THALASSAEMIAS MAJOR AND MINOR
The β thalassaemias result from over 150 different mutations of the β-globin
genes that result either in the absence of the β globin chains (βo
thalassaemia / β-
thalassemia major) or a reduction in their output (β+
thalassaemia / β-
thalassaemia
minor).33
Since β chain synthesis replaces γ chain synthesis during the first few months
of life it might be expected that β thalassaemia would manifest at about that time.
The disease commonly presents within the first year of life.25
Symptomatology :
Clinical manifestations appear insidiously.
Clinical features may be attributable due to ;
o Severe anemia
o Blood transfusion
Frequently, affected infants fail to thrive or gain weight. They show
progressive pallor, feeding problems, diahorrea, irritability, recurrent bouts of fever
and progressive enlargement of the abdomen due to hepatosplenomegaly. If an
accurate diagnosis is made at this stage and the infant started on a regular blood
transfusion, morbidity may be reduced. However if the child is not adequately
transfused the typical picture of homozygous thalassaemia develops in the next few
years.
Modell (1976)34
and Costin G, Kogot MD et al (1979)35
explained that the
child who is not transfused fails to thrive and shows growth retardation early in life, in

29
association with severe anemia and hypersplenism. He also shows poor musculature,
reduction of body fat, poor appetite and lethargy. On the other hand, growth
retardation yet persists inspite of high transfusion regimes and this was manifested
initially as failure or reduction in the pubertal growth spurt.
Improvement in growth and height with regular transfusions have been
reported by some workers34,36
but disapproved by others.37
Splenomegaly is one of the most constant findings in homozygous
β thalassemia. Progressive enlargement of the spleen in an untransfused or poorly
transfused child is the rule. However, there is evidence that children maintained on
high transfusion regime develop less marked spleenomegaly.34
Hyperspleenism may produce numerous complications including RBC
sequestration, shortening of the autologous RBC survival and a striking expansion of
the total blood volume. Pancytopenia, thrombocytopenia and purpura with bleeding
are rare but well recognized complications of hyperspleenism seen in under transfused
or un-transfused β- thalassemia cases.38
Smith CH, Erlandson ME et al (1964)39
were the first to notice that
spleenectomy in a young thalassaemic patient was followed by increased incidence of
severe infections. Most common being pneumococcal or streptococcal. The highest
incidence being in the first few years.
Skeletal changes are one of the predominant features observed in untransfused
children. Characteristic findings were bossing of the parietal and frontal bones,
protrusion of maxilla and prominent malar eminences with depression of the bridge of

30
nose and puffiness of the eyelids which gives an appearance of typical thalassaemic
facies. There is also a tendency to a mongoloid slant of eyes.34,35
Magli A, Fuslo R, et al (1982)14
reported the 33.3% ocular manifestations in
96 thalasemic minor patients. 14 patients showed colour alterations and 6 of them
presented alternations of static perimetry as well. They concluded that those changes
were due to bad oxygen perfusion of the retinal receptive units.
In older children, iron over loading has been recognized as a complication of
thalassemia for many years. The excess of iron of more than 28 gms, will result in
overt symptoms34
and this is characteristically seen in children on high transfusion
regimes, usually by the age of 11 years. Iron overloading affects many systems
chiefly – cardiac, hepatic and endocrine.
Inadequately transfused children show cardiac dysfunction. It presents as
cardiomegaly or as sudden death or congestive cardiac failure.40
Endocrine dysfunction is due to wide spread haemosiderosis secondary to iron
overload and causes diabetes mellitus. This is seen in the second decade. Failure or
delay of puberty is well documented and presents as the first symptom in a well
transfused homozygous patient. This is due to iron overloading which invades either
pituitary or Gonads.34
Transfusion has changed the pattern of the disease and most children treated
in this manner may survive towards the end of the 2nd
decade.
Modell CB (1976)34
suggested the following prognostic pattern. :
Deaths in childhood or early in second decade result from inadequate
transfusion leading to severe anemia, infections and complications of

31
hyperspleenism such as thrombocytopenia and bleeding from other recurrent
illness.
Deaths in the 2nd
and 3rd
decade results from iron overload involving
particularly myocardium.
Transfusion dependent thalassaemics are unlikely to survive much beyond the
third decade, although recent advances in iron chealating therapy may make it
possible to reduce the effects of iron loading and hence a longer survival.
Fucharoen S, Ketrichit P, et al (2000)41
reviewed the clinical manifestations
of 378 β thalassemic patients by retrospective analysis. Most patients showed clinical
symptoms by 10 years of age. The majority of patients survive with or without
occasional transfusion. Spleenectomy was performed in 26.5% of patients. Patients
came to the hospital because of anemia, fever, abdominal mass and jaundice.
Gastrointestinal tract disturbances were the most common presenting symptoms
(34.6%), especially abdominal pain (10%) and cholecystitis (5.1%), respiratory tract
infection were found in 21.8% of patients and cardiovascular complications including
congestive heart failure, occurred in 11.9%. Other less common symptoms and
complications included bone pain, chronic leg ulcers, paraplegia and hypertension –
associated convulsions and cerebral hemorrhage after multiple blood transfusion.
Patients usually died between 20 to 40 years of age (6%), mainly from CCF and
Septicemia.

32
OROFACIAL MANIFESTATIONS OF
β THALASSEMIAS MAJOR AND MINOR
The oro-facial manifestations of β-thalassemia are numerous and intense and
are the result of bony changes occurring due to ineffective erythropoiesis, with
formation of a bone expanding erythroid mass.42
The oral manifestations are more pronounced in thalassemia than in other
dyscrasias of hemoglobin.43
If the abnormality has been present for a sufficient
period of time, the facies may assume a somewhat mongoloid appearance owing to
maxillary, and in particular premaxillary remodeling as a result of reactive marrow
hyperplasia. This phenomenon does not occur in association with other
hemoglobinopathies.43
Kalpan RI, Werther R et al (1964)44
commented that most noticeable
changes that took place in the oral structures are associated with maxillary
enlargement. The maxilla is mainly composed of cancellous bone containing marrow
spaces, which was a part of hematopoietic system. Under the influence of the disorder
these spaces and the entire maxilla go through a progressive enlargement producing
the typical facial appearance, with high bulging cheek bones, retraction of the upper
lip, protrusion of the anterior teeth, spacing between the teeth, increased overbite or
open bite and varying degree of malocclusion. In severe cases, the maxillary
tuberosity areas became widened and bulbous. The dentofacial appearance has been
described as having a more of a “rodent” than a Mongoloid” cast.

