|Year : 2015 | Volume
| Issue : 2 | Page : 113-117
Consanguinity and clefts in the craniofacial region: A retrospective case-control study
Betty Anna Jose1, Subramani Arumugam Subramani2, Varsha Mokhasi2, Mini Jayan3
1 Department of Anatomy, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, Karnataka, India
2 Department of Plastic Surgery, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, Karnataka, India
3 Department of Statistician, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, Karnataka, India
|Date of Web Publication||17-Aug-2015|
Asst prof. Betty Anna Jose
Department of Anatomy, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru - 560 066, Karnataka
Source of Support: None, Conflict of Interest: None
Objective: The objective was to investigate the association between consanguinity and clefts in the craniofacial region. Materials and Methods: Sample consists of 179 non-syndromic cases of clefts in the craniofacial region and 200 healthy controls with no cleft or family history of clefting. A standardized questionnaire was prepared to investigate the information on the demographic characteristics and consanguinity. Chi-square and odds ratio were used to evaluate the risk of consanguinity in clefts in the craniofacial region. Results: There is a significant association between consanguinity and clefts (P = 0.001) when comparing the consanguinity and no consanguinity in cleft group and non-cleft group, and the association is more with the second degree consanguinity than the third degree consanguinity. Conclusion: Consanguinity is a risk factor for clefts in the craniofacial region.
Keywords: Cleft, consanguinity, risk factor
|How to cite this article:|
Jose BA, Subramani SA, Mokhasi V, Jayan M. Consanguinity and clefts in the craniofacial region: A retrospective case-control study. J Cleft Lip Palate Craniofac Anomal 2015;2:113-7
|How to cite this URL:|
Jose BA, Subramani SA, Mokhasi V, Jayan M. Consanguinity and clefts in the craniofacial region: A retrospective case-control study. J Cleft Lip Palate Craniofac Anomal [serial online] 2015 [cited 2019 Jul 17];2:113-7. Available from: http://www.jclpca.org/text.asp?2015/2/2/113/162965
| Introduction|| |
The cleft is a fissure or elongated opening occurring during the embryonic development due to the failure of parts to fuse. The clefts in the craniofacial region are the anatomical distortions of the cranium and face with deficiencies or excesses of tissue.  Bone and soft tissue alone or together are involved in clefts. The cleft results in the disfigurement and damage to the tissues. It affects the psychosocial development and causes a financial burden to the family of the affected. The corrective measures of the clefts start from the 1 st year of life and its follow-up is continued for decades depending upon the severity and the extent of the cleft. The cleft cases require a multidisciplinary approach.
The clefts in the craniofacial region are the most disfiguring among the craniofacial anomalies. The incidence of clefts in the Indian subcontinent is approximately between 27,000 and 33,000 clefts per year.  The most common cleft in the craniofacial region is the cleft lip and palate (CLP). The CL can occur alone or associated with cleft palate (CP). If the cleft affects only the palate it is called an isolated CP.
According to the multicentric study conducted in different regions of India, the CL with or without CP is 9.3/10,000 and CP alone (isolated CP) is 1.7/10,000.  The etiology of clefting is multifactorial. It includes both environmental and genetic factors. 
The objective of this study was to estimate the association between the consanguinity and the risk of offspring with cleft in the craniofacial region.
| Materials and Methods|| |
In this retrospective case-control study, 179 non-syndromic congenital cleft cases of the craniofacial region from South Indian population and a control group of 200 healthy normal children matched for gender and age with cases are included. It is a four years study from 2010 to 2014. During this period, 211 cleft cases were reported. Among this, syndromic clefts were excluded. The remaining 179 preoperative and postoperative cleft cases were included in the study. The clefts in this study were categorized into the craniofacial cleft, facial cleft, CLP, CL (cheiloschisis), and CP (palatoschisis). According to this, there were eight craniofacial clefts, seven facial clefts, 22 CL, 120 CLP, and 22 isolated CP cases. The cleft cases were collected from the Plastic Surgery Department and the Department of Maxillofacial Surgery, and the controls were collected from the Pediatrics and Obstetrics and Gynecology Departments. These cases were either in the hospital at the time of interview, or came for follow up, or were referred for surgery. Approval of Ethical Committee was obtained. The study group and their parents were interviewed and data collected about the consanguinity and the degree of consanguinity. The data also included the locality of residence, cleft type, date of birth, birth order, gender, laterality (affected side), and severity of the clefts. Informed written consent was obtained from the patients, who participated in the study or from their parents in case of minor.
| Results|| |
Chi-square test and odds ratio (OR) were done for statistical analysis using IBM SPSS, South Asia Pvt. Ltd. version 21 and P < 0.05 was considered statistically significant. Among the cases, 37% of parents had second or third degree consanguinity and in the control group it was found only in 6%. There was no association found between consanguinity and cleft type [Table 1] and [Table 2]. However, the association between consanguinity and cleft was highly significant [Table 3].
