Abstract
Thalassemia beta major is a hereditary hemolytic anemia disease with various grades
of severity, which can be found with no or less globin chain qualitative synthesis. The patient
often experiences hepatosplenomegaly, growth retardation and bone disorder and the
thalassemia facies/chipmunk face protrusive premaxillae due to erythroid hyperplasia with
depressed bridge of the nose. The dentition shows protrusion, flaring and spacing of the
maxillary anterior teeth, open bite that leads to malocclusion. The oral cavity of the beta
major thalassemia patients shows the following characteristics the upper jaw seems to be
bigger due to the bone marrow expansion.The thalassemias were first discovered by Thomas
Cooley and Pearl Lee in 1975. Early cases of the disease were reported in children of
Mediterranean descent and therefore the disease was named after the Greek word for
sea, thalasa. Thalassemia faces is one of the important symptoms of this disease. This kind of
symptoms may occur at birth or the first two years of life.
CHAPTER I
Introduction
Thalassemia is an inherited disorder of hemoglobin (Hb) synthesis, so it is an anemia
transmits congenitally. Thalassemia varies from asymptomatic forms to severe or even fatal
entities. Thalassemia has names as “Mediterranean anemia”, (Whipple et al) Cooley anemia
“Thomas Cooley”, or β thalassemia. The malocclusion “Thalassemia caused” is available to
be prevented by “intensive blood transfusion programme or by
bone-marrow-transplantation”. However, such preventive procedures should be followed for the growing
children since the first years of their lives. Unfortunately, the substitution of preventive
treatments (since the childhood first years) is the surgery with its sequels and aftermaths.
It has been reported in the literature that the major oral change in thalassaemic patients is
enlargement of the maxilla caused by bone marrow expansion. This results in a characteristic
appearance known as chipmunk faces. Affected patients usually suffer from spacing of the
teeth and forward drift of the maxillary incisors, so that orthodontic treatment may be
CHAPTER II
THALASSEMIA
Beta-thalassemia syndromes are a group of hereditary blood disorders characterized by
reduced or absent beta globin chain synthesis, resulting in reduced Hb in red blood cells
(RBC), decreased RBC production and anemia. Most thalassemias are inherited as recessive
traits. Beta-thalassemias can be classified into:
- Beta-thalassemia
• Thalassemia major
•Thalassemia intermedia
•Thalassemia minor
- Beta-thalassemia with associated Hb anomalies
• HbC/Beta-thalassemia
• HbE/Beta-thalassemia
• HbS/Beta-thalassemia (clinical condition more similar to sickle cell disease than to
thalassemia major or intermedia)
- Hereditary persistence of fetal Hb and beta-thalassemia
- Autosomal dominant forms
- Beta-thalassemia associated with other manifestations
• X-linked thrombocytopenia with thalassemia
Clinical presentation of thalassemia major occurs between 6 and 24 months. Affected infants
fail to thrive and become progressively pale. Feeding problems, diarrhea, irritability,
recurrent bouts of fever, and progressive enlargement of the abdomen caused by spleen and
liver enlargement may occur. In some developing countries, where due to the lack of
resources patients are untreated or poorly transfused, the clinical picture of thalassemia major
is characterized by growth retardation, pallor, jaundice, poor musculature, genu valgum,
hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis,
and skeletal changes resulting from expansion of the bone marrow. Skeletal changes include
deformities in the long bones of the legs and typical craniofacial changes (bossing of the
skull, prominent malar eminence, depression of the bridge of the nose, tendency to a
mongoloid slant of the eye, and hypertrophy of the maxillae, which tends to expose the upper
teeth).
