1- INTRODUCTION

Environmental, genetic, or idiopathic factors can lead to congenital abnormalities. Among the highly prevalent congenital disorders are orofacial anomalies including isolated cleft lip (CL), isolated cleft palate (CP), and cleft lip and palate (CLP) (1, 2). These orofacial anomalies are estimated to account for 1 out of every 500 to 1000 live births (3). Furthermore, Asian races are more prone to orofacial defects than other races and the least observed orofacial anomalies are among African races (4).

CL comprises 70% of all detected craniofacial anomalies and the incidence of CP and CLP without an association with another disease is lower than CL cases (5). Vallino-Napoli proposed that around 30% of orofacial anomalies occur coincidentally with other disorders (6). Around 300 syndromes have been found to present with a combination of an orofacial cleft and other congenital abnormalities (7). Beriaghi reported higher concomitant congenital malformations in CP than CLP (38.7% vs. 26.4%) (8). Natsume et al. reported the prevalence of coincident anomalies with CL, CLP, and CP to be 11.4%, 16.2%, and 20.7%, respectively (5). Sarkozi stated that 8 out of every 10 CP patients demonstrated no concomitant malformation (9).

Stoll et al. reported central nervous system anomalies to be the most commonly associated disorder with craniofacial disorder (10). However, Luijsterburg et al. found head and neck anomalies as the most commonly associated disorder with craniofacial disorders (11). Some studies reported musculoskeletal disorders to be the most commonly associated disorder in craniofacial defects (9, 12, 13). However, many other studies reported congenital heart disorders (CHDs) as the most commonly concomitant abnormality accompanying craniofacial defects (6, 14-17). The associated incidence of CHDs in orofacial clefts differs between various races. Shafi et al., in a study done on Pakistani children, found that around half of the children with orofacial defects suffered from CHDs (16), while Barbosa et al. reported this rate to be approximately 10% in Brazilian children (18). Another study in Taiwan reported a coincidence rate of 5.4% for craniofacial and cardiovascular anomalies (19) while Nancy et al. reported 6.7% (20).

As shown above, the literature has only reported the incidence rates, and we couldn’t find any study comparing the different congenital abnormalities between the different types of orofacial clefts. Thus, in this study, we aimed to assess the distribution and coincidence of cardiac anomalies between different orofacial defects.

2- MATERIALS AND METHODS

In this cross-sectional study, we enrolled all isolated cleft lip, isolated cleft palate, and cleft lip and palate patients referring to hospitals affiliated with the Mashhad University of Medical Sciences between 2015 and 2016. The patients’ records were extracted and the data was inserted into the researcher-made forms. The data comprised demographic features (age, gender, birth weight, and gestational age), type of orofacial cleft (isolated cleft lip, isolated cleft palate, or cleft lip and palate), presence or absence of auscultatory signs (e.g., murmurs or clicks) before echocardiography, presence or absence of congenital heart diseases, and the type of congenital heart disease.

The extracted data were entered into the software Statistical Package for Social Sciences (SPSS) version 20 for further analyses. After describing the quantitative statistics of frequencies and percentages, Chi-square test was used to compare the qualitative data. P-values under 0.05 were considered significant.

2-1. Ethical Considerations

All the patients’ parents or guardians gave their written consent after the study method and goal were explained to them and their records were coded and kept confidential. All the stages of the study were based on the Helsinki Declaration. Furthermore, the Ethics Committee of the Mashhad University of Medical Sciences approved the protocol of the study (Research code: 931608).

3- RESULT

Totally, 122 cleft lip and/or palate patients were enrolled in the study. 49.2% of the patients were male and 49.2% were female. The mean age of the patients was 36.26 months. The most commonly found type of orofacial anomaly was isolated cleft palate (52.5%), and the least found was isolated cleft lip (8.2%). Most of the patients were in the age range of 0-12 months (73.8%) while the other patients were placed into the ≥73 month group (6.6%). Cardiac anomalies were found in 57.4% of the patients. Table 1 shows the details of the above mentioned data. The patients also had a mean weight of 11.37 kg. According to the calculated Z-scores, the weight of 71 (58.2%) of the patients was more than the fiftieth percentile, 20 (16.4%) were between the tenth and the fiftieth percentiles, and 31 (25.4%) had a weigh less than the tenth percentile.

Seventy (57.4%) of the patients had cardiac anomalies. The most common type of cardiac anomaly was ventricular septal defect (VSD) comprising 25 cases. The least found anomaly was atrioventricular septal defect (AVSD) comprising only 3 cases. Furthermore, there was no significant difference regarding the type of cardiac anomalies between different orofacial clefts (p>0.05). Table 2 shows the details of the comparison of cardiac anomalies between different craniofacial defects.

Table 3 shows the comparison of age, gender, and birth weight Z-score between the different types of orofacial clefts. No significant difference was found regarding the age between different types of clefts (p=0.577); however, the differences regarding the gender were significant (p=0.019). Most of the females had isolated cleft palate (61.3%) and most of the males had cleft lip and palate (51.7%). In addition, no significant difference was revealed regarding the birth weight Z-score between different orofacial defects (p-value=0.010). The highest frequency of birth weight Z-score in the ≥0 group was found in the isolated cleft palate group (63.6%), in the 0 to -1.3 group the highest frequency was in the cleft lip and palate (61.3%), and in ≤ -1.3 the highest frequency was in the isolated cleft palate group (55.5%). Table 3 shows the above mentioned comparisons.

