- Email: [email protected]
or palate anomaly
Int. J. Oral Maxillofac. Surg. 2007; 36: 200–206 doi:10.1016/j.ijom.2006.10.012, available online at http://www.sciencedirect.com
Clinical Paper Congenital Craniofacial Deformities
Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly
M. Zandi1, A. Miresmaeili2 1 Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Hamedan University of medical sciences, Hamedan, Iran; 2Department of Orthodontics, Faculty of Dentistry, Hamedan University of medical sciences, Hamedan, Iran
M. Zandi, A. Miresmaeili: Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly. Int. J. Oral Maxillofac. Surg. 2007; 36: 200–206. # 2006 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. The purpose of this retrospective case-control study was to compare the cephalometric features of parents of children with cleft anomalies to those of parents of normal children in the hope of finding potential markers of predisposition for this condition. There were 22 sets of parents of cleft children (study group) and 22 sets of parents of normal children (control group). A total of 88 lateral cephalograms were traced twice by two observers separately and analyzed using Student’s t-test. Seven linear, two angular and five triangular cephalometric variables were measured. Mandibular body length (Go–Gn) in mothers was larger in the study than the control group, posterior cranial base (S-Ba) in fathers was shorter in the study than the control group, anterior maxillary triangle (S.N.A) in parents in the study group was larger than in the control group and posterior maxillary triangle (S.N.Pns) in study group mothers was larger than in control group mothers. In conclusion, the craniofacial morphology of the parents of children with cleft anomalies differs from that of parents of normal children and may have some predictive value.
Orofacial clefts are one of the most frequently encountered congenital malformations. They are produced by genetic and environmental factors and exhibit an interesting racial predilection, being less frequent in black people and more common in those of Oriental descent. Many studies have shown that identification of the individuals at risk of producing a child with a cleft anomaly using only a genetic approach is very difficult at the present 0901-5027/030200 + 07 $30.00/0
time. The genetic assessment of parents for this risk should be supplemented with craniofacial data analysis16. Many investigators have reported that the craniofacial morphology of the parents of children with orofacial clefting differs from that of normal individuals6–8,13,17–21. MCINTYRE & MOSSEY in a systematic review of fifteen cephalometric studies investigating the craniofacial morphology of the parents of children with orofacial
Key words: cephalometry; cleft palate; cleft lip; craniofacial morphology; parents. Accepted for publication 4 October 2006
clefting found that, although the craniofacial morphology of such parents differs from that of the parents of normal children, the data from these studies are conflicting and insufficient to accurately localize these differences, so further studies are required15. The objective of this study was to compare the cephalometric features of parents of affected and normal children, and to correlate the results with those of
# 2006 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Cephalometric features of parents of children with cleft deformities
201
other investigators, in the hope of finding some cephalometric features that could act as markers of predisposition of parents to have a child with a cleft deformity. Cephalometric analysis could then be used in conjunction with genetic screening to identify ’at-risk’ parents. Materials and method
The subjects of this study were 22 sets of parents (22 mothers and 22 fathers) of children having cleft anomaly (study group) and 22 sets of parents (22 mothers and 22 fathers) of normal children. All parents who participated in this study had no experience of previous surgical and orthodontic treatment, no history of injury to craniofacial structures and no gross skeletal defect. All of them were drawn from Hamedan, one of the 30 provinces of Iran, so ethnic variability of craniofacial morphology was eliminated (the race of the sample studied is Aryan). The mean age of the mothers and fathers in the study and control groups at the time the cephalograms were taken was 30.41, 33.45, 31.04 and 32.85 years, respectively (Table 1). A total of 88 lateral cephalograms of the study and control groups were traced on acetate paper, twice by two observers separately, with an interval of approximately 40 days between replicate tracings. The intra-observer and inter-observers errors were insignificant for purposes of statistical analysis. Landmarks for lateral cephalograms used in this study are shown in (Fig. 1). Seven linear, two angular and five triangular lateral cephalometric variables were measured (Table 2). Some of these variables that are not commonly used are as follows: anterior maxillary triangle (S.N.A): a triangle constructed by joining the points S, N and A (Fig. 2); posterior maxillary triangle (S.N.Pns): a triangle constructed by joining the points S, N and Pns (Fig. 3); mandibular triangle (Co.Gn.Go): a triangle constructed by joining the points Co, Gn and Go (Fig. 4); cranial base triangle (S.N.Ba): a triangle constructed by joining the points S, N and Ba (Fig. 5); nasopharyngeal triangle (S.Pns.Ba): a triangle constructed by joining the points S, Pns and Ba (Fig. 6).