33
Baty JM, Blackfan KD et al (1932)44
commented that the patient with
Thalassemia major resembled each other than they resemble the other members of
their own families.
The mandible ordinarily undergoes less enlargement than the maxilla. Jan
Hess et al (1990)46
quoted that, in mandible marrow enlargement was less
pronounced because of the dense cortical plates of mandible which prevented the
expansion.
Kaplan RI, Werther R et al (1964)44
described that oral mucosa displayed a
characteristic pallor in Thalassemia major. The gingival tissues appeared thin and pale
but are often otherwise normal. The incidence of gingivitis in children with the
disease seems likely related to local factors such as poor oral hygiene, malocclusion
and drying of the gingiva through the patient’s inability to close his mouth over the
protruding teeth. The chronic anoxemia may in some cases predispose to gingival
disorders.
Kaplan RI, Werther R et al (1964)44
reviewed 50 patients with Cooley’s
anemia to study dental and oral findings. They found maxillary enlargement in 32
(64%), 18 (36%) had deep overbite, 15 (30%) showed an open bite condition and 4
(8%) had some degree of cross bite, 25 (50%) showed more than one dentofacial
deformity and 10 (20%) had apparently normal occlusion. The soft tissue changes
included some degree of gingival inflammation in 16 (32%), 5 (10%) had one or more
periodontal pockets, 5 (10%) showed supra and subgingival calculus and 2 (4%)
showed only supragingival calculus. The author thought that gingival inflammation
was not related to disease process.

34
Johnston and Krogman (1964)47
studied the growth of face in 50
thalassemic major patients ranging from 2 years 10 months to 28 years 5 months.
They concluded that children with Cooley’s anemia had their growth patterns altered
in two ways, a retardation in their normal growth expectations and a retardation in
their rates of growth. Cephalofacial manifestations of orthodontic significance was
considered to be concentrated mainly in maxillary alveolar bone and in the palate.
Parkin SF (1968)11
reviewed 5 cases of thalasssemia and remarked that they
all had a characteristic facial appearance, with a broad base to the nose and a marked
enlargement of the zygomatic and maxillary parts of the face. He described the child
as “a child wearing grandama’s upper full dentures. The occlusal plane was much
lower than usual in both deciduous and permanent dentitions, with increased overbite
and overjet. There was a tendency toward buccal occlusion of maxillary teeth in the
posterior segments. The teeth had a yellowish tinge, probably tetracyclins may have
been administered at times to deal with recurrent infection.
Willian NA, Richard L, et al (1980)48
reported a case of β Thalassemia
minor with a rare combination with cleidocranial dysplasia in a 10 year old patient.
Goldfaub A, Nitzna DW, et al (1983)49
reported two cases of β Thalassemia
major who presented with pain and swelling of the parotid salivary gland. It was
postulated that the impaired function of parotid gland was linked to iron deposits in
the serous cells of this gland, which was particularly susceptible to iron damage, as
demonstrated by low isotope incorporation as in scintigraphic imaging.
Margot LVD, Robert PL (1986)50
reported a case of Thalassemia minor
with glossodynia, depapillation of tongue and with median rhomboid glossitis with

35
contact lesions on the palate and palatal petechiae with superimposed candidal
infection. He also considered the risk factors of bacteremia and viral hepatitis in
those patients.
Weel F, Jackson IT, et al (1987)51
described a case of thalassemia major
with gross dental and jaw deformities, who was operated to achieve a satisfactory
aesthetic and functional result.
Cannell H (1988)52
discussed the development of oral and facial signs in β-
thalassaemia major like retraction of the upper lip, spacing and protrusion of the upper
labial segment, anterior open bite and generalized maxillary enlargement. He
reported a case of β thalassaemia major in a 26 year old man with corrugated
maxillary alveolus. This sign warned of serious decline in the patient’s condition.
The corrugations appeared to be a stage in the development of the well recognized
“chipmunk facies”.
Lamabadusuriya SP (1989)53
described a case of β thalasaemia major in a 11
year old Sinhalese girl who developed a lower motor neuron facial nerve palsy on the
left side, together with a phernic nerve palsy, on the same side, during the course of
the illness. Author attributes the cause of facial palsy as pinching of nerve at one of
the narrow points along its course, such as within the facial canals, due to widening of
diploe bone. The reason for phrenic nerve palsy was postulated as due to pressure
from a small paravertebral mass of haematopoietic tissue.
Jan Hess, Isaac Van Der Waal et al (1990)46
emphasized on the typical
facial expression of thalassemic patients. he discussed the possibility of surgical
treatment of the maxillary hypertrophy. However he concluded that in view of the