The patients who had positive findings in their history and physical examination (71.2 %) also showed positive findings in their echocardiography. However, around 40% of the patients without notable findings in their history and physical examination, had positive findings in their echocardiography (Table 4).

The differences were significant (p<0.001). History and physical examination had a sensitivity of 72% and specificity of 58% in detecting cardiac anomalies. Significant differences did not exist regarding the positive pathologic findings in the history and physical examination between different types of orofacial clefts (p=0.761). The parents of 45 patients with cardiac abnormalities had consanguinity, while 23 patients with these abnormalities had no consanguinity, and the differences were significant (p=0.023).

Although significant differences existed regarding having or not having pathologic findings in the history and physical examination for ventricular septal defect (VSD) and pulmonary stenosis (PS) (p=0.001 and 0.018. respectively), no significant difference was found in regard to the other anomalies. Also, no significant difference existed regarding consanguinity between the different types of clefts (p=0.559). Furthermore, no significant difference was found regarding the family history between different types of orofacial clefts (p=0.868).

Table 5 presents the comparison of the anomalies other than cardiac problems between different orofacial defects. The orthopedic problems had the highest frequency in the CLP group, and the isolated cleft palate group had the second position in showing high pathologic findings. However, none of these differences were significant (p>0.05).

4- DISCUSSION

Orofacial clefts are reported to be the most common congenital anomaly and in some cases accompany the congenital heart disease. However, the prevalence rate of this anomaly is not exactly known. Studies propose varying ranges from 1.5% to 63% for orofacial anomalies and CHDs coincidence (21, 22). Assessment of the prevalence of cardiac anomalies accompanied with orofacial clefts is important, since it can help in developing new protocols for screening and improving the existing ones.

We found that 57.4% (70.12) of cleft lip and/or palate patients had CHDs, concurrently. Most of the patients with orofacial defects had isolated cleft palate while the most common cleft in males was cleft lip and palate. The most and the least common cardiac anomalies were VSD and AVSD, respectively. However, there was no notable statistical difference regarding the different cardiac anomalies between different orofacial clefts.

Most of the patients with ≥0 Z-score had an isolated cleft palate. Patients with a Z-score between 0 and -1.3 had mainly cleft lip and palate, and those with a ≤ -1.3 Z-score were mostly cleft palate cases. No significant difference was found regarding the birth weight Z-score between different orofacial defects.

Similar to our results, Miri et al. reported the most common type of orofacial cleft to be the cleft palate (23). However, several other studies in Iran (24), Europe (25), Latin America (26), and India (27) proposed the cleft lip and palate to be the most frequent type. In our study, the cleft lip and palate was ranked second; and these differences may be due to different sample sizes in the studies. The importance of this epidemiologic finding is due to the fact that the isolated cleft lip and the cleft lip and palate can cause feeding problems. Thus, the high prevalence of these two problems is important.

Regarding the prevalence of CHD, different numbers have been reported. MO et al. reported a prevalence of 20% in 30 cases of isolated cleft lip and isolated cleft palate. Sun et al. reported a prevalence of 26% for orofacial cleft and CHD coincidence among 2180 studied cases (28). A study by Altunhan et al. in Turkey proposed a prevalence of 66% (29). Another study done on a US population reported a prevalence of 32.2% (8). The reported prevalence in Australia (6) was 33.3%, and in Taiwan (30) it was 56%.

Our study found VSD to be the most prevalent type of accompanying cardiac anomaly. However, many other studies proposed ASD to be the most common type of CHD accompanying orofacial problems (14, 28, 31-34). Two similar studies in France (35) and Japan (36) proposed VSD to be the most frequent type of cardiac anomaly in patients with orofacial clefts. However, we found no significant difference regarding the different types of cardiac anomalies between CP, CL, and CLP patients. Furthermore, there were no significant differences in cases of other anomalies including neurology, orthopedic, ENT, and urogenital problems.

Most of the patients (71.2 %) who had positive findings in their history and physical examination also showed positive findings in their echocardiography. However, only around 40% of the patients without notable findings in their history and physical examination, had positive findings in their echocardiography. The specificity and sensitivity of echocardiography in detecting associated cardiac anomalies were 72% and 58%, respectively; hence, the reported specificity and sensitivity were not enough to detect cardiac problems.

In short, CHDs are common congenital problems associated with craniofacial anomalies and hence, it is advisable that the patients be screened for cardiac problems. However, echocardiography could not satisfactorily fulfill the criteria for being a great screening tool. History and physical examination also missed 20 out of 122 patients. Thus, it seems that developing superior screening methods is required.

4-1. Limitations of the study

Our study, similar to other studies, had some limitations. One of them was its retrospective manner. Furthermore, we only had access to the data of a few health centers, and the causes of accompanying cardiac diseases with orofacial clefts remained unknown.

5- CONCLUSION

The aim of this study was to define the prevalence of the association of CHDs with orofacial clefts. We found that around 1 out of 2 patients with cleft lip and/or palate had some type of CHD. However, no statistical difference regarding the type of CHDs between different orofacial clefts was found.