Fig. 1. Landmarks: N,nasion; S,sella; A,subspinale; Ans,anterior nasal spine; Pns,posterior nasal spine; Go,gonion; Gn, gnathion; Co,condylion; Ba,basion.
Fig. 2. Anterior maxillary triangle.
With all variables, the mean values obtained for mothers, fathers and parents in the study group were compared with the mean values of their counterparts in the
control group. These were subjected to statistical evaluation using Student’s t-test and the statistically significant differences between the groups evaluated by calculating the P-value.
Table 1. Age of parents in years Study group Range Mean
Control group
Fathers
Mothers
Fathers
Mothers
22–48 33.45
18–46 30.41
23–48 32.85
22–46 31.04
Results
The mean and standard deviation values of the cephalometric variables of the
Asterisks indicate a significant difference between corresponding values in study and control groups. * P < 0.01.
Control group (N = 22)
80.72 3.92 129.93 6 55.73 3.93 122.4 8.37 47.46 3.73 54.22 4.28 47.98 3.57 80.23 5.72 110.25 6.15 2207.53 217.83* 1716.68 194.14 2479.8 445.87 1334.9 198.1 962.91 133.73 81.13 3.99 131.71 5.83 56.97 4.04 123.77 8.23 47.58 4.28 54.7 3.89 49.25 3.68 81.02 4.73 111.18 5.71 2297.41 208.58* 1794.52 193.18 2470.64 432.57 1319.8 236.1 984.44 144.26 82.15 3.83 128.87 5.35 57.55 3.29 128.42 6.32 49.82 2.63* 55.6 4.29 50.4 2.59 83.95 4.57 113.65 5.37 2314.67 211.96 1845.81 162.19 2782.38 345.6 1454.56 154.9 1051.43 104.21 79.5 4.14 130.89 6.36 54.33 3.86 116.58 5.95 45.37 3.1 52.77 4.45 45.85 2.78 76.22 4.76* 106.79 4.67 2087.27 196.2 1581.31 117.1* 2145.62 316.16 1210.07 155.25 871.56 88.93 SNA NSBa Ans-Pns Co-Gn SBa N-Ans S-Pns Go–Gn N-Ba Anterior maxillary triangle Posterior maxillary triangle Mandibular. triangle Cranial base triangle Nasopharyngeal triangle
79.45 3.95 123.6 5.81 55.12 3.01 117.52 5.92 44.85 3.38 53.5 3.86 46.81 2.07 78.79 4.13* 108.6 4.78 2173.44 174.96 1655.75 124.1* 2250.84 345.78 1168.17 150.16 890.21 104.21
82.47 3.34 129.22 5.11 58.80 4.09 129.57 5.89 49.5 4.5* 55.75 4.23 51.65 3.29 83.6 5 113.92 5.82 2402.87 208.8 1921.82 161.5 2732.63 418.7 1456.16 226.8 1065.51 132.2
Study group (N = 22) Control group (N = 22)
Fathers
Study group (N = 22) Control group (N = 22)
Mothers
Study group (N = 22) Measurements
Midparents
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Table 2. Mean and standard deviation values of the lateral cephalometric measurements
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experimental and control groups are presented in Table 2. The most significant differences in craniofacial morphology between mothers of affected and normal children were mainly expressed in mandibular body length (Go– Gn) and posterior maxillary triangle (S.N.Pns). The mandibular body length (Go–Gn) and the posterior maxillary triangle (S.N.Pns) were significantly larger in mothers of children having cleft anomalies (P < 0.01). All the other measurements were almost the same in mothers of the study and control groups. Only the length of posterior cranial base (S-Ba) proved to be significantly different for fathers of affected children as compared to fathers of normal children. The fathers in the study group had a significantly shorter posterior cranial base (SBa) than those in the control group (P < 0.01). All the other measurements were not significantly different between fathers of affected and normal children. A significant difference between parents of affected and normal children was noted in the anterior maxillary triangle (S.N.A), which was larger in experimental group parents than in those of the control group (P < 0.01). None of the other measurements showed any significant difference between parents of affected and normal children. Discussion
