Hussain Dashti,Devipriya Sundaram,Aref Ghayyath,Hassan Al-Jafar,Mariam Baghdady
Orofacial anatomical and occlusal changes in patients with sickle cell disease in Kuwait
Sickle cell anemia,Sickle cell disease,Cephalometric analysis,SNA angle,ANB angle,Malocclusion
Objective Sickle cell disease (SCD) is the most common hemoglobinopathy where morphologic changes to red blood cells affect the development of hard and soft tissues. The purpose of this study is to identify the craniofacial characteristics and maxillomandibular relationship in SCD patients and compare with unaffected subjects, through cephalometric radiographic assessment. Materials and Methods The study included 44 Kuwaiti SCD patients (20 female, 24 male) as well as 44 age and gender matched controls. Digital lateral cephalometric, radiographs were recorded. SNA and ANB angles were measured and compared. Results The mean SNA angle was found to be higher among the SCD cases (83.00 ± 3.22) than in controls (81.78 ± 4.58), but the difference was not statistically significant, (p = 0.146). The mean ANB angle in SCD cases (5.27 ± 2.36) was significantly higher, than that in controls (3.97 ± 2.23). The difference in means was statistically significant, (p = 0.01). Almost 50% of the SCD patients had class II malocclusion and 61.5% of the patients had prognathic maxilla. Conclusions Patients with SCD in Kuwait exhibited characteristics of skeletal class II pattern malocclusion. They also showed evidence of compensatory maxillary expansion.
Orofacial anatomical and occlusal changes in patients with sickle cell disease in Kuwait

Sickle cell disease (SCD) is the most common hemoglobinopathy where morphologic changes to red blood cells affect the development of hard and soft tissues. The purpose of this study is to identify the craniofacial characteristics and maxillomandibular relationship in SCD patients and compare with unaffected subjects, through cephalometric radiographic assessment.

The study included 44 Kuwaiti SCD patients (20 female, 24 male) as well as 44 age and gender matched controls. Digital lateral cephalometric, radiographs were recorded. SNA and ANB angles were measured and compared.

The mean SNA angle was found to be higher among the SCD cases (83.00 ± 3.22) than in controls (81.78 ± 4.58), but the difference was not statistically significant, (p = 0.146). The mean ANB angle in SCD cases (5.27 ± 2.36) was significantly higher, than that in controls (3.97 ± 2.23). The difference in means was statistically significant, (p = 0.01). Almost 50% of the SCD patients had class II malocclusion and 61.5% of the patients had prognathic maxilla.

Patients with SCD in Kuwait exhibited characteristics of skeletal class II pattern malocclusion. They also showed evidence of compensatory maxillary expansion.

Sickle cell disease (SCD) is an inherited blood disorder characterized by sickle-shaped red blood cells due to a mutation in the hemoglobin (Hb) gene on chromosome 11, which leads to the replacement of glutamic acid with valine in the beta chain. Sickle-shaped red blood cells have the propensity to obstruct blood vessels including capillaries, which restricts the blood flow leading to ischemia, infarction and aseptic necrosis of several tissues (Bunn, 1997). Repeated microinfarctions in both jaws cause multiple skeletal and dental malformations in patients with SCD, which disrupt craniofacial function and integrity (Al-Jafar et al., 2016). Compensatory hematopoiesis, hemolysis, and vaso-occlusive and avascular necrotic events in the maxilla and mandible result in craniofacial abnormalities such as maxillary protrusion and mandibular retrusion in patients with SCD (Costa et al., 2012), which subsequently cause malocclusion (Mello et al., 2012). The most prevalent malocclusion reported among patients with SCD is Class I malocclusion, although the exact etiology cannot be explained (Buschang, 2014). Class I malocclusion is characterized by a normal molar relationship and abnormal positions of the teeth, including rotation, spacing, overbite, open bite, and posterior and anterior crossbites. Class II malocclusion, both skeletal and dental, has also been observed in patients with SCD. A prognathic maxilla, retrognathic mandible, or a combination of both leads to Class II malocclusion (Freitas et al., 2005). Patients with severe class II malocclusions face difficulties in chewing, swallowing, phonation, and breathing. Additionally, psychosocial disorders related to malocclusion affect patients’ self-esteem and interpersonal relationships (Freitas et al., 2005). Moreover, they can experience orofacial complications related to their personal habits such as improper oral hygiene, dietary habits, and low socioeconomic conditions (Santos et al., 2013). SCD is typically mild in Kuwaiti patients with infrequent crises and other complications (Akar and Adekile, 2008). However, to date, no cephalometric studies or craniofacial data have been reported in patients with SCD in Kuwait. Therefore, the purpose of this study was to investigate the presence and type of malocclusion that is generally prevalent among patients with SCD in Kuwait. Based on the maxillary compensatory effect in patients with SCD, we decided to measure only two cephalometric angles in this study, SNA and ANB, which are skeletal parameters, not dental. SNA uses the skull base as a reference and indicates the anteroposterior position of the maxilla in relation to the cranial base, whereas ANB indicates the anteroposterior relationship between the maxilla and mandible. Therefore, in this study, SNA and ANB (Fig. 1a, Fig. 1b) were measured to determine the percentage and type of malocclusion observed among patients with SCD in Kuwait. These data were compared with cephalometric data collected from a healthy group matched for sex and age.

This comparative cross-sectional study recruited 44 patients with SCD (20 female, 24 male) from Al-Amiri Hospital who presented for routine dental check-ups. Human rights were protected, and ethical approval for conducting the study was obtained from the Ministry of Health. Among the 44 patients, 23, 11, 9, and 1 had sickle cell anemia (SCA), SCD with alpha-thalassemia, SCD with beta-thalassemia, and Hb C/sickle cell disease, respectively. All patients with SCD provided written informed consent. No participant presented with major craniofacial abnormalities or congenital syndromes, although some had a history of systemic complications associated with SCD such as splenectomy, cholecystectomy, pneumonia, and blood transfusion. No patient with SCD had bone metabolic diseases or had undergone radiation or chemotherapy. Edentulous patients, those who had completed or were currently undergoing orthodontic treatment, and those who had undergone orthognathic surgery were excluded. Patients with SCD were matched with a control group of 44 healthy individuals who were randomly selected from the archives of the Kuwait University College of Dentistry. Routine dental examination was performed on all participants with SCD at Kuwait University Dental Clinics, including facial examination, intraoral soft and hard tissue inspection, and radiographic examination. Certified dental practitioners obtained the following radiographs: panoramic, cephalometric, two mandibular right/left first molar periapical, and four bitewings. Further periapical radiographs were obtained as needed, for example, in case of pain in the area or teeth with large carious lesions. Furthermore, occlusal, and facial profile evaluations were conducted. The following rules were applied in accordance with the ethical research guidelines: 1. Patients who had undergone orthodontic treatment in the past were asked for their previous cephalometric radiographs to prevent further radiation exposure, unless they were interested in orthodontic re-treatment; 2. Panoramic, bitewing, and periapical radiographs were obtained as part of a regular dental check-up; 3. Patients with existing recent radiographs were not subjected to further radiation, and were asked to provide their recent radiographs for evaluation. SNA and ANB were measured using ImageJ, an application developed by the National Institutes of Health and the Laboratory for Optical and Computational Instrumentation, University of Wisconsin. Fig. 2, Fig. 3 show two patients with malocclusions in our study. Demographic, clinical, and radiographic data were recorded and statistically analyzed using SPSS software (version 25; IBM SPSS Statistics for Windows, Armonk, NY, USA). Means and standard deviations of the cephalometric variables were calculated and compared using Student’s t‐test for both patients with SCD and healthy controls. One-way analysis of variance and Dunnett’s multiple comparison test were used to analyze the differences between the control group and SCD subtypes. Differences were considered statistically significant at p < 0.05.

The demographics of the study sample and cephalometric measurements are shown in Table 1, Table 2, respectively. The mean age of controls was 33.32 ± 14.31 years while that of cases was 34.23 ± 16.32 years. Almost 50% of patients with SCD had class 2 malocclusion, and 61.5% had a prognathic maxilla. The mean SNA among the controls was 81.78 ± 4.58°, while that in cases was 83 ± 3.22°. Although the difference in means between cases and controls was not significant, the mean SNA was larger among participants with SCD (p = 0.146). The mean ANB among cases was 5.27 ± 2.36°, which was higher than that among controls (3.97 ± 2.23°). The difference in means was statistically significant (p = 0.01). Posthoc tests between SCD subtypes could not be performed, as one subtype had less than two cases. Dunnett’s multiple comparison test was performed, excluding this case. In our study sample, statistically significant variations in the mean SNA and ANB were not found among the subtypes of SCD. However, the mean ANB in the SCD with alpha-thalassemia subgroup was significantly different from that of the controls (p = 0.0024). Further analysis revealed no significant difference in the mean SNA and ANB between the controls and specific subtypes.

The Steiner method of cephalometric analysis was introduced in 1953 and is used as a diagnostic tool for orthodontic treatment planning. SNA and ANB are the major measurements in Steiner’s method for orthodontic treatment planning (Steiner, 1953, Steiner, 1960). Riedel was the first to use SNA and ANB to determine the anteroposterior jaw relationship cephalometrically, and since then, these angles have become an important part of many analyses (Riedel, 1950, Riedel, 1952, Riedel, 1957). Orthodontists utilize many cephalometric analyses, such as Down, Steiner, Tweed, Ricketts, Jerabek, and Bjorg, to describe dentofacial morphology and help in treatment planning. The analyses are based on the skeletal, dental, and soft tissue angles, and each criterion has advantages and disadvantages (Naragond, 2012). In our study, other dental and soft tissue measurements/angles were excluded, because we mainly focused on skeletal development. Furthermore, we mainly focused on maxillary development due to the higher chance of vaso-occlusion in the maxilla because of the higher vascularity of the maxilla compared to that of the mandible. In 2006, Al-Jame et al. established lateral cephalometric hard-tissue norms for adolescent Kuwaitis and compared them with previously published norms (Al-Jame et al., 2006). In our study, SNA and ANB in the control group were different from those reported by Al-Jame et al. (SNA, 83.04 ± 3.60°; ANB, 3.60 ± 2.16°) in Kuwaiti adolescents (13–14 years). This disparity is clearly due to the wider age range in the current study (12–75 years). Riedel (Riedel, 1952) published norms in American adults aged 18–36 years (SNA, 82.01 ± 3.89°; ANB, 2.04 ± 1.81°). Although the mean SNA was not statistically different from that in our control group, the mean ANB was significantly different. This could be explained by differences in racial profiles. In the present study, both SNA and ANB were larger in patients with SCD than in controls. The larger SNA indicates a prognathic maxilla, and the larger ANB suggests that patients with SCD generally exhibit a tendency for Class II malocclusion. In a study by Adekile et al., Hb SS (βS/βS) was the most common genotype followed by (Hb S-β-thal) and Hb S/Hb D-Punjab in Kuwait (Adekile et al., 2019). Similarly, in our study, Hb SS was the common genotype. In our study sample, based on the mean SNA values, patients with SCA showed the most maxillary prognathism, followed by those with SCD with beta thalassemia and SCD with alpha thalassemia, compared with the normal group. Further, the mean ANB was the largest in the SCD with alpha thalassemia group, followed by the SCA and SCD with beta thalassemia groups. The values of all subtypes showed a definite skeletal class II pattern. On comparing the mean SNA in the subgroups with those in controls, none of the differences in means were statistically significant. However, the mean ANB in the SCD with alpha-thalassemia subgroup was significantly different from that in the control group (p = 0.0024). This implies that on average, patients with SCD with alpha thalassemia exhibit features of skeletal class II malocclusion. Our findings were similar to those reported in Saudi Arabia (Basyouni et al., 2018). The mean SNA among patients with SCD was 86.7 ± 3.5°, while the mean ANB was 9.9 ± 3.2°. A summary independent samples t-test between patients with SCD in Saudi Arabia and Kuwait showed a significant difference in the means of both SNA and ANB. This difference could be related to selection bias, as the age range in the Saudi study was 12–18 years while that in the present study was 12–74 years. The Saudi study included participants in the bone-growth phase with unstable malocclusion, whereas our study participants had completed bone growth; therefore, a higher incidence of malocclusion can be expected. Pithon et al. concluded that patients with SCA and sickle cell trait exhibited characteristics of class II skeletal pattern. The findings in our study, especially the larger ANB, corroborate these findings (Pithon et al., 2014). In patients with SCD, vaso-occlusion and restricted blood flow, which lead to reduced oxygenation, are compensated by extramedullary hyperplasia. The maxilla has a wider medullary cavity and thinner cortical bone than the mandible, allowing for further compensatory growth that increases oxygenation in the region to avoid hypoxia and infarction (Brown and Sebes, 1986). Consequently, maxillary expansion and bone deformities occur (Costa et al., 2012). Few studies have suggested alterations in the positioning of the mandible in patients with SCA (Altemus and Epps, 1974, Licciardello et al., 2007, de Souza et al., 2008, Shnorhokian et al., 1984). Our study showed that either mandibular retrusion or short mandibular length is observed in these patients. Some studies have associated maxillary protrusion with SCD, which theoretically induces bone-marrow hyperplasia (Mourshed and Tuckson, 1974, Brown and Sebes, 1986, Oredugba and Savage, 2002, Shnorhokian et al., 1984, de Souza et al., 2008). In contrast, other studies concluded that no maxillary protrusion but shorter mandibular length is observed in patients with SCD (Maia et al., 2011, Altemus and Epps, 1974). These studies support the hypothesis that environmental and genetic factors affect clinical manifestations of SCD. Interestingly, Jacobson and Bandeen found that patients with SCD have reduced craniofacial dimensions, contradicting the compensatory bone marrow hyperplasia hypothesis (Jacobson and Bandeen, 2006). In Nigeria, 50% of patients with SCD demonstrate severe malocclusion (Onyeaso and DaCosta, 2009). Schiliro et al. (1992) reported severe craniofacial abnormalities in African black patients with SCD (Schiliro et al., 1992). Licciardello et al. indicated that Sicilian patients with SCD present with moderate craniofacial changes, whereas patients with SCD in Saudi Arabia and India show milder forms of craniofacial changes (Licciardello et al., 2007). Santos et al. reported a slight maxillary protrusion associated with mandibular retrusion in Brazilian individuals with SCD of African descent, which contradicts previous studies in the black population. However, they did not include a control group in their study, which resulted in a lack of cephalometric normalization in patients with SCD, thus limiting their results. Due to slave trading in the fifteenth and nineteenth centuries, SCD spread worldwide, especially in the Americas. When these abducted individuals integrated into the new society, less severe forms of SCD developed owing to genetic diversity (Santos et al., 2018). In a recent critical literature review, the prevalence of malocclusion was reported to be high in patients with SCD, considered a risk factor. Moreover, the malocclusion was very severe compared to that in healthy participants (Costa et al., 2015, Lopes et al., 2021). The results of the above studies indicate that populations of different origins have different characteristics. In addition, age plays an important role since individuals who are still growing demonstrate different changes from those who have reached skeletal maturity. The main limitation of our study is its cross-sectional design. A critical review of the literature by Costa et al. concluded that there is a lack of evidence regarding SCD as a causative factor for craniofacial bone abnormalities and dental malocclusion (Costa et al. 2012). Inappropriate study design, lack of estimates of association, and lack of hypothesis testing are some of the limiting factors. They proposed that a cohort study was the most appropriate for making inferences. In addition, age and bone-growth phases must be considered during sample selection. Among the studies included in their review, only two studies had samples matched for age and sex, as in the current study.

• Patients with SCD had a different craniofacial morphology than controls. Moreover, they had larger SNA and ANB angles. • It is recommended that the orthodontic treatment needs of patients with SCD be met at the appropriate time to improve their quality of life. • Public health policies and community programs are needed to create awareness for the early recognition of the disease and to seek help. • This study is the first of its kind in Kuwait and reports craniofacial traits in patients with SCD and in age- and sex-matched controls. • Future cohort studies with larger sample sizes and a more uniform distribution of cases across subtypes are recommended. 

The authors declare that the work has been approved by the appropriate ethical committee related to the institution in which it was performed, and the patients gave informed consent. The work described in the article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans and Uniform Requirements for manuscripts submitted to Biomedical journals.

Hussain Dashti: Conceptualization, Methodology, Investigation, Writing – original draft. Devipriya Sundaram: Formal analysis, Writing – original draft, Writing – review & editing. Aref Ghayyath: Software, Investigation. Hassan Al-Jafar: Resources, Supervision. Mariam Baghdady: Software, Investigation.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.