36
limited life expectancy of these patients correction should not be performed before
adolescence.
Bucci E, Lo Muzio L, et al (1990)54
reported the findings of a study on 46
subjects affected by β-thalassaemia major who underwent periodic transfusion
therapy. A reduced incidence of the caries process was observed, in all subjects
treated from the first months of life. After a short review of the main problems posed
by these patients during dental treatment, the authors propose a course of preventive
antibiotic treatment to be carried out before the start of dental work.
Siamopoulou-Mavridou A, Mavridis A, et al (1992)55
evaluated flow rates
and chemistry of parotid saliva to dental caries and gingivitis in thalassemia major
patients. Twenty one child patients with thalassaemic major (TM) and 83 healthy
control children were examined for dental caries and gingivitis. Stimulated parotid
saliva flow rates was measured and the saliva samples were tested for calcium,
phosphorus, potassium, sodium, urea, lysozyme and immunoglobulin levels IgA, IgG,
and IgM. The results showed that dental caries experience was significantly higher in
the TM group. Parotid salivary flow rates in TM patients was not significantly
different from those in the healthy controls. However the median saliva
concentrations of phosphorus and IgA were significantly lower in the patients than in
the controls. The concentration of lysozyme was also lower in the TM group, but the
difference was not statistically significant. The findings could provide an explanation
for the higher dental caries experience and gingivitis observed in the TM group.
Scutellari PN, Orzincolo C, et al (1994)56
reviewed fifty four homozygous β
thalassemic patients (26 men and 28 women) aged 7 to 24 years, who had been treated
with high transfusion regimen (Hb levels = 9-10 g/dl) and chelation therapy

37
(desferrioxamine, 35-50 mg/kg), underwent clinical and radiographic investigations.
Their study was aimed at assessing the clinical and radiographic changes in the
stomatognathic system (teeth, mandible and maxilla, occlusion relationship and dental
bases). All patients underwent orhtopantomography and teleradiography of the skull.
Twenty thalassemic patients (13 men and 7 women) of the same age but treated with
low transfusion regimes (Hb levels = 5-6 g/dl) were examined as a control group.
Results indicated that ; 1) in the control group, osteopenia was observed in both the
alveolar process and the mandible, following marrow expansion, with diastema of
incisors and several types of malocclusion nearly all of them associated with Angle’s
Class II pattern 2) In adequately transfused patients, no lesions were observed in 55%
of cases, which meant that current treatment methods can prevent bone abnormalities,
especially if transfusions begin at birth. Nevertheless, osteopenia of the mandible
(31.4%) and dental and/or skeletal malocclusions (40.7%) remained in many cases,
because of persistent marrow expansion, which usually follows incorrect treatment.
3) General dental diseases – eg. caries, gingivitis, etc – affect both populations with
the same incidence.
Mason C, Porter SR, et al (1995)57
conducted a retrospective study to note
the prevalence of clinically significant anemia and haemoglobinopathy in children
requiring dental treatment under general anaesthesia in 1000 patients having low
hemoglobin. 11 patients had sickle cell trait and 2 had β-Thalassemia trait. They
concluded that pre-anesthetic haematological assessment of children needing minor
dental surgery is rarely of any significant clinical value.
Bassimitci S, Emel Yucel-Eroglu et al (1996)58
studied the effects of
thalassaemia major on components of the craniofacial complex using cephalometric

38
analysis of two samples consisting of 30 thalassaemic patients and 30 controls.
Differences between the groups were tested by variance analysis. It was found that
thalassaemia major had significant effects on components of the craniofacial complex.
The typical thalassaemia patients had a moderate class II skeletal discrepancy with
prounced vertical mandibular growth direction, prominent mandibular incisors,
everted lips and a narrowed nasal cavity.
Gotte P, Consolo U, et al (2001)59
evaluated the feasibility of orthodontic
and maxillofacial surgical corrective treatment associated with an appropriate
transfusion therapy in a β-thalassemic patient. They treated a patient who received a
combined haematological, orthodontic and maxillofacial surgical treatment. Controls
for evaluating the statement of results obtained were performed at different times after
the end of the therapy and have shown that the therapeutic objectives had been
achieved and maintained. Their results suggested that this facial disfigurement
requires surgical and orthodontic correction by consolidated surgical-orthodontic
techniques performed according to the appropriate anaemia therapy.
Motalebnejad M, Jenabian N, et al (2002)60
reviewed the relationship of
gingivitis and salivary immunoglobulins in 55 patients with thalassemia major. The
results showed no significant difference between the rate of IgA, IgG and IgM in two
groups. Also there was no relationship between severity of gingivitis and rate of
salivary immunoglobulins.
Abu Alhaija Es, Al-Wahadni AM, et al (2002)61
investigated
cephalometrically the uvulo-glosso-pharyngeal dimensions in 15 subjects with β-
thalassaemia major. The study group comprised of 8 males and 7 females with a
mean age of 14.13 ± 1.06 years. The variables measured on the lateral cephalograms

39
were tongue height and length, soft palate length and thickness, superior, middle and
inferior pharyngeal airway space, and hyoid bone position. The thalassaemic group
was compared with a normal control group matched for age and sex using a t-test.
The results showed that thalassaemic patients had a smaller tongue size (length
P<0.05, height P<0.001), shorter soft palate (p<0.001), smaller upper (p<0.001) and
middle (p<0.05) pharyngeal airway spaces, and a shorter vertical pharyngeal length
(p<0.05). The hyoid bone in thalassaemic patients was closer to the mandibular plane
(p<0.001).
Al-Wahadni AM, Taani DQ, et al (2002)62
conducted a study to determine
whether β-thalassemia major is associated with an increase in the severity of
periodontal disease and dental caries in 61 thalassemia patients. They were compared
with 63 healthy controls for gingival index, probing pocket depth and DMFT. Thus,
they concluded from their results that thalassaemia is not associated with increased
levels of gingivitis or periodontitis. But is associated with higher dental caries
experience
Elham SJA, Hattab FN et al (2002)63
studied cephalometric measurements
and facial deformities is 54 (24 M, 13 F) thalassaemic patients with mean age of 7.5
and compared with age and sex matched controls. The authors concluded that a Class
II skeletal pattern short cranial base length, short mandible, increased anterior and
reduced post vertical dimensions and severe facial disfigurement in 17% of patients
was noted.
Luglie PF, Campus G, et al (2002)64
carried out the investigation to
determine the oral status in a group of 18 (15 males ; 3 females) patients with
thalassaemia major (TM) with 18 healthy controls using the decayed, missing, and