The etiology of facial clefting is complex and has been extensively investigated. There are both major and minor genetic influences involved, with variable interactions from environmental factors. The relative contribution of each factor for an individual case is unknown, and even in those individuals whose genetic backgrounds verify familial tendencies for facial clefting, the mode of inheritance is complex and not completely understood. Some important findings have recently come from studies of syndromic forms of facial clefting. These include several genes that have been shown to have a major effect in the etiology of clefting4,5,10,12,14,22–24. For example, it has recently been demonstrated that the interferon regulatory factor-6 (IRF6) gene plays a role in causing Van der Woude syndrome, the most common of the syndromic conditions5,22,24. These genes have been used to demonstrate a significant overlap between syndromic and non-syndromic forms of orofacial clefts. As several hundred different genetic causes of cleft lip and palate may be
Cephalometric features of parents of children with cleft deformities
Fig. 3. Posterior maxillary triangle.
underlined by different changes in the basic DNA structure, understanding the genetic component of each individual form of the condition is extremely difficult. Environmental factors and a variety of unknown causes that play some role in producing cleft deformities make the problem even more complicated. For example, the concordance rate in monozygotic twins is approximately 25–45%5. This lack of total concordance illustrates the importance of environmental factors in the etiology of orofacial clefting.
Fig. 4. Mandibular triangle.
Orofacial clefting arises as a complex multifactorial trait, being a myriad of Mendelian patterns exhibiting varying levels of penetrance, sex differences and environmental overlays, with the result that identification of the individuals at risk for producing a child with a cleft using only a genetic approach is very difficult at the present time. In this study, based on the results of many other studies6–8,13,17–21, a supplementary approach of craniofacial data analysis was investigated to identify ’at-risk’ individuals.
203
In order to compare the craniofacial morphology of parents of children with cleft anomalies and parents of non-cleft children, 14 lateral cephalometric variables were measured. The main significant differences between the two groups were with regard to mandibular body length (Go–Gn), posterior cranial base (S-Ba), anterior maxillary triangle (S.N.A) and posterior maxillary triangle (S.N.Pns), as shown in (Fig. 7). One of the most consistent findings concerning the craniofacial morphology of parents of cleft children was the increase in mandibular body length. The mandibular body length (Go–Gn) in mothers in the study group was larger than in mothers in the control group (P < 0.01) (Fig. 7B). Similarly, MOSSEY et al. observed a significant increase in mandibular body length (Go–Gn) in mothers of children with cleft anomalies17. PROCHAZKOVA & VINSOVA in their Czech study found that the fathers of children with cleft anomalies have a larger mandible19. RAGHAVAN et al. did not observe a significant difference in mandibular body length between their study and control groups, but they had not segregated fathers and mothers in their investigation20. The fathers in the study group had a shorter posterior cranial base (S-Ba) than those in the control group (P < 0.01) (Fig. 7A). This finding is in contrast to the findings of MOSSEY et al.17 who found a larger posterior cranial base in their study group. As some information may be lost when craniofacial morphology is assessed with traditional linear and angular measurements, five triangular variables were also used, and two were found to be significantly different between the study and control groups. These triangular variables have not been used in previous studies. The anterior maxillary triangle (S.N.A) in parents of the study group was larger than in those of the control group (P < 0.01) and the posterior maxillary triangle (S.N.Pns) in mothers of the study group was larger than in those of the control group (P < 0.01) (Fig. 7C and D). These findings may indicate that the parents of children with cleft anomalies have a larger nasomaxillary complex, but further studies are required for confirmation. In this study the cranial base angle, upper anterior facial height and palatal length did not show any significant differences between the two groups. Other investigators found that these three measurements differed between study and control groups, but their results were conflicting6–8,13,17,18,20,21.
