Dental and oral management in beta major thalassemia in children

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 appearance. The orofacial manifestations of beta thalassemia major are prominent cheek bones and 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 anemic condition makes the patient is difficult to do all oral hygiene instruction thus caries index will increase. Dental practitioners especially pediatric dentists are required to have awareness towards the nature of the disease and its implication on dental care. Collaboration with hematologist has to be made in every dental treatment.


INTRODUCTION
Recently, thalassemia has been found in several countries.The main distribution of this disease includes boundary areas of the Mediteranian Sea, most of Central Africa, Middle East, India sub-continent and South East Asia including Indonesia with an incidence of 5-20%.¹ ,³ Currently, in Indonesia it is estimated that there are around 5,000 beta major thalassemia patients with around 380 patients are treated in Dr. Hasan Sadikin General Hospital Bandung.Six to ten of 100 Indonesian carry the gene for this disease.The Ministry of Health estimates that one of 1,600 newborn in Indonesia suffers from severe thalassemia and 200,000 of all newborn suffers from minor thalassemia.The Thalassemia Center in Cipto Mangunkusumo General Hospital Jakarta serves 1,200 patients every month, while the thalassemia clinic at Dr. Hasan Sadikin General Hospital serves about 380 patients.The data shows that thalassemia disease prevalence in Indonesia is quiet high.
Talking about thalassemia, it is difined as a hereditary hemolytic anemia with various degrees of severity characterized by no or less globin chain synthesis due to the abnormal genetic globin chain quantitative synthesis that is commonly found in the whole world.This disease may be caused by marriage between two thalassemia carriers and is often found among children because the patients of this type of thalassemia rarely reach adulthood.In Ferrara, the thalassemia patients who reach the age of six years are only 9% in the period of 1949 to 1957.In the half 1970's, half the of the patients in Italy died before the age of 12.About 3% of the world population, i.e. 150 millions, have beta mayor thalassemia gene.The genetic factors appears to trigger thalassemia, which is in line with the findings reported by the researchers from Lembaga Biologi Molekuler Eijkman (Eijkman Biology Molecular Center) in Sumatera and East Nusa Tenggara that shows a small percentage in South Sumatera may reach 15 percent; in Sumba East Nusa Tenggara, it reaches 36%.
Meanwhile, stated that thalassemia is a typical genetic disease of the tropical population such as Sardinia, Italy, Cyprus, Mediteranian, and all Asian country to Papua New Guinea.This difference shows an evident the relationship between the genetic factors and thalassemia. 4n general, this disease shows severe chronic anemia that is characterized by paleness, weakness, fatigue and malaise.The most severe symptoms are found in beta mayor thalassemia.This type of thalassemia is also known as Cooley anemia, which is the most severe congenital hemolytic anemia.The chronic hemolytic anemia symptoms in patients progressively appear since the age of 3-6 months leading to the need of routine blood transfusion.This condition makes the patients lazy to clean their teeth leading to poor oral hygiene and high caries index.While the typical thalassemia patients have a particullarly face called as facies rodent because of the protrusive anterior teeth and disturbed maxilla growth that may cause malocclussion.In this case, it is no doubt that that thalassemia may give alteration of oral cavites condition.