40
filled teeth (DMFT) index and the oral hygiene index (OHI)-S. Spontaneous saliva
was collected from each subject, and the biochemical composition (calcium,
phosphorous, potassium, sodium, urea) were determined and salivary Streptococcus
mutans levels were evaluated. Dental status (DMFT index) was almost equal in the
two groups (10.3 in TM vs 9.4 in controls, p=0.34). The occurrence of plaque (OHI-S
2) was higher in the control group, but no statistically significant association was
observed between oral hygiene conditions in the two groups (Fisher’s exact test 0.47,
p=0.79). Biochemical saliva composition was very similar in the two groups; only the
urea concentration was lower in TM, and this difference was statistically significant
(p=0.002). The TM patients had an increased presence of mutans streptococci at
detectable levels. Their findings confirmed that, although no substantial differences
were found between the two observed groups, further investigations are needed to
determine the theoretical risk of oral diseases in thalassemic patients.
Piras V, Tuveri F, et al (2003)65
suggested that the type of malocclusion most
often seen in β thalassemic patients was represented by Angle’s class II, they
evaluated the influence of other factors on malocclusion particularly sexual
development, the level of serum ferritin, ALT, and age at first transfusion. 122 β-
thalassemic patients and 39 homozygotes, (Age 16-27 years), undergoing treatment
have been analysed. The results of the statistical analysis showed that hypogonadism
can play an important role in determining malocclusions in male β thalassemic
patients (Odds ratio 4, 5; CI 1, 5-13). No other factor has shown any statistically
relevant influence on dental occlusion. They concluded, it would therefore be
interesting to further investigate the hormonal mechanisms that can alter bone
development in thalassemic youngsters; the prevention of such alterations will surely
contribute to improving the quality of life in these patients, particularly now that their

41
life expectancy has been significantly extended by the progress made in transfusional
therapy and ferrochelation.
Al-Wahadni A, Qudeimat MA, et al (2005)66
examined the arch dimensions
of Jordanian patients with β-thalassemia major in comparison with an unaffected
control group. The sample consisted of 24 patients who suffered from beta-
thalassaemia major (mean age = 13.9 ± 3.1 years) and an unaffected 24 control group
(mean age = 13.5 ± 2.9 years) matched for dental age, sex, and incisor and molar
relationships. Alginate impressions of the maxillary and mandibular dental arches of
all participants were taken. All measurements of the arch dimension were made on
the casts using an electronic digital sliding caliper. In the mandibular arch, when
compared with the patients with thalassaemia, the unaffected control group subjects
showed a (statistically) significantly larger incisor width, larger arch depth, and larger
left and right anterior arch lengths (1.18, 2.58, and 1.85 and 1.12 mm, respectively).
In the maxillary arch, there was a statistically significant difference in the mean
incisor width (±2.16 mm), arch depth (±3.14 mm), inter molar width (±121 mm) and
in the left anterior arch length (±1.97). The canine widths, premolar widths, left and
right posterior arch length, and curve of Spee of both arches showed no statistically
significant differences between the two groups. The authors concluded patients with
β-thalassaemia major exhibited; a narrower maxilla; a shorter maxilla and mandible
and smaller incisor widths for the maxillary and mandibular arches when compared to
unaffected subjects.

42
CARIES RISK IN THALASSAEMIA PATIENTS
Ventura (1955)67
theorized that the endocrine dysfunction caused by
thalassaemia is responsible for increased dental caries prevalence.
Kaplan RI, Werther R, et al (1964)44
in their DMF study in 50 β
thalassaemia major patients found that there was a total of 110 carious primary teeth
(average 2.2 per patient), 125 carious permanent teeth (average 2.5), 25 missing
permanent teeth (average 0.5), 38 filled primary teeth (0.75 average) and 126 filled
permanent teeth (average 2.5 per patient). There was also 10 patients (20%) who
showed teeth in perfect condition with no carious areas and no restorations. The
overall DMF rate was 8.3 per patient which was compared to DMF rate of 7.0 per
child in control group. The authors concluded that dental caries in these patients
appeared to be associated primarily with dental neglect. The parents are more
concerned with the serious physical problems, paying less attention to the dental
ailments and only seek dental care when the child is in pain.
Bucci E, Lo Muzio L, et al (1990)54
reported the findings of a study of 46
subjects affected by β-thalassaemia major who underwent periodic transfusion
therapy. A DMFT rate of 4.70 for males and 5.90 for females was observed the
authors concluded that, reduced incidence of the caries process was seen in subjects
treated from the first months of life. After a short review of the main problems posed
by these patients during dental treatment, the authors propose a course of preventive
antibiotic treatment to be carried out before the start of dental work.

43
Leonardi R, Verzi P, et al (1990)68
stated that mean DMFT values for
thalassaemic males and females were as low as 1.5 and 1.6 respectively. They also
found that 90% of males and 66% of females were affected by caries.
Siamopoulou-Mavridou A, Mavridis A, et al (1992)55
evaluated flow rates
and chemistry of parotid saliva to dental caries and gingivitis in thalassemia major
patients. 21 children with thalassaemic major (TM) and 83 healthy control children
were examined for dental caries. Stimulated parotid saliva flow rates were measured
and the saliva samples were tested for calcium, phosphorus, potassium, sodium, urea,
lysozyme and immunoglobulin levels (IgA, IgG, IgM). The results showed that
dental caries experience was significantly higher in the TM group. Parotid saliva flow
rates in TM patients were not significantly different from those in the healthy
controls. However the median saliva concentrations of phosphorus and IgA were
significantly lower in the patients than in the controls. The concentration of lysozyme
was also lower in the TM group, but the difference was not statistically significant.
The findings could provide an explanation for the higher dental caries experience and
gingivitis observed in the TM group.
DeMattia D, Pettini PL, et al (1996)69
evaluated the oro-maxillofacial
alterations and correlating them to transfusion indexes, serum ferritin levels,
splenectomy and age in 60 thalassaemia major patients. The caries index (DMF) for
the permanent teeth in 60 subjects was 5.12 ± 4.76. By utilizing Spearman’s rank
test the number of teeth with caries in the permanent dentition (DMF) and in the
mixed dentition (DMF + dmf) was correlated to the average value of ferritin, with the
ferritin peak, with transfusion requirements and with the age of the patient at the date
of the clinical examination. A significant inverse correlation was demonstrated

