Craniofacial Characteristics of Thalassemia Major Patients

Objective: Thalassemias major are the most common autosomal recessive disorders; they are characterized by anomalies in the synthesis of the beta chains of hemoglobin and are often associated with varying degrees of craniofacial anomalies. The purpose of this study was to evaluate the craniofacial dimensions of b-thalassemia patients and to identify differences by comparing them to those of a control group.


Introduction
Thalassemia is an inherited blood disease demonstrating clinical differences, resulting in hypo chromic microcytic anemia, and is characterized by the lack or deficient production of alpha or beta globin protein chains.Thalassemia major is a term used to describe the condition of homozygote or combined heterozygote beta thalassemia patients.
Thalassemia major are a group of hereditary blood disorders characterized by absent or reduced b-globin chain synthesis that results in hypochromic microcytic anemia [1].Thalassemia major, also known as "Cooley' s anemia" or "Mediterranean anemia, " is the most severe form of beta-thalassemia; thalassemia major patients are homozygotes or compound heterozygotes for beta 0 or beta + genes [2].
The clinical onset of disease symptoms occurs in the last six months of the first age.Patients present with severe and progressive hemolytic anemia.Clinical findings include serious anemia, ineffective erythrocyte production, extramedullary hematopoiesis, and overaccumulation of iron as a result of blood transfusions.Treatment of the disease requires blood transfusions at regular intervals to prevent heart failure associated with profound anemia.Hypertrophy associated with excess erythropoiesis of the bone marrow and the extramedullary region is observed in patients who receive insufficient transfusions [2,3].The orofacial symptoms of thalassemia are due to bone changes associated with ineffective erythropoiesis.The bones become thinner, and pathological fractures may occur.Changes in facial and cranial bones have been identified as the overexpansion of the bone marrow results in a typical facial appearance.The craniofacial features of thalassemia major patients include larger cheekbones, a rodent or "squirrel-like" face, a depressed nasal bridge, and a protruding maxilla.The deformations of the "squirrel-like" face are attributed to multi-directional growth, covering the maxillary region in particular, and dental protrusion involving the affected teeth [4][5][6].Features characterized by prominent frontal and parietal bones, a collapsed nasal bridge, depression of the zygomaticus, and upward-slanted eyes are defined as a slightly mongoloid facial deformity in some patients [4,6].
Thalassemia major is widespread throughout Turkey; the frequency of carriers of the disease is 2.1%, and this rate increases to 10% in some areas.In Turkey, the number of homozygote b-thalassemia patients is estimated to be 4000, while the number of carriers of thalassemia major is estimated to be 1,300,000 [7][8][9].
Anthropometry is a method used in the measurement of compositions of bones, muscles, and fatty tissues in the human body [10].Craniofacial anthropometry involves the measurement of the skull and face [11].The numerical identification of the present disproportion of a morphological facial deformity is the main purpose of these measurements [11,12].Craniofacial anthropometry is a useful numerical identification method that assists clinicians to identify deformities and helps surgeons at the stage of reconstructive intervention [13].
In this study, our main purpose was to evaluate the craniofacial dimensions of thalassemia major patients and to identify differences by comparing them to those of a control group of comparable age, sex, and ethnicity.

Materials and Methods
Subjects Forty-three thalassemia major patients (22 females and 21 males) aged between 4 and 36 years from the pediatric or hematology clinics of state hospitals in Aydin, Turkey were included in the study group.The control group comprised 26 subjects (12 females and 14 males) with matched ages, ethnicities, and social backgrounds.All controls were healthy subjects with no history of craniofacial abnormalities or facial surgery.

Ethics approval
The study protocol was approved by the Human Ethics Committee of Adnan Menderes University and from Ministry of Health, Turkey.All subjects or their parents/guardians were informed about the study and signed the appropriate consent forms complying with the regulations of the Ethical Committee.

Craniofacial anthropometric measurements
All subjects or their parents were informed about the craniofacial anthropometric measurements.A total of 23 anthropometric measurements in six craniofacial regions (two on the head, five on the face, four on the nose, five on the eyes, three on the lips and mouth, and four on the ears) per subject were performed using calipers.Briefly, all landmarks were labeled on each subject' s face with a surgical marking pen.Linear measurements were taken directly on the labeled faces of the subjects while applying minimal pressure to the soft tissues, according to the Farkas method [14].

