INTRODUCTION

Hereditary hemoglobinopathies are common diseases that constitute a public health problem.1 Sickle cell anemia (SCA), one of these most common diseases worldwide, reaches a significant portion of the population.2–4 It is caused by a mutation in the beta globin gene of hemoglobin, which leads to an abnormal hemoglobin called hemoglobin S (HbS).2–5

The designation SCA is restricted to the form of the disease that occurs in homozygous (SS) children (ie, a child who receives from each parent a recessive gene determinant of the pathology). A heterozygous (AS) child receives only one parent recessive gene and does not develop the disease, but is a carrier of sickle cell trait (SCT). Studies have found a greater susceptibility to oxidation of HbS in these children, regardless of their genotype or its concentration, compared with oxidation of hemoglobin A.1,6

HbS has certain chemical characteristics: in situations of absence or reduction of oxygen tension it becomes unstable, does not support physical changes, and forms crystals. The red blood cell (RBC) bends and shapes in the form of sickle.2,5 This has consequences such as reduced ability to transport oxygen to the tissues, vasoclusive events, and shorter lifetime of the RBC.7,8 Constant production of RBC becomes necessary, which causes hyperplasia and compensatory growth of the bone marrow, possibly resulting in changes in bone structure that can be observed radiographically as postulated by Souza et al.9 and Natour et al.10 Craniofacial abnormalities may be noted, such as overgrowth/protrusion of the midface, maxillary expansion, predominantly vertical growth, mandibular retrusion, convex profile, and protruding maxila.11

Though SCA is one of the most studied diseases in the world, little is known about SCT, especially regarding craniofacial alterations. Thus, the aim of this study was to identify the craniofacial characteristics of patients with SCT and SCA and to compare these measurements with those of clinically normal subjects.

MATERIALS AND METHODS

A cross-sectional descriptive study was conducted that analyzed clinically normal patients, patients with SCT, and patients with SCA (n  =  45 (15 in each group); mean age  =  20.8 years). All patients enrolled in the Newborn Screening Program n Jequié, Bahia, Brazil. This study was approved by the ethics committee of Southwest Bahia State University under protocol 077/2011 (CAAE: 0057.0.454.000-11).

Patients with SCA and SCT were randomized into a treatment center for SCA. Patients in the control group belonged to the same community but did not have SCA or SCT.

Inclusion criteria were SCA or SCT verified by laboratory methods and no treatment with fixed orthodontics or facial orthopedics. Excluded were patients with congenital syndrome and craniofacial abnormalities, patients who had already undergone any facial surgery (bone or soft tissues), and patients who were fully edentulous.

Each subject underwent a radiographic recording of the skull in lateral view. The radiographs were taken by one radiologist using a conventional technique and the same equipment (Digital System X-ray Imaging PAX-400, Vatech Co Ltd, Lee, VA, USA). Images were acquired with a focal point of 0.5 mm, total filtration of 2.8 mm of aluminum and apparatus settings of 90 kVp and 10 mA, the latter determined according to the height of the patient.

To obtain the lateral cephalogram and cephalometric analysis, a sheet of transparent acetate paper was placed over each radiograph, and tracings were done using a 0.5 mm mechanical pencil (Pentel, Tokyo, Japan) under illumination from a negatoscope. Faced with a double image for bilateral structures, we chose to draw the left side. We used the following anatomic structures for the cephalometric tracing: facial profile, glabellar and nasal bones, average base of the skull, sella, orbit contour, pterigo-maxillary fissure, jaw, lower edge and posterior mandible, central incisors, upper and lower first molars, and upper and lower permanent molars. Reference points, planes, and angles used in the cephalometric analysis are shown in Figure 1. For error checking, 20 cephalometric radiographs were randomly selected and analyzed by the same examiner after an interval of 15 days. None of the variables showed statistically significant errors.