44
between transfusion requirements and caries in the mixed dentition. The overall
number of caries in both groups of splenectomized and non splenectomized subjects,
of the same average age, was almost identical. Consequently, spleenectomy and the
higher number of caries are statistically more probable in individuals affected by
thalassemia, of increasing age, without however being mutually correlated.
Hattab FN, Abdalla MH, et al (2001)70
conducted a study on caries risk in
54 patients with Thalassemia major. They found a higher DMFT rate (22.7%) more
than that reported in normal Jordanian sample (DMFT 6.26 vs 4.84). The authors
emphasized the need for effective preventive measures, education and dental
treatment need to be stressed for this caries risk group.
Al-Wahadni AM, Taani DQ, et al (2002)62
conducted a study to determine
whether β-thalassemia major is associated with an increase in the dental caries risk in
61 thalassemia patients. They were compared with 63 healthy controls DMFT. Thus,
they concluded from their results that thalassaemia is associated with higher dental
caries experience
Luglie PF, Campus G, et al (2002)64
carried out the investigation to
determine the oral status in a group of patients with thalassaemia major (TM). 18 TM
patients (15 M, three F) and 18 healthy controls randomly matched for age and sex
were examined for dental caries DMFT index. Dental status (DMFT index) was
almost equal in the two groups (10.3 in TM vs 9.4 in controls, p=0.34). They
concluded that, although no substantial differences were found between the two
observed groups, further investigations are needed to determine the theoretical risk of
oral diseases in thalassemic patients.

45
RADIOLOGICAL CHANGES IN THALASSAEMIA
The first detailed description of bone changes in thalassaemia appeared in
1927 report under the name of radiologist Lawrence Reynolds.71
Cooley, Witwer, and Lee (1927)11
described the basic changes that occur in
thalassaemia major and Caffey (1965)9
reviewed new radiographic findings.
Roentgenologic findings are so characteristic and striking that the X-ray film
alone sometimes clinches the diagnosis or at least provides a strong clue to the nature
of the disease, the blood picture and other examinations subsequently helps in
establishing the diagnosis.72
The radiographic changes in thalassemia are derived from erythroid
hyperplasia of bone marrow, having a more noticeable appearance than the other
hemolytic anemias.
The persistence and overgrowth of the erythrocyte forming marrow causes
enlargement of the medullary cavities and thinning of the overlying cortical walls in
the long bones and skull. As the patient reaches puberty, these changes are less
obvious in peripheral skeleton but they become more pronounced in the skull, spine
and pelvis.9
In skull, spine and pelvis, in which red marrow persists throughout life,
the roentgenographic changes may in contrast become more pronounced, even after
puberty, thus hands which are the optimal sites for roentgen identification of disease
during infancy and early childhood become the least diagnostic sites after puberty.71
Mukherji M. (1938)72
described the radiographic changes in the cranial bones
as, widening of the diploic space, thinning of the tables especially of the outer,

46
sometimes so marked that the outer table may be totally deficient and closely packed
striations at right angles to the tables. The striations may be coarse or fine.
Baty JM, Blackfan KD et al (1932)45
described this appearance as “hairs
standing on end”. Early in the disease or in mild cases striations may be absent, but
there is always diffuse osteoporosis and expansion and later on thickening of the
cranial bones. Early changes start in the horizontal plate and squamous portion of the
frontal bone gradually spread backwards to the parietals and the occipital. The
striations follow a different order, begin in the parietals, extend to the occipital and
affect lastly the superior and temporal portions of the frontal bone, the lower portions
of the frontal do not usually show the striae.
In paranasal bones, overgrowth of marrow impedes their pneumatization from
the outset and in some cases completely suppresses it. In temporal bones,
pneumatization may be normal or completely suppressed. The frontal sinuses maybe
normal, small or absent.70
When the remaining of the calvarium is thickened, there is usually a
conspicuous lack of such thickening in the occipital squamosa
In some severe cases, localized destruction of the overlying bone suggests the
development of localized tumors of red marrow in the generally hyperplastic marrow.
Caffey J. (1957)71
described that pneumatization is most consistently and
most markedly retarded in the maxillary sinuses, in contrast pneumatization of the
ethmoidal labyrinths is not affected, probably because normally there is little or no
marrow or marrow space in these bones.

47
The long and short tubular bones show expansion of the medullary canal,
atrophy of the cortical layer, destruction of the cancellous tissue and a few coarse
irregular trabeculations near the ends of the shafts, giving a “ground glass
appearance” or “rain-drop” spaces within the cortex and a “chicken wire” appearance
of enlarged marrow spaces and coarse trabeculation.50
Expansion of the shafts is usually uniform throughout their entire extent
causing a rectangular contour of the tubular bones, but sometimes expansion is more
pronounced at the ends producing an hour-glass, or dumb-bell shape; occurring at the
lower ends of the femur the picture is that of an erlenmyer flask as in Gaucher’s
disease.72
Flat bones are similarly involved. They show osteoporosis and reticulation.
In fact all the bones of the skeleton are affected.3
Other radiographic manifestations include – osteoporosis of the vertebral
bodies. Radionuclide studies show a generalized decrease in the skeletal uptake.
Premature fusion of the epiphysis in the tubular bone of the extremities.
Pathologic fractures take place as the result of cortical atrophy in 33% of
patients and were most frequently in the long bones of lower extremities. Secondary
hemochromatosis due to repeated transfusions. Arthropathy may also be noted.
Jonh Caffey (1951)71
reported that the skeletal changes are absent or minimal
during the first year of life in thalassaemia and that the rarefaction characteristic of
the disease during early childhood is followed by a relative sclerosis during later
childhood.