BETA MAYOR THALASSEMIA
1][12] Beta thalassemia is classified into two categories; beta plus, where the beta chain production is reduced; and beta zero, where there is no beta chain production found. 2,7This beta zero thalassemia is known as beta mayor thalassemia and beta plus thalassemia is known as intermediate beta thalassemia. 4,7,9Beta mayor thalassemia is a homozygote beta thalassemia disorder that is often called Cooley anemia.Its clinical manifestation usually appears after 4-6 months of life 7,9,13 and the patients experience severe anemia with less than 20% hematocryte that leads to dependency towards blood transfusion. 7,9,11It shows that this kind of thalassemia is the most severe form of thalassemia.
In fact, this disease is a recessive autosomal familial disease and particularly attacks beta globin gene. 12-14When both parents are carrier of the disease, there is a possibility that one of their four children has thalassemia, two are carriers and one of them is normal 14 and is often caused by the inheritance of two different mutation, each recognizes beta globin synthesis (mixed heterozygote).][8][9][10] As a result, globin beta chain synthesis is reduced.
As mentioned above, beta chain production will be disturbed leading to drastically decreased hemoglobin level.This is caused by excessive destruction of ineffective red blood cells in the spleen that a routine blood transfusion is a must. 15There is a severe hypochrome microcystic, anisopoikilocytosis with a high reticulocyte percentage along with normoblast, target call and basophilic stippling on the peripheral blood smear preparation of the beta mayor thalassemia patients.  Thicondition provides a certainty that the diagnosis must be made through hemoglobin electrophoresis by showing the absence of HbA, normal, low or a bit higher percentage of HbA2 and almost all hemoglobin in the blood are HbF.A positive Kleihauer test result that determines HbF using acid elution method is used to support diagnosis.  Talg about decreased hemoglobin due to beta chain deficiency, there is compensation from decreased HbA level and increased production of HbA2 and HbF will lead to various clinical signs. 5,9,14The most common symptoms are spleen and liver enlargement, delayed bone growth and changes in bones. 7The changes in bones are due to the bone marrow hyperactivity that causes excessive growth in frontal bone, zygomatic, and maxillary protrusion.This changed form leads to a typical facial appearance called thalassemia facies.The dental growth of the beta mayor thalassemia patients is poor and is accompanied by jaw bone refraction. 14Beside, beta mayor thalassemia patients have a short life expectancy.The most severe patients rarely reach adulthood.] Meanwhile, there are two factors related to anemia pathogenesis in beta thalassemia are reduced beta globin synthesis and beta thalassemia hemolytic components.Beta globin synthesis reduction continues into abnormal erythroblast formation so that the total hemoglobin level for each cell is lower and the cell looks hypochromic. 13,15The beta thalassemia hemolysis component is not caused by beta globin deficiency but due to the excessive globin alpha chain with normal synthesis.The alpha free chain forms insoluble pool and creates sediment in the erythrocyte.This input damages the cell layer, reduce the flexibility and decrease the red cells. 16

The clinical manifestation of beta mayor thalassemia
4][15][16][17][18][19] The child's weight is usually lower than the average weight for his/her age.Fever, diarrhea and various gastrointestinal disorders are usually found during the first year of life. 14The skin looks pale and yellowish and will become dark due to the iron sedimentation caused by repeated transfusion. 7hile the bone abnormalities happen mostly due to the erythroid marrow hypertrophy and expansion that leads to widen bone marrow, thin cortex and osteoporosis. 15,190][21][22][23] Older patients commonly show a typical face called facies Colley with abnormal facial and cranial bone growth.The nose looks flat without nasal bridge, the distance between eyes is wide and the forehead bone is wide too.There is a thickening of cheek bones and deep nose bridge that leads to the typical features of facies Cooley.][21][22][23][24] Moreover, medullar tubercle gives a mosaic feature of the bone.Osteoporosis and cortical thinning may lead to pathological fracture in long bones and shortened arms due to irregular fusion of the humerus proximal area. 36,39,42] The characteristic and the severity of the bone abnormalities increase with age.In older patients, the bony changes are more commonly found in the distal areas such as legs and arms. 31,46,48ther than clinical symptoms have mentioned above, there is a heart abnormality that is often found and is included into one of the death causes.Myocardial hemocyderosis or heart disorder caused by hemochromatosis is one of the death causes in patients who receive routine transfusion. 2,7,9emocyderosis evokes arrhythmia that also causes sudden death.The abnormality that is caused by severe anemia is hearth enlargement that can be accompanied by congestive heart failure. 11,13,17ericarditis may happen due to the severe iron sedimentation in the pericardium as well as the bacterial infection. 20eta mayor thalassemia patient growth and development are commonly disturbed even though the relative intelligence level development is not affected.This obstructed growth is caused by the severe anemia and low Hb level leading to tissue hypoxia.The secondary sexual growth is disturbed by the endocrine disorders that puberty is reached later and the growth acceleration is delayed or even does not occur.Menstruation in girls and secondary sexual signs in boys are delayed. 17hile in the older patients, Diabetes mellitus and hypoparatiroidism is commonly found due to the endocrine disorder. 12,16,17he beta mayor thalassemia patients are also medically compromised patients because they are susceptible to infections.The kidney is usually enlarged as a result from extra medullar hematopoiesis with dark brown urine cased by heme catabolism product excretion. 17-20