If a regular transfusion program that maintains a minimum Hb concentration of 9.5 to 10.5 g/
dL is initiated, growth and development tends to be normal up to 10 to 12 years. Transfused
patients may develop complications related to iron overload. Complications of iron overload
in children include growth retardation and failure or delay of sexual maturation. Later iron
overload-related complications include involvement of the heart (dilated myocardiopathy or
rarely arrythmias), liver (fibrosis and cirrhosis), and endocrine glands (diabetes mellitus,
hypogonadism and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly,
adrenal glands). Other complications are hypersplenism, chronic hepatitis (resulting from
infection with viruses that cause hepatitis B and/or C), HIV infection, venous thrombosis, and
osteoporosis. The risk for hepatocellular carcinoma is increased in patients with liver viral
influences frequency and severity of the iron overload-related complications. Individuals who
have not been regularly transfused usually die before the second-third decade. Survival of
individuals who have been regularly transfused and treated with appropriate chelation
extends beyond age of 40 years. Cardiac disease caused by myocardial siderosis is the most
important life-limiting complication of iron overload in beta-thalassemia. In fact, cardiac
complications are the cause of the deaths in 71% of the patients with beta-thalassemia major.
The etiology is more than 200 mutations have been so far reported; the large majority are
point mutations in functionally important regions of the beta globin gene. Deletions of the
beta globin gene are uncommon. The beta globin gene mutations cause a reduced or absent
production of beta globin chains.
The pathophysiology is the reduced amount (beta+) or absence (beta0) of beta globin chains
result in a relative excess of unbound alpha globin chains that precipitate in erythroid
precursors in the bone marrow, leading to their premature death and hence to ineffective
erythropoiesis. The degree of globin chain reduction is determined by the nature of the
mutation at the beta globin gene located on chromosome 11.
Peripheral hemolysis contributing to anemia is less prominent in thalassemia major than in
thalassemia intermedia, and occurs when insoluble alpha globin chains induce membrane
damage to the peripheral erythrocytes. Anemia stimulates the production of erythropoietin
with consequent intensive but ineffective expansion of the bone marrow (up 25 to 30 times
normal), which in turn causes the typical previously described bone deformities. Prolonged
and severe anemia and increased erythropoietic drive also result in hepatosplenomegaly and
Tests and diagnosis
Most children with moderate to severe thalassemia show signs and symptoms within their
first two years of life. If your doctor suspects your child has thalassemia, he or she may
confirm a diagnosis using blood tests.
If your child has thalassemia, blood tests may reveal:
A low level of red blood cells
Smaller than expected red blood cells
Pale red blood cells
Red blood cells that are varied in size and shape
Red blood cells with uneven hemoglobin distribution, which gives the cells a
bull's-eye appearance under the microscope
Blood tests may also be used to:
Measure the amount of iron in your child's blood
Evaluate his or her hemoglobin
Perform DNA analysis to diagnose thalassemia or to determine if a person is carrying
mutated hemoglobin genes
Prenatal testing
Testing can be done before a baby is born to find out if it has thalassemia and determine how
Chorionic villus sampling. This test is usually done around the 11th week of
pregnancy and involves removing a tiny piece of the placenta for evaluation.
Amniocentesis. This test is usually done around the 16th week of pregnancy and
involves taking a sample of the fluid that surrounds the fetus.
Assisted reproductive technology. A form of assisted reproductive technology that
combines pre-implantation genetic diagnosis with in vitro fertilization may help parents who
have thalassemia or who are carriers of a defective hemoglobin gene give birth to healthy
babies. The procedure involves retrieving mature eggs from a woman and fertilizing them
with a man's sperm in a dish in a laboratory. The embryos are tested for the defective genes,
and only those without genetic defects are implanted in the woman.[3]
Treatments and drugs
Treatment for thalassemia depends on which type you have and how severe it is.
Treatments for mild thalassemia
Signs and symptoms are usually mild with thalassemia minor and little, if any, treatment is
needed. Occasionally, you may need a blood transfusion, particularly after surgery, after
having a baby or to help manage thalassemia complications.
Treatment for moderate to severe thalassemia
Treatments for moderate to severe thalassemia may include:
Frequent blood transfusions. More-severe forms of thalassemia often require
frequent blood transfusions, possibly every few weeks. Over time, blood transfusions cause a
your body get rid of the extra iron, you may need to take medications that rid your body of
extra iron.