48
Kaplan RI, Weather R et al (1969)44
reviewed dental and oral findings in 50
Cooley’s anemia cases. Roentgenographically the maxillary and mandibular bones
showed a coarsened trabecular pattern in 43 cases (86 percent), with increased
radiolucency, enlarged marrow spaces and thinning of the cortical layer of bone.
Johnston FE and Krogman WM (1964)47
reviewed the patterns of growth in
50 children with thalassemia major. Each child was subjected for posterior-anterior
(PA) radiograph of the hand and wrist to permit an assessment of skeletal age and
growth rate, lateral and PA cephalometric image of head and face were taken for an
accurate evaluation of cephalofacial growth. The authors concluded that cephalofacial
manifestations of orthodontic significance seem to be concentrated mainly in
maxillary alveolar bone and in the palate.
Wolman IJ and Ortolani M (1964)73
reported that transfusions can help
control the changes on the exterior of the skull and in other bones which are
reflections of the extramedullary hemopoiesis process.
Poyton HG and Davey KW (1968)74
recorded the changes visible in
radiographs used in dentistry in 16 cases of thalassemia. In their series, the
radiographs taken were – periapical views of posterior teeth, anterior occlusal
projections of mandibular and maxillary teeth and surrounding bone and a lateral skull
radiograph. The frequency of occurrence of certain radiographic appearances were ;
1. Teeth
Short roots and spike shaped – This was most frequently seen in mandibular
first molars and central incisors. This was observed in 9 (56.25%) of their cases.
2. Alveolar bone
- Blurring or effacement of trabeculae (87.5%).

49
- Large bone marrow spaces and pronounced trabeculae – 7 (43.75%) cases
showed this change. This was seen most frequently in the anterior region of
mouth.
- Circular radiolucencies in the alveolus. This was observed in the lower
anterior region (31.25%).
3. Lamina dura and crypts of teeth
- Thin lamina dura and crypts – was seen in 14 cases (87.5%).
- Crypts separated from teeth – This was seen less frequently than the thinning
of crypts and was observed in posterior regions only (37.5%).
4. Maxilla and mandible
- Osteoporosis was present in seven (43.75%) cases. It was considered an
associated factor of the disease.
- A sharply demarcated intermaxillary suture. It was thought as a recognized
variant of normal (43.75%).
- Prominent anterior maxilla – 12 (75%) cases
- Small paranasal sinus – 10 (62.5%) cases
- Enlarged muscle attachment at the angle of the mandible – 3 (18.75%) cases.
- Thin cortex at posterior and inferior margins of the ramus (87.5%).
5. Skull
- Thickening of calvarium of skull, mostly in the anterior region – 14 (87.5%)
cases.
- Fine granular pattern of bone (93.7%).
- Circular holes in the diploe – 5 (31.25%) cases.
- Condensed inner plate of Calvarium – All cases (100%).
- Striations in the calvarium – 2 (12.5%) cases.

50
- Shape of pituitary fossa – In 12 (75%) case the pituitary fossa was modified in
shape over anterior surface.
Thus the authors analysed and assessed the importance of radiographic changes.
The authors concluded that following radiographic observations were
significant in thalassaemia - blurring of the trabeculae, large bone marrow space and
pronounced trabeculae; thin lamina dura and crypts, osteoporosis, prominent anterior
maxilla, small paranasal sinus thin cortex at posterior and inferior margin of ramus,
thickening of calvarium of skull, fine granular pattern of bone and condensed inner
plate of calvarium.
Parkin SF (1968)11
described the striations on the skull radiograph as “crew-
cut” appearance. He also reported 4 cases of thalassaemia with radiographic changes.
He reported that intraoral radiographs showed normal teeth and lamina dura, with a
slightly altered periapical bone pattern consistent with hyperplastic bone marrow.
Lateral radiographs of the skull showed the typical widened dipole in the frontal bone
with hair-on-end appearance.
Roy AN et al (1971)75
reviewed 150 cases of Thalassemia to study
radiological changes in the bone. In their study, skull radiographs showed
enlargement of dipole, thinning of cortices and generalized mottling in 74% of cases.
12% of patients had hair-on-end appearance whereas 14% of patients had normal
appearance.
Logothetis J, Ruth BL, et al (1971)76
conducted a cross-sectional study on
138 patients with Cooley’s anaemia from 2 to 28 years of age. They reported hair-on
end appearance in 5.8% of their patients on the skull radiographs.

51
Negovanovic D, Stojimirovic E, et al (1977)77
discussed Roentgeno
morphologic aspects of osseous lesions in thalassaemia. They mentioned, in bones
two functionally different organs are closely mingled: osseous tissue and osseous
hematopoietic system. In cases of aggression toward osseous hematopoetic system
osseous lesions, with their evolutive stages, are formed. Certain evolutive stags are so
characteristic in their morphology that radiologic diagnosis of the illness can be made
without any hesitation.
conducted xeroradiographic
investigations of the skull, hand, and elbow on 27 patients with homozygous β-
thalassaemia. The results were compared with plain radiographic examinations.
Xeroradiography was shown to demonstrate cortical thinning of long bones, swelling
of the diploic space in the skull, and reticulated patterns in the elbow better than
standard radiography. Moreover, the use of “positive’ mode imaging was shown to
have advantages in the study of the skull and extremities.
Weel F, Jackson IT, et al (1987)51
reported that the bone marrow of
membranous bone is used extensively as an ancillary haemopoetic organ and the
“rodent facies” with increased overbite and upper teeth exposure results.
reviewed that the main
abnormalities of the hand and skull in a group of patients who underwent
hypertransfusion regimen and compared with the lesions observed in a control group
of low-transfused patients. A possible correlation with transfusion regimen was
discussed; since bone lesions are explained on the basis of relationship between
proliferating bone marrow and bone cortex, hypertransfusion regimen will prevent the