DISCUSSION
Growth and development of oral cavity in beta mayor thalassemia patients show several differences compared to normal children especially in terms of facial bone structures, dental arrangement and gingival color.

Beta mayor thalassemia craniofacial growth and development characteristics
The face and head of beta mayor thalassemia patients show a typical form known as facies Cooley or fasies thalassemia.The cranial bone is thickened resulting in frontal bone protrusion with widened diploe space and thin external and internal plate.The excessive malar bone grow due to the erythroid marrow expansion creates prominent cheeks and deep nasal base.According to Meredith and Higley, there is a relationship between the transversal grow of the head and face with dental arch.The excessive maxillary bone grow creates dental malocclusion.The pneumatization of the maxillary sinus is commonly delayed in beta mayor thalassemia patients. 9,20-3

Radiographic characteristics of beta mayor thalassemia
The changes in beta mayor thalassemia patient bones that are caused by bone marrow hyperplasia can be observed in the radiographic images.Diploe in the cranial bones experience expansion that the inter plate space becomes widened while the external and internal part of the plate becomes thinner.The frontal bone creates a vertical tubercle that is parallel with the diploe plate external plate and, due to erythroid hyperplasia, the parietal bone has a porous part in the diploe plate external part that creates hair on end or sun ray appearance. 3, The[21][22][23][24]

Oral cavity characteristics of beta mayor thalassemia patients
The oral cavity of the beta mayor thalassemia patients shows the following characteristics.  Theper jaw seems to be bigger due to the bone marrow expansion.This facial feature is known as chipmunk facies.The lower jaw is wider than a normal lower jaw.The tooth size is similar to normal child tooth except for the multiple diastema due to faster jaw growth.The periodontal ligament will seem widened as a result from Class II Division 1 malocclusion.The gingiva is pale especially when the patient's Hb drops to below 8 gr/dl.The color of the gingiva sometimes tends to be dark, which is caused by the high ferritin level in the blood.The tongue size is bigger/macroglossi as a result from bigger arches.

Considerations during dental treatment
The treatment for beta mayor thalassemia is performed routinely especially when patients experience decreasing hemoglobin level.Therefore, the dental treatment should be performed by paying attention to these following considerations: 24,29 Consult all dental treatments planned with the hematologist.The dental treatment should be performed in a short time as possible and should be done after the patient receives blood transfusion.Do not do dental treatment when the hemoglobin level is less than 100 g/l.Provide antibiotics prophylaxis especially for children who have undergone splenectomy.If an orthodontic treatment is needed, the dental movement should be watched closely because there may be faster movement compared to the normal situation.The retention phase is also more difficult in these patients.

CONCLUSION
The anemic condition in beta major thalassemia patients makes patients lazy to clean their teeth that the oral hygiene becomes poor and a high caries index is found.The dentist, especially the pediatric dentist, should be careful in giving dental treatment.The cooperation with the hematology expert should be established in each treatment action.

Figure 1 .Figure 2 .
Figure 1.Beta mayor thalassemia genetic pattern. 7 on end appearance in the cranium and (B) Honeycomb appearance in the panoramic image.19,24