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Descriptive statistics are presented as mean ± standard deviation. Two-way analysis of variance was used to evaluate the effect of the group factor (sickle cell anemia × sickle cell trait × normal) alone or in interaction with the sex factor (group × sex). The normality of residuals was verified by the Shapiro-Wilk test, and variables with skewed distribution values were transformed to a logarithmic scale (log10). When the F test was significant (P ≤ .05) for the factor group, a Tukey or Tamhane post hoc test was conducted to determine differences between groups. Tamhane's test was used when the data presented heteroscedasticity (P ≤ .05 for Levene's test), and the Tukey test was used for the case of homoscedasticity (P > .05 for Levene's test). When the F test was significant (P ≤ .05) for the interaction between group and sex (group × sex), we proceeded with the interactive effect of the planned comparisons to determine differences between the sexes for each group.

In all analyses, the significance level was 5% (α  =  .05). The data were analyzed using IBM SPSS Statistics for Windows (SPSS. 21.0, 2012, IBM Corp, Armonk, NY).

RESULTS

The distribution of the sample according to evaluated groups and gender is shown in Table 1. The cephalometric analysis of data according to both groups is shown in Table 2. The analysis of variance showed significant effect for groups for the following variables: ANB, mandibular length, S line (upper lip), S line (lower lip), 1.NA (angle), 1-NA (distance), 1-NB (angle), amd 1-NB (distance). Multiple comparison tests showed that the average of the ANB and S line (upper lip) was higher in the SCA group than in the normal group, but there was no difference between the SCA and SCT groups or between the SCT and normal groups.

Table 1. Distribution of the Sample According to Evaluated Groups and Gender

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Table 2. Mean values ± standard deviations of cephalometric parameters, according to the groups

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The average 1.NA (angle) was lower in the SCA group (20,5 ± 7.3) than in the normal group (26.7 ± 4.8), but there was no difference between the SCA and SCT groups (24.6 ± 2.5) or between the SCT and normal groups. The average mandibular length was lower in the SCA (113.9 ± 8.2) and SCT (111.3 ± 9.7) groups than in the normal group (122.6 ± 8), but no difference was observed between the SCA and SCT groups. The average 1.NB (angle) was greater in patients with SCA (35.3 ± 6.2) and SCT (31.5 ± 4.1) than in the normal group (26.5 ± 5.8), but no difference was observed between the SCA and SCT groups. The average S line (lower lip) was higher in patients with SCT (3.4 ± 2.5) than in the normal group (1.1 ± 2), but there was no difference between the SCA (3.9 ± 4.2) and SCT groups or between the SCA and normal groups.

The average 1-NA (distance) and average 1-NB (distance) were higher in the SCT group (4.1 ± 0.3 and 3.7 ± 0.6, respectively) than in the SCA group (3.5 ± 0.5 and 3.07 ± 0.5, respectively), but no difference was observed between the normal and SCT groups or between the normal and SCA groups. There was a significant group × sex interaction for the variable SN-GoGn. The interactive effect of the planned comparisons showed that the average SN-GoGn differed between sexes only in the SCD group, where men exhibited higher values of SN-GoGn than women (Figure 2). There was no significant effect for groups or the group × sex interaction for the variables SNA, SNB, maxillary length, AFAI, palatal plane, and 1.1.

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DISCUSSION

A single cephalometric analysis may not be applied to all populations; the many differences in available studies are owing to the great variety in the characteristics of a determined population.11 The present study aimed to evaluate the craniofacial characteristics of patients with SCA and SCT and to compare these populations with a population of subjects not affected with this condition. Studies evaluating the craniofacial characteristics of patients with SCA are found in the literature,9,11 but nothing can be found about craniofacial characteristics of patients with SCT. Considering the high prevalence of SCA and SCT in the world, the absence of such data in the literature reveals the needed to better understand this large group of patients.