52
development of abnormalities, only if established early in life. For this reason,
skeletal lesions in Cooley’s anaemia have changed their “classical” radiographic
patterns. In the skull, the diploic space may become normal, and the overgrowth of
facial bones moderate; the pneumatization of paranasal sinuses may not be completely
impeded by the swelling of the jaws, the “hair-brush” pattern may disappear
completely. The normalized picture of the hand remains a typical differential sign of
prepubertal and adult patients.
Orzincolo C, Castaldi G, et al (1988)80
described the solitary or multiple
circumscribed osteolytic areas in seven patients, selected from 250 patients with
homozygous β-thalassaemia. On radiographic examinations, these areas appear as
purely osteolytic lesions with well defined margins not associated with sclerosis.
Orzincolo C, Castaldi G, et al (1989)81
described that the skull in
homozygous β-thalassaemia may present several abnormalities, such as osteopenia,
widening of the diploic space, and a “hair-on-end” appearance. In some cases it
presents also a particular stratified appearance caused by a variable number of osseous
lamellae, parallel with the inner table. This “lamellated skull was observed in 16 out
of 150 (10.6%) patients affected by the disease. Possible mechanisms were discussed.
The lamellar osseous changes could be due to repeated periosteal osteoblastic
reactions to the sinusoidal neovascularization associated with marrow hyperplasia in
poorly transfused patients.
Leonardi R., Verzi P, et al (1990)82
evaluated dental age in growing subjects
with Cooley’s anemia. 34 patients aged from 4 to 11.8 years were examined. They
noted that there were no difference between dental age and chronological age.

53
Wisetsin S. (1990)83
studied cephalography in 60 thalassemic patients
between the age of 11-16 years and 60 age matched controlled patients. He found that
18.2% showed absence of frontal sinus, 63.3% had thickening of frontal bone and
parietal bone, mostly in anterior region. 36.6% had fine granular patterns of bone,
8.3% had hair-on-end appearance and 73.3% had thin cortex at posterior and inferior
margins of ramus.
De Luca B, Magnano C, et al (1991)84
evaluated the skull, thorax, hand and
wrist standard radiographs of 29 patients affected by Cooley’s disease who were
treated upto 1983 with a low transfusion regimen, rather with a high transfusion
regimen. The patients have been divided into two groups, according to the prevalence
of the first or the second transfusion regimen. Almost all the changes described in the
literature have been found in the radiographs but completely modified. In the
youngest patients the most significant appearances were ribs and hand changes, that
can be considered as the most important feature in their radiological monitoring.
However they mentioned that the new transitional radiological syndrome will rapidly
modify with the establishment of the high transfusional regimen.

54
MANAGEMENT OF THALASSEMIA
The thalassaemia are the most common single gene disorder in the world and
represent a major health burden worldwide. Over the last two decades broader
understanding of the disease pathophysiology led to successful prenatal diagnosis,
improved supportive care that resulted in decreased morbidity and prolonged life
expectancy. The various treatment modalities are85,86
;
Transfusion therapy in Thalassemia has two goals
1. To prevent anemia
2. To suppress endogenous erythropoiesis as to avoid ineffective erythropoiesis.
• Blood transfusion is mandatory for all children with thalassaemia
major and for those children with thalassaemia intermedia who cannot
maintain Hb% above 7 gm% or for those who show evidence of
growth retardation, severe bony changes or hypersplenism. Regular
blood transfusions are presently the mainstay of treatment of
thalassaemia.
Transfusion regimen may be (1) low transfusion regimen where Hb% is
maintained around 6-10 gm% (2) hypertransfusion ; Hb level 10-12 gm% and
supertransfusion where Hb% is maintained at 12-14 gm%.73
The popular transfusion regime of today is a hypertransfusion regime which
aims at maintaining men hemoglobin levels at 12.5 gm/dl and pre-transfusion level
not less than 10 gm%.
Such a regimen permits normal growth and physical activity, suppresses
erythropoiesis, thus preventing skeletal changes and gastrointestinal iron absorption

55
and also inhibits extra-medullary hemopoiesis, thereby preventing splenomegaly and
hypersplenism.
With this regime, requirement of blood is high only at the initiation of therapy,
and does not produce more iron overload than the low transfusion regime.
Complications of Transfusions :
1) Febrile Reactions : It is seen in 3-20% of patients and may be due to leucocyte or
platelet antibodies, antibodies against RBC antigens, allergic reactions to other plasma
or blood proteins, or due to pyrogens present in transfused blood.
2) Hemolytic transfusion reactions
3) Other reactions uncommonly seen and thought to be of uncertain etiology are
sudden development of hypertension, convulsions, cerebral hemorrhage and edema
after multiple transfusions.
4) Transfusion transmitted diseases like malaria, syphilis, hepatitis B, Hepatitis C,
Cytomegalovirus and HIV infection can occur.
IRON OVERLOAD AND CHELATION THERAPY87
:
Two factors contribute to iron overload in thalassemic child :
a) Enhanced gastrointestinal absorption of iron
b) Transfusional siderosis
Transfusional iron overload leads to deposition of iron in the heart leading to
cardiomyopathy and irregularity of heart beats, in the pancreas, in the islet of
Langerhans leading to diabetes, in the liver and spleen leading to
hepatosplenomegaly, hepatic fibrosis and cirrhosis of liver, in the pituitary glands
leading to growth retardation, delayed puberty, in the thyroid and parathyroid gland

56
leading to those sub clinical or clinical organ dysfunction, and in the skin leading to
bronze or black discoloration of skin.
Increased susceptibility to bacterial infection especially yersenia is seen with
iron overload.
Iron accumulation in the myocardium can lead to death, either by involving
the conducting tissues or by causing intractable cardiac failure due to
cardiomyopathy.
Despite extensive research for ideal chelating agent, desferrioxamine currently
the only chelating agent of real value for the management of thalassaemia, being able
to promote the excretion of iron.
DESFERRIOXAMINE (DFO) :
Given on daily basis for a minimum of 5-6 times per week, it is given
subcutaneously over 6-8 hours using an infusion pump. The daily dose of Desferal is
about 30-70 mg/kg and should be tailored according to the need for the patient.
In general, the goal is to keep the serum ferritin level below 1000 ng/ml.
ROLE OF VITAMIN C :
Ascorbic acid deficiency increases insoluble iron (hemosiderin). Vitamin C
helps in conversion of hemosiderin into ferritin from which iron can be chelated.
Addition of vitamin C 100 mg daily prior to DFO therapy increase iron
excretion. 60% of DFO chelated iron is excreted in urine, and 40% in stool.