Stem cell transplant. Also called a bone marrow transplant, a stem cell transplant
may be used to treat severe thalassemia in select cases. Prior to a stem cell transplant, you
receive very high doses of drugs or radiation to destroy your diseased bone marrow. Then
you receive infusions of stem cells from a compatible donor. However, because these
procedures have serious risks, including death, they're generally reserved for people with the
most severe disease who have a well-matched donor available — usually a sibling.[4]
Prognosis
Prognosis of thalassemia minor subjects is excellent. An increased risk for cholelithiasis,
especially in association with the Gilbert mutation has been demonstrated. Patients with
thalassemia intermedia who do not usually have severe hemosiderosis are less prone to
cardiac problems. However, pulmonary hypertension, thromboembolic complications,
overwhelming postsplenectomy sepsis, and the development of hepatocarcinoma may reduce
survival in this group of patients. The prognosis of betathalassemia major was very grim
before there was any treatment available. With no treatment, the natural history was for death
by age five from infections and cachexia. The first advance in treatment was the initiation of
episodic blood transfusions when the patient was having a particularly bad time. With the
advent of this type of therapy, survival was prolonged into the second decade, but it soon
became evident that the treatment that saved lives in children caused death from cardiac
disease in adolescence or early childhood. Prognosis for individuals with betathalassemia
major has dramatically improved with the advent of DFO. However, many
transfusion-dependent patients continued to develop progressive accumulation of iron. This can lead to
transfusion, and the introduction of new iron chelators and chelation regimes have further
prolonged survival in recent years.
Assessment of myocardial siderosis and monitoring of cardiac function combined with
intensification of iron chelation have converted a once universally fatal disease to a chronic
illness and an excellent long-term prognosis is expected for children who have been chelated
since a very young age.
Bone marrow transplantation is at present the only available definitive cure for patients with
thalassemia major.[2]
CHAPTER III
TOOTH DEVELOPMENT
The oral structures begin to form during the third and fourth weeks of embryonic
development. Germ cells from the ectoderm, mesoderm, and endoderm all contribute to tooth
formation.
Tooth development is divided into the following stages: the bud, the cap, the bell, and crown
(maturation). Additional detail is beyond the scope of this effort and the necessary knowledge
base of practicing pediatricians.
However, it is important to know that the teeth begin to develop around the sixth week of
fetal life and that development continues throughout fetal life and beyond. Thus, an insult can
happen at any or multiple points in the development process and lead to abnormal outcomes.
For example, a febrile illness can cause enamThe order of eruption of the 20 primary and 32
permanent teeth is fairly predictable, although the timing can range considerably among
children.
Primary Teeth
The primary teeth begin to erupt around 6 months of age and eruption is completed by 24 to
36 months. Girls’ teeth usually erupt slightly earlier than boys. Delays in tooth eruption can
be familial, but delays of more than 12 months merit further dental evaluation.
Eruption is usually symmetrical (lower teeth usually before upper) in the following pattern
for the primary teeth: central incisors, lateral incisors, first molars, canines, second molars.
Exfoliation often follows a similar pattern. A helpful mnemonic to remember the timing of
primary eruption is the 7+4 rule. At 7 months of age, children should have their first teeth; at
11 months (4 months later), they should have 4 teeth. At 15 months of age
19 months = 12 teeth
23 months = 16 teeth
27 months =20 teeth
Permanent Teeth
Eruption is similar for the permanent teeth, beginning between 5 and 7 years and usually
finishing by 13 to 14 years. The typical pattern is: central incisors, lateral incisors, first
molars, premolars, canines, second molars, and third molars (wisdom teeth), although not
everyone develops or erupts third molars.
Natal and Neonatal Teeth
Some infants erupt teeth, usually lower incisors, before birth (natal teeth) or shortly thereafter
(neonatal teeth). This is relatively rare, with an incidence of 1 in 2000 children. Extraction of
these incisors may be considered if they are mobile, interfere with breastfeeding, or lead
to Riga-Fede ulceration.
Delayed tooth eruption of more than 12 months can be caused by the following medical
problems:
Endocrine disorders (eg, hypothyroidism, disorders of
calcium/phosphorus metabolism, hypopituitarism)
Genetic disorders (eg, ectodermal dysplasias, Down syndrome,
cleidocranial dysostosis)
Oral space issues (eg, another tooth blocking eruption, impacted
teeth)
Dense gingival tissue (eg, anti-convulsant medications)
Radiation therapy
Therefore, it is reasonable to refer a child who has not erupted a tooth by 18 months of age to
a dentist if they are not seeing one already.