We found a high prevalence of SCA in women (73.3%), which is in line with the findings of Rosa and Magalhães12 and Ribeiro et al.13 Brown and Sebes14 studied 50 patients with SCA and 25 control subjects and found no significant difference in the SNA variable between them. One Brazilian study found an average of 84.56° for SNA, while Souza and colleagues9 showed an average of 85.42° and Altemus and Epps15 found an average of 86° in their samples. These studies reinforce our data, despite the lip advancement in the SCA group, because the average values were 83.0° for the SCA group, 82.1° for the SCT group, and 79.7° the for normal group. It is important to note that all values were within the standard deviation for this variable, based on the normative value for the SNA angle (82°). Despite the fact that there are no significant differences between these groups, it can be noted that, on average, patients with SCA showed the most maxillary projection, followed by patients with SCT, when compared with the normal group.

These partially results corroborate those of Souza et al.,9 Brown and Sebes,14 Mourshed and Tuckson,16 and Shnorhokian et al.,17 who reported that persons with SCA have maxillary protrusion that results from the increased bone marrow activity to compensate for the premature destruction of RBCs. But other studies, such as those of Maia et al.,11 Altemus and Epps,15 and Alves et al.18 concluded that SCA is a disease in which clinical manifestations are modulated by genetic variations and environmental factors. The value found by Fortes19 for black Brazilians with normal bite was 88.20°, which was considerably higher than the value found in our study, indicating that maxillary protrusion may not only be related to hemoglobinopathies but may also be related to racial issues.

In the study by Zuccato et al.,20 SNB angle, which expresses the mandible anteroposterior position relative to the skull base, showed an average of 78° (standard value  =  82°). It was also observed by Shnorhokian et al.,17 who also found decreased values for this angle (mean  =  77.6°), relative to the standard value they used (79.2°). The tendency to mandibular retrusion was also described by Altemus and Epps.15 In the present study, this variable was 77.5° for the SCA group, 78.3° for the SCT group, and 77.9° for the normal group. Compared with the standard value used by Ricketts21 (80°), patients with SCA and SCT had lower values, indicating a discreet mandibular retrusion.

The ANB angle (standard value  =  2°) shows the anteroposterior relationship between maxilla and jaw and, when increased, suggests facial features of patients with skeletal Class II. Souza and colleagues9 reported that the ANB (7.07°) for patients with SCA was higher than the standard value they used. In the study of Altemus and Epps15 the average was 6.1° (standard value  =  4°). In our study, the average ANB was also increased in the SCA group (5.47°) and the SCT group (3.80°). Claro et al.22 evaluated 50 Brazilian adults and found that 41% had a Class II skeletal pattern.

Maia et al.11 found smaller mandibular length in 76% of patients with SCA. These data confirm the values found in the present study, as the mean mandibular length was lower in the patients with SCA and SCT, though there was no significant difference between them, which corroborates the findings of Halstead23 that some heterozygous patients had abnormal bone development.

Fernandez et al.24 reported that the bones of the face are not often affected by marrow hyperplasia. When it does occure, however, the jaw and the orbital roof are the structures most commonly affected, confirming our findings.

The SN-GoGn angle, determined by the intersection of Steiner mandibular plane (GoGn) with the SN line, expresses the degree of mandibular plane opening, length of the mandibular branch, and vertical height of the anterior portion of the jaw. In the study of Souza et al.,9 this angle was higher (40.5°) than the angle found by Fortes19 (32.15°) and Ricketts21 (32°). Altemus and Epps15 also found increased values for this angle (38.7°) relative to the standard value used (32°). On the other hand, Shnorhokian et al.17 found a slight decrease in this angle (38°) compared with the standard value used as reference (38.2°). In the present study, the average SN-GoGn was lower in the SCA and SCT groups than in the normal group. The interactive effect of the planned comparisons showed that the average SN-GoGn differed between sexes only in the SCA group, in which higher values were observed in men than women.

CONCLUSION

• The facial features of patients with SCT are similar to the characteristics of clinically normal patients.

• Patients with SCA and SCT exhibit characteristics of Class II skeletal pattern.

• Patients with SCA and SCT did not shown compensatory maxillary expansion, which was determined by the normal jaw length and absence of maxillary protrusion.