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Fig. 5. Cranial base triangle.
Craniofacial development is a highly complex phenomenon that is largely determined genetically and is dependent on a spectrum of signaling molecules, transcription factors, growth factors and cell–cell interactions. Any disturbance of this coordinated process can result in a facial anomaly such as clefting. The craniofacial morphology that is characteristic of parents of children with nonsyndromic facial clefting is not inherited following Mendelian rules (autosomal
Fig. 6. Nasopharyngeal triangle.
dominant or recessive and X-linked dominant or recessive) and is different from the morphologic features of the cleft-affected children. One widely accepted model to explain the genetic basis of non-syndromic cleft anomaly is the multifactorial threshold model. According to this model, the risk of cleft anomaly is assumed to be continuously distributed in the population and to be determined by multiple factors, some genetic and others environmental, with a
threshold dividing the population into unaffected and affected groups. The hypothesis to be tested by this study is that the parents of children with facial clefting are characterized by some cephalometric features that can be used as a marker of predisposition for having a child with a cleft deformity. The individuals who have more of these landmarks are more at risk of having a cleft-affected child, and their children are nearer to the threshold point. If enough of the predisposing factors (genetic and environmental) are present, the embryo of such parents is pushed over the threshold and becomes affected by a cleft deformity. So, a parent with cephalometric features characteristic of at-risk individuals may have an affected child with cephalometric features characteristic of cleft patients. Comparing the results of this investigation with other cephalometric studies, it can be concluded that the craniofacial morphology of the parents of children with cleft anomalies differs from that of the parents of normal children, but the results are not sufficiently consistent to accurately localize these differences. These conflicting results may be due to: (a) methodological differences between various studies; (b) sex and age differences between samples of parents studied; (c) wrong assumption that both parents have equal role in contributing predisposing factors to an affected child; (d) geographic and ethnic variability in craniofacial morphology. Considering (c), there is an accumulation of evidence suggesting that the predisposing factors are unevenly distributed within parental pairs and may be heavily weighted to one parent15,17. Many previous studies investigating the cephalometric features of the parents of children with orofacial clefting have not segregated males and females in their analysis, but have compared the parents en masse, and this method does not allow for one parent to confer more of a predisposing factor on an affected child. MOSSEY et al. segregated the fathers and mothers in their study and observed a significant increase in mandibular body length (Go–Gn) in mothers of children with cleft anomalies17. Similarly, FIGALOVA et al.11 and BLANCO et al.3 found that only the mothers of children with orofacial clefting have differences in certain cephalometric measurements. PROCHAZKOVA & VINSOVA in their study found that the fathers of children with cleft anomaly have a larger mandible19. The results of these investigations indicate the importance of segregating males and females in cephalometric studies.
Cephalometric features of parents of children with cleft deformities
205
Fig. 7. Histograms showing main significant differences in lateral cephalometric variables between study and control groups: (A) SBa in fathers, (B) Go–Gn in mothers, (C) Posterior maxillary triangle in mothers, (D) Anterior maxillary triangle in parents.