The second degree consanguinity found in the study was between the uncle-niece, double first cousins, and in grand-parents. The third degree consanguinity was between first cousins and in great grand-parents.
When comparing the consanguinity and no consanguinity in cleft group and non-cleft group, the consanguinity was statistically significant in cleft group. In the control group, the consanguineous relation of parents was very low [Table 3].
The second degree consanguinity was more than the third degree in cleft group and was statistically significant [Table 4].
When the second degree of consanguinity was compared with third degree consanguinity, the Test of proportion showed the risk of the cleft is more in second degree consanguinity than the third degree consanguinity (P < 0.001).
The OR showed increased risk (OR = 9.15, 95% confidence interval [CI] = 4.740-17.666) of consanguinity for cleft cases in this study. This association of cleft and consanguinity was highly significant (P < 0.001).
| Discussion|| |
A consanguineous marriage is the marriage between the blood relatives. These blood relatives have at least one common ancestor not more remote than a great-great-grandparent. In some parts of the world, the consanguineous marriage is common. In Kuwait, the incidence of consanguineous marriage is 54% and in France, UK, and USA it is only 2%. In India, the incidence of consanguineous marriage is between 5% and 60%. In the Indian subcontinent, uncle-niece marriages are commonly seen,  but in Kerala it is not between uncle-niece, it is between the first cousins. The first degree consanguinity is the genetic relationship between parent-child or between brother-sister. In this case, the proportion of gene sharing is 1/2 and risk of abnormality in the offspring is 50%. The second degree consanguinity is the relationship between uncle-niece, aunt-nephew, half-siblings, double first cousins, and grandparents to grandchildren. The third degree consanguinity is between first cousins, half uncle-niece, and great grandparents to great grandchildren. The proportion of shared genes is 1/4 in second degree and 1/8 in third degree. In second degree relationship, the risk of abnormality in offspring is 5-10% and in third degree it is 3-5%. ,, Thus, the risk of abnormality is decreasing as the degree of consanguinity increases. Considering these factors, the consanguinity and the cleft occurrence need to be evaluated. This study demonstrates the association between clefts in the craniofacial region and consanguinity in cleft group and control group. It also sheds light on the degree of consanguinity. The association of clefts shows that second degree consanguinity is more associated with the occurrence of clefts than the third degree consanguinity [Table 4]. In this study, when considering each cleft as a separate group, no cleft group showed statistically significant association with consanguinity. The consanguinity did not show any significance when CLP was considered as one group and all other clefts in another group. Comparing the cleft group with control group, the difference in the occurrence of clefts with the consanguinity is statistically significant.
It is a study from the south Indian population as the cases were available only from the south India. Another reason is that the Indian population has a heterogeneous origin, so study population of the particular geographic area can be more relevant than the general population. The syndromic cases of clefts were excluded as it has a different etiology.
In a Brazilian hospital-based case-control study, to investigate the association between parental consanguinity and non-syndromic orofacial clefts (NSOFC) showed that association was only with CL/P, with OR 3.8 and 95% CI = 1.27-12.18, and not with other clefts.  In a meta-analysis of 16 studies on parental consanguinity and NSOFC showed the association between consanguinity and NSOFC was statistically significant (P = 0.0003) with OR = 1.83 and 95% CI = 1.31-2.54. The six cross-sectional studies and 10 case-control studies included in the meta-analysis also showed a strong association of consanguinity and OFC. The OR implies parental consanguinity increased the risk 2 times to have a child with NSOFC. 
In our study, the OR is (OR = 9.15, 95% CI = 4.740-17.666) which is more than the meta-analysis. The parental consanguinity is 36.9% in cleft group and it is only 6% in control group [Table 3]. Consanguinity was reported in 31% cases in a study conducted in Iran.  In a 2 years study, on 370 subjects in Brazil showed 53.5% of CLP followed by 26.8% CP and 19.7% CL. The parental consanguinity was present in 5.7% and 26% had a familial history of clefts.  In a Saudi Arabian study, to investigate the influence of consanguinity in NSOFC, demonstrated that consanguinity was statistically higher in parents of CP cases than the CL with or without CP (CL/P) patients and the consanguinity is not related with the severity of cleft.  In our study, the consanguinity is found more in CL cases (54.5%) as in [Table 1].