57
NEWER CHELATING AGENTS88
:
Deferriprone (L1) :
It mobilizes from transferrin, ferirtin, and hemosiderin. It is undergoing
extensive trials in USA, UK, Canada, India and various other centres.
SPLENECTOMY:
With the advent of hyper and super-transfusion therapy, splenomegaly and
hypersplenism have become a rarity and hence splenectomy is usually not needed in
these patients.
If the child has already developed splenomegaly and signs of hypersplenism
and is above 5 years of age, splenectomy is indicated.
The indications for splenectomy are ;
1) An increase in the yearly requirement of packed cells more than double the
basal requirement i.e. packed cell 200 cc/kg / year or more.
2) Decrease in WBC and platelet count, which is a late manifestation of
hypersplenism.
All children needing splenectomy should receive pneumococcal vaccine
(pneumoax MSD), H-influenaza vaccine, and meningococcal vaccine 4 weeks prior to
surgery. In endemic areas, prophylactic antimalarial treatment may be given to
prevent malaria.
Prophylactic penicillin therapy must be continued life long.
Episodes of infection should be treated promptly and newer antibiotics may be
empirically started to prevent septicemia and other complications. Blood culture and
sensitivity of antibiotics must be performed to guide treatment.

58
BONE MARROW TRANSPLANTATION89
:
A ray of hope for permanent cure and better future for children with genetic
disorders has brightened with the rapid advancement in the techniques and the success
of bone marrow transplantation.
The principles of bone marrow transplantation in thalassaemia are ;
a) To destroy and prevent regeneration of defective stem cells, b) sufficient
immune suppression for good engraftment of normal marrow, c) to infuse
stem cells with normal gene for β-globin; d) to prevent GVHD with high doses
therapy of Busulphan, Cyclophosphamide, total body irradiation and other
modalities. All over the world over 1000 transplantations have been done
with a 70-80% cure rate.
NEOCYTE TRANSFUSION :
Propper et al (1980)86
introduced the concept of transfusing thalassemic
children with young red cells (neocytes).
In conventionally used unit of blood, red cells have a survival of 60 days. The
mean age of a neocytes being 120 days, they survive in the recipient for 90 days, thus
reducing the amount of blood required and prolonging the interval between two
transfusions.
PHARMACOLOGICAL METHODS TO INCREASE GAMMA CHAIN
PRODUCTION AND GENE MANIPULATION :
It has been noted that hypomethylation of gene increases its expression and
when methylated, the gene is not expressed. A number of drugs like 5’Azacytidine
and hydroxyurea have been shown to increase the production of γ chains both in

59
animals and human beings by causing hypomethylation of gene by decreasing the
activity of the enzyme DNA methyl transferase.
This increase in γ chain synthesis prevents the α chain precipitation by
forming HbF (a 2 g2) and thereby increasing the life span of red cells.
Butyrates :
This drug is given I.V. infusion slowly over 6-8 hours in dose of 200-400
mg/kg/day and has shown to increase HbF to 8-12% and cause a rise in Hb% by 2-3
gm%. The problem with this drug is the tedious I.V. route. L-carnitine, an analogue of
butyrate, has been tried in thalassemic patients but response obtained has been poor in
most of the trials.
Genetic Engineering90
:
Insertion of normal gene in the stem cells of recipient remains a known
challenging goal of future therapy. There are two main approaches to gene therapy;
1) Somatic approach in which non germ line cells are involved; 2) Transgenic
approach in which transfused gene can be expressed in subsequent generations. This
therapy is still in experimental stage and likely to be the therapy of future
management of thalassaemia.
Antenatal Diagnosis and Genetic Counseling :
As thalassaemia is inherited in an autosomal recessive manner there are 25%
chances of producing thalassaemia major child in each pregnancy.
Population screening, identification of carriers, genetic counseling, antenatal
diagnosis in women at risk and selective termination of affected fetus can prevent the
birth of thalassaemia major child.

60
Prenatal diagnosis can be done by estimation of relative rate of globin
biosynthesis by fetoscopy and fetal blood sampling around 16-18 weeks of
intrauterine life or by analysis of foetal DNA by ultrasound guided chorionic villous
biopsy at around 8-9 weeks of gestation or fetal amniocytes by amniocentesis, if both
the parents are carriers.

61
DENTAL TREATMENT OF PATIENTS WITH THALASSEMIA
When subjecting a patient with Thalassemia for dental treatment, attention
should focus on the obtainment of as much information as possible to ensure safe
dental management and adequate distinction among thalassemic subjects. In this
sense, the type of thalassemia must be established, along with the treatments received,
the degree of iron accumulation related organ involvement, and consequently also
patient prognosis and life expectancy.
The medical diagnosis of the specific type of thalassaemia involved is of great
help, since the planning of dental treatment differs according to whether the patient
presents thalassemia major or intermedia and is always conditioned by the current
medical condition of the patient, future medical therapies and therefore life
expectancy. In patients with thalassaemia trait, more complex treatments can be
considered. The simple case history recorded by the dental professional is therefore
essential for providing oral health, adequate dental treatment and quality of life.42
The salient characteristics of such patients are clearly the possible orofacial
deformities and malocclusions. Such problems in patients with thalassaemia
intermedia and other less severe variants maybe dealt with surgically, including
remodeling of the maxillary protuberance prior to simple dental therapies for aligning
the anterior incisors. Likewise, a maxillary osteotomy for positioning the jaw more
posteriorly in relation to the mandible can afford an improved esthetic outcome.
However, such treatments are not indicated in patients with thalassaemia major,
particularly if blood transfusion and chelator therapy has been shown to be scanty
effective.

Dental Management of Thalassemia Patients

Dental Management of Thalassemia Patients

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