With regard to (d), many studies have demonstrated that there is ethnic and geographic variability in craniofacial morphology, and the norms and standards of one racial group cannot be used without modification for another racial group1,2. The race of the Iranians is Aryan. In a study, DAVOODY & SASSOUNI investigated the dentofacial pattern differences between Iranians and American Caucasians and concluded that the Iranians have a straighter profile, smaller anterior and posterior facial height and smaller interincisal angle9. The present study differs from previous similar investigations in the following ways. (1) In order to allow fathers and mothers to confer predisposing factors to the children separately, fathers were compared with a male control group, mothers with a female control group and midparents with midparents in the control group. It was found that some measurements differ only in the paternal or maternal group. (2) Five triangular variables were used that had not been used in previous cephalometric studies. It was found that two of these triangular variables were significantly different between the study and control groups. This indicates that some information may be lost when craniofacial morphology is assessed with simple linear and angular measurements, and there should be a trend toward assessing craniofacial structures three dimensionally. Further consistent cephalometric studies, particularly using postero-anterior cephalometry, are required to evaluate
the non-cleft parental craniofacial complex, and the information derived from conventional cephalometric studies should be supplemented with that obtained using 3-dimensional cephalometric analysis and morphometric measurements such as thin plate spline analysis and finite element morphometry. Craniofacial measurements are tools that in conjunction with genetic screening would allow more accurate identification of the individuals at risk of producing a child with a cleft anomaly. References 1. Alcalde RE, Jinno T, Pogrel MA, Matsumura T. Cephalometric norms in Japanese adults. J Oral Maxillofac Surg 1998: 56: 129–134. 2. Altemus LA. A comparison of cephalofacial relationships. Angle Orthod 1960: 30: 223–239. 3. Blanco R, Cifuentes L, Maldonado MJ, Rameaue MX, Munoz MA. Cleft lip and cleft palate, cephalometric features of affected individuals, their relatives and control population. Rev Med Chil 1992: 120: 13–19. 4. Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, NewburyEcob R, Hennekam RC, Van Buggenhout G, van Haeringen A, Woods CG, van Essen AJ, de Waal R, Vriend G, Haber DA, Yang A, McKeon F, Brunner HG, van Bokhoven H. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 1999: 99: 143–153. 5. Cobourne MT. The complex genetics of cleft lip and palate. Eur J Orthod 2004: 26: 7–16.
6. Coccaro PJ, D’Amico R, Chavoor A. Craniofacial morphology of parents with and without cleft lip and palate children. Cleft Palate J 1972: 9: 28–38. 7. Cronin DG, Hunter SW. Craniofacial morphology in twins discordant for cleft lip and/or palate. Cleft Palate J 1980: 17: 116–126. 8. Dahl E. Craniofacial morphology in clefts of lip and palate. Acta Odontol Scand 1970: 28(Suppl.):1–167. 9. Davoody PR, Sassouni V. Dentofacial pattern differences between Iranians and American caucasians. Am J Orthod 1978: 73: 667–675. 10. Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, SanchezFranco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003: 33: 463–465. 11. Figalova P, Hajnis K, Smahel Z. The interocular distance in children with cleft before the operation. Acta Chir Plast 1974: 16: 65–77. 12. Gorski SM, Adams KJ, Birch PH, Friedman JM, Goodfellow PJ. The gene responsible for X-linked cleft palate (CPX) in a British Columbian native kindred is localized between PGK1 and DXYS1. Am J Hum Genet 1992: 50: 1129–1136. 13. Kurisu K, Niswander JD, Johnston MC, Mazaheri M. Facial morphology
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as an indicator of genetic predisposition to cleft lip and palate. Am J Hum Genet 1974: 26: 702–714. Lidral AC, Romitti PA, Basart AM, Doetschman T, Leysens NJ, DaackHirsch S, Semina EV, Johnson LR, Machida J, Burds A, Parnell TJ, Rubenstein JL, Murray JC. Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. Am J Hum Genet 1998: 63: 557–568. McIntyre GT, Mossey PA. The craniofacial morphology of the parents of children with orofacial clefting: a systematic review of cephalometric studies. J Orthod 2002: 29: 23–29. Mossey PA, Arngrimsson R, McColl J, Viatner GM, Connor JM. Prediction of liability to orofacial clefting using genetic and craniofacial data from parents. J Med Genet 1998: 35: 371–378. Mossey PA, McColl J, O’Hara M. Cephalometric features in the parents of children with orofacial clefting. Br J Oral Maxillofac Surg 1998: 36: 202–212. Nakasima A, Ichinose M. Characteristics of craniofacial structures in parents of
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children with cleft lip and/or palate. Am J Orthod 1983: 84: 140–146. Prochazkova J, Vinsova J. Craniofacial morphology as a marker of predisposition to isolated cleft palate. J Craniofac Genet Dev Biol 1995: 15: 162–168. Raghavan R, Sidhu SS, Kharbanda OP. Craniofacial pattern of parents of children having cleft lip and/or cleft palate anomaly. Angle Orthod 1994: 64: 137–144. Sato T. Craniofacial morphology of parents with cleft lip and palate children. Shikwa Gakuho 1989: 89: 1479–1506. Stanier P, Moore GE. Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet 2004: 13(1):R73– R81. Suzuki K, Hu D, Bustos T, Zlotogora J, Richieri-Costa A, Helms JA, Spritz RA. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palateectodermal dysplasia. Nat Genet 2000: 25: 427–430.
24. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 2004: 351: 769–780. Address: Mohammad Zandi Department of Oral and Maxillofacial Surgery Faculty of Dentistry Hamedan University of medical sciences Felestin square Hamedan Iran Tel: +98 811 8231322 Fax: +98 811 8231322 E-mail: [email protected]
Clinical Paper Congenital Craniofacial Deformities
Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly
M. Zandi1, A. Miresmaeili2 1 Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Hamedan University of medical sciences, Hamedan, Iran; 2Department of Orthodontics, Faculty of Dentistry, Hamedan University of medical sciences, Hamedan, Iran
M. Zandi, A. Miresmaeili: Study of the cephalometric features of parents of children with cleft lip and/or palate anomaly. Int. J. Oral Maxillofac. Surg. 2007; 36: 200–206. # 2006 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. The purpose of this retrospective case-control study was to compare the cephalometric features of parents of children with cleft anomalies to those of parents of normal children in the hope of finding potential markers of predisposition for this condition. There were 22 sets of parents of cleft children (study group) and 22 sets of parents of normal children (control group). A total of 88 lateral cephalograms were traced twice by two observers separately and analyzed using Student’s t-test. Seven linear, two angular and five triangular cephalometric variables were measured. Mandibular body length (Go–Gn) in mothers was larger in the study than the control group, posterior cranial base (S-Ba) in fathers was shorter in the study than the control group, anterior maxillary triangle (S.N.A) in parents in the study group was larger than in the control group and posterior maxillary triangle (S.N.Pns) in study group mothers was larger than in control group mothers. In conclusion, the craniofacial morphology of the parents of children with cleft anomalies differs from that of parents of normal children and may have some predictive value.
Orofacial clefts are one of the most frequently encountered congenital malformations. They are produced by genetic and environmental factors and exhibit an interesting racial predilection, being less frequent in black people and more common in those of Oriental descent. Many studies have shown that identification of the individuals at risk of producing a child with a cleft anomaly using only a genetic approach is very difficult at the present 0901-5027/030200 + 07 $30.00/0
time. The genetic assessment of parents for this risk should be supplemented with craniofacial data analysis16. Many investigators have reported that the craniofacial morphology of the parents of children with orofacial clefting differs from that of normal individuals6–8,13,17–21. MCINTYRE & MOSSEY in a systematic review of fifteen cephalometric studies investigating the craniofacial morphology of the parents of children with orofacial
Key words: cephalometry; cleft palate; cleft lip; craniofacial morphology; parents. Accepted for publication 4 October 2006
clefting found that, although the craniofacial morphology of such parents differs from that of the parents of normal children, the data from these studies are conflicting and insufficient to accurately localize these differences, so further studies are required15. The objective of this study was to compare the cephalometric features of parents of affected and normal children, and to correlate the results with those of
# 2006 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Cephalometric features of parents of children with cleft deformities
201
other investigators, in the hope of finding some cephalometric features that could act as markers of predisposition of parents to have a child with a cleft deformity. Cephalometric analysis could then be used in conjunction with genetic screening to identify ’at-risk’ parents. Materials and method
The subjects of this study were 22 sets of parents (22 mothers and 22 fathers) of children having cleft anomaly (study group) and 22 sets of parents (22 mothers and 22 fathers) of normal children. All parents who participated in this study had no experience of previous surgical and orthodontic treatment, no history of injury to craniofacial structures and no gross skeletal defect. All of them were drawn from Hamedan, one of the 30 provinces of Iran, so ethnic variability of craniofacial morphology was eliminated (the race of the sample studied is Aryan). The mean age of the mothers and fathers in the study and control groups at the time the cephalograms were taken was 30.41, 33.45, 31.04 and 32.85 years, respectively (Table 1). A total of 88 lateral cephalograms of the study and control groups were traced on acetate paper, twice by two observers separately