In a hospital-based study on consanguinity and occurrence of OFC, reported 56.8% parents of cleft cases had a consanguineous relationship. It was also important that parents with consanguinity had a positive family history of clefts than those who were non-consanguineous and was statistically significant for OFC. However, recurrence among siblings did not find any significance with consanguinity.  The family history is not included in the present study.
A retrospective study in Brazil found consanguinity only in 6% non-syndromic CLP cases, and it was first degree consanguinity. The consanguinity was more frequent in CLP cases than CL cases.  There was a significant association between first degree consanguinity and bilateral CLP.  In our study, the consanguinity found was 37% and it was more frequent in CL cases than the CLP [Table 1]. There was no first degree consanguinity in our study.
As the degree of consanguinity increases, the abnormality and sharing of genes is reduced.  In our study, the second degree consanguinity is more (27.3%) than the third degree consanguinity (9.5%) in the cleft group whereas the consanguinity is only 6% in the control group. This shows the strong association of consanguinity with clefts. It is also significant that the second degree consanguinity is more associated with clefts than the third degree. This substantiates that the risk of abnormality is decreasing as the degree of consanguinity increases. This is because of the chance of sharing the gene from the common ancestor is reduced. 
In a South Indian study, conducted in Andhra Pradesh also showed the result of the significant correlation of cleft cases for the parents with consanguineous marriage. The poor nutrition was also found in addition to the consanguinity. The incidence of CLP in India was found 1.09 in every 1000 live births and CLP is predominant in India than isolated CP.  The present study is in accordance with this where CLP was more frequent than the other clefts. The Iranian study, showed that the consanguinity is a significant risk factor in oral clefts.  The consanguineous parents had a high risk of CL than the CLP.  Our study is in accordance with these studies where consanguinity is a risk factor for clefts. However, there is a differing result from the positive association of consanguinity and clefts. The association between consanguinity and oral cleft did not show any significance in a case-control study and among the cases, the consanguinity was 33.3%, which was slightly higher than the control group 31.7%. 
The association of consanguinity varies with the type of cleft. A case-control study reported the association of consanguinity was not statistically significant in CL (4.74%), CLP (17.46%) or in CP (8.28%).  However, the study from Belgaum showed there was a significant association of consanguinity with CL (27%) and CLP (63.5%) but not with CP.  The present study showed that consanguinity is more in CL (54.5%) followed by cranial and facial cleft (46.7%), CLP (34.2%), and least is in isolated CP (27.2%), when each cleft group was considered as a separate group. However, this was not statistically significant. When comparing the CLP as one group and all other clefts in another group, the consanguinity was more in other clefts (42.4%). There was only 34.2% consanguinity in CLP group and is not statistically significant [Table 2].
Parental consanguinity was found in 28% cases of clefts in an Iranian study.  The study in Jerusalem, Denmark, and China showed increased birth defects with parental consanguinity. ,, Another risk analysis study from China could not show any association of consanguinity with birth defects.  The parental consanguinity was a significant factor in the incidence of CLP. ,, In a study on craniofacial anomalies in Saudi Arabia showed 55% children with craniofacial anomalies to the parents who had consanguineous marriage.  The prevalence rate of CLP is low in Nigeria where the consanguineous marriage is less.  The consanguinity is a significant risk factor in causing cleft. ,,
In our study, the consanguinity is categorized according to its degree. The study group included only second and third degree consanguinity and no first degree consanguinity. The cleft group had 27.4% second degree consanguinity and 9.5% third degree consanguinity. The risk of abnormality is reduced in third degree consanguinity than the second degree and chance of sharing the gene is reduced to 1/8. There was a significant association between the consanguinity and clefts (P = 0.001) in the case-control group. This is similar to the study conducted in Jerusalem and Denmark. ,,
| Limitation of the Study|| |
The results would have been more relevant if each cleft group is compared with matched controls instead of considering all clefts in one group. The clefts other than CL with or without palate are less common, and it makes the comparison of each cleft group a difficult one. Each cleft type can be considered separately according to state and control group also can be considered from each state would have been given a better result.
| Conclusion|| |
The study shows that the consanguinity is associated with the occurrence of clefts. The awareness about the consanguinity and occurrence of genetic abnormalities should reach the individuals to avoid the occurrence. When illiteracy and poor nutrition is added up to the consanguinity the risk factor may increase. Further studies are required in that field along with or without genetic factors.
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[Table 1], [Table 2], [Table 3], [Table 4]