Abnormal Teeth
A number of tooth abnormalities can occur in development. These can relate to the shape,
color, physical structure, or number of teeth.
Number of Teeth
Hypodontia can be caused by some of the same problems that cause delayed tooth eruption
(eg, Down syndrome, ectodermal dysplasias, chemotherapy, radiation therapy). The
prevalence of hypodontia is approximately 3% in the United States, excluding the absence of
the third molars (wisdom teeth), which occurs in approximately 20% of individuals.
Anodontia is extremely rare and most often associated with hypohydrotic ectodermal
dysplasia.
Hyperdontia prevalence ranges from 0.1% to 3.8% and can be associated with genetic
disorders such as cleidocranial dysostosis and Gardner’s syndrome.
(Familial Adenomatous Polyposis).
Tooth Shape
Abnormal tooth shape can result from a variety of medical conditions. Some recognizable
names of these abnormal teeth and their causes include Hutchinson incisors (congenital
Malocclusion, or a misalignment of the teeth, can be a functional problem (eg, eating), an
aesthetic issue, or a hindrance to maintaining good oral hygiene. Examples of malocclusion
include
anterior open bite,
anterior crossbite, and
posterior crossbite. [5]
Signs and symptoms of malocclusion include abnormal alignment of teeth, abnormal
appearance of the face, difficulty or discomfort when biting or chewing, and bruxism.
Malocclusion is usually genetic or congenital in origin. Examples of genetic causes include
congenital absence of teeth, cleft lip or palate, skeletal disorders, and muscular problems.
Malocclusion can also result from environmental factors, such as prolonged thumb sucking,
pacifier use, or tongue thrusting.
Many malocclusions are not preventable, as they are genetic in nature. However, helping
families address pacifier and thumb sucking issues at an early age may prevent or minimize
this problem.
Patients with malocclusions should be referred to a dental professional. Physicians can also
encourage patients treated by dental professionals to use prescribed appliances consistently
CHAPTER IV
Correlation
The Correlation between Thalassemia and the development of jaw and teeth is that
Thalassemia patient will have bone abnormalities such as overgrowth of the maxilla and the
mandible. Chipmunk faces or Cooley faces is one of the most common sign of Thalassemic
Orthodontist treating of this condition need to be aware of the importance of good diagnosis,
investigations and treatment plan.
CHAPTER V
Conclusion
Thalassemia is a hereditary hemolytic anemia disease with various grades of severity, which
can be found with no or less globin chain qualitative synthesis. The patient often experiences
hepatosplenomegaly, growth retardation and bone disorder and the thalassemia
facies,protrusive premaxillae due to erythroid hyperplasia with depressed bridge of the nose.
that leads to malocclusion. The oral cavity of the beta major thalassemia patients shows the
following characteristics the upper jaw seems to be bigger due to the bone marrow expansion
We can confirm Thalassemia with blood test,and pre natal test,so we will know the severity
of the patient. The treatment for the patient have a variation of severity, and for the treatment
is also different.The prognosis of thalassemia minor patient is excellent but for the
thalassemia major patient,the only definitive treatment is bone marrow transplantation,that
can make an excellent prognosis.
References
1. The Orthodontic Cyber Journal. Thalassemia Patient With Malocclusion.
Available at :
http://orthocj.com/2006/06/case-report-thalassemia-patients-with-malocclusion. Accessed December 26, 2012.
2. Orphanet Journal of Rare Diseases. Beta Thalassemia. Available at :
3. Thalassemia. Test and Diagnosis. Available at :
http://www.mayoclinic.com/health/thalassemia/DS00905/DSECTION=tests-and-diagnosis. Accessed December 26, 2012
4. Thalassemia. Treatment and Drugs. Available at :
http://www.mayoclinic.com/health/thalassemia/DS00905/DSECTION=treatm
ents-and-drugs. Accessed December 26, 2012
5. American Academy of Pediatrics. Dental Development. Available at :
http://www2.aap.org/ORALHEALTH/pact/ch2_intro.cfm. Accessed
December 26, 2012
6. American Academy of Pediatrics. Maloclussion. Available at :
http://www2.aap.org/ORALHEALTH/pact/ch2_sect6.cfm. Accessed