Results
The times required to perform the craniofacial measurements were approximately equal, aver-aging approximately 30 minutes per subject.Definitive statistics of the patient groups are given in Table 1.Comparisons of the craniofacial measurements in each region between the patient and control groups are shown in Tables 2 to 7.There was a difference in head circumference between the patients and control subjects; however, it was not statistically significant (p=0.051,Table 2).A general evaluation of the patients revealed that their face heights (n-gn), upper face lengths (n-sto), and lower face depths (t-gn) were significantly smaller than those in the control group (p<0.05,Table 3).These facial measurements in male patients were also significantly smaller than those in the control group; however, there were no significant differences in the facial measurements between the female subjects (p>0.05,Table 3).All patients' measurements in the nasal region were significantly different from the controls (Table 4).The nose height (n-sn) and nasal tip protrusion (sn-prn) measurements in males were significantly smaller than those of the controls.The nasal root width (mf-mf) and nose width (al-al) measurements in female patients were significantly larger than those of the controls; however, the nasal tip protrusion (sn-prn) measurements were significantly smaller than those of the controls (Table 4).Evaluation of the eye region measurements between the patient and control groups did not yield statistical significance (p>0.05,Table 5).The mouth widths (ch-ch) of all the patients were significantly smaller than the mouth widths of the controls (p<0.05).The upper lip heights (sn-sto) of all the patients were significantly larger than those of the controls (p<0.05);however, the lower lip heights (sto-is) were not significantly different from those of the controls (Table 6).The right and left ear widths of both male and female patients were not significantly different from those of the controls.However, the right and left ear widths of the entire patient group were measured to be smaller than those   of the controls (p<0.05).Ear lengths were not significantly different between the patients and controls (p>0.05,Table 7).

Discussion
Beta-thalassemia is distributed worldwide, particularly in Mediterranean countries.The Ministry of Health and National Hemoglobinopathy Council reported a 4.3% prevalence of the beta-thalassemia trait in 16 cities of the Turkish Mediterranean and Aegean region, which is more than twice the national thalassemia frequency [9].Uysal et al. (15) reported that the prevalence of the beta-thalassemia trait in Izmir, which is the neighboring city of Aydin, was the highest in the Aegean region of Turkey (4.96%).Therefore, premarital screening or other necessary precautions should be strictly followed to -the increased prevalence of beta-thalassemia in this region.
During our study, measurements were taken from six craniofacial regions of the thalassemia major patient group and the control group.A total of 23 measurements were taken (2, 5, 4, 3, 5, and 4 for the cranial, bilateral ophthalmic, nasal, oral, facial, and bilateral aural regions, respectively).The results of the measurements increased our understanding of the craniofacial anatomy of thalassemia major patients and enabled us to obtain quantitative results.Similarly craniafacial measurements were performed by Farkas et al. [16] on Down syndrome patients.The authors identified measurements above and below the normal levels using 23 linear and 2 angular measurements taken from six craniofacial regions of 127 Down syndrome patients [16].
Our literature review did not yield any study that craniofacial anthropometric measurements in thalassemia patients.According to a review of craniofacial cephalometric studies conducted on thalassemia patients, it was found that Takriti et al.
[17] had compared the skeletal and dental craniofacial parameters of 51 thalassemia major patients in Syria, obtained via lateral cephalometric radiograms, with the parameters of healthy subjects in the same age group.Class II malocclusion (where the upper teeth are more protruded than the lower teeth), maxillary prognathia and mandibular retrograph, rear face height reduction, and an increase in front facial height were identified [17].
In Qatar, Abu Alhaija et al. [5] conducted measurements of the lateral cephalograms of 37 thalassemia patients (24 males and 13 females between 5 and 16 years of age).The thalassemia group patients were found to have a class II skeletal model, and their maxillae were found to be normal in size; meanwhile, the smaller length of the cranial base was suggested to result from the short mandible [5].
Although our measurement methods were different, our measurements yielded a signifi-  Abu Alhaija et al. [5] suggested that the severity of craniofacial deformities (CFDs) in b-thalassemia major patients would increase depending on age and the duration of symptoms.In a study conducted in Malaysia, Toman et al. [6] studied the frequency of CFDs and their relationship with the clinical picture.In total, 19 of 43 patients were found to have a CFD (44.2%; safety range, 30.2% to 58.2%), while no significant difference was found in the comparison between the CFD+ and CFD− groups in terms of clinical parameters [6].
In a study conducted in India, Girinath et al. [18] showed that oral and maxillofacial changes such as protrusion of the upper and lower jaws, saddle-shaped nose, gaps and protrusion in the frontal teeth, and frontal bulges were observed in 84% of the patients.They emphasized that the severity of the orofacial changes would increase with declines in both the health and blood charts of the patients.Moreover, they suggested that the prevalence of oral and maxillofacial changes would decrease in patients who underwent blood transfusions at a young age [18].
The subjects enrolled in our study were those who received regular treatment and controls.Therefore, the deformities observed in our subjects were not severe.The ability to demonstrate certain differences during the visual examination of the head and face were rather limited in previously conducted studies.These studies focused on a single craniofacial complex or only evaluated the morphological changes of certain craniofacial deformities [5,17,18].Our study generated an extensive picture of all craniofacial complexes, and detailed data for visual examination were provided.The quantitative data obtained from the cranial and facial regions will assist in determining the defective elements to be surgically corrected in patients scheduled to undergo an operation.

Table 2 .
Comparison of head measurements between the patient group and the control group

Table 3 .
Comparison of facial measurements between the patient group and the control group Face width (zy-zy); face height (n-gn); upper face height (n-sto); midface depth (t-sn); and lower face depth (t-gn)

Table 4 .
Comparison of nasal region measurements between the patient group and the control group Nose width (al-al), nose height (n-sn), nasal root width (mf-mf ), and nasal tip protrusion (sn-prn)

Table 5 .
Comparison of the eye region between the patient group and the control group

Table 6 .
Comparison of the measurements of the lip and mouth region between the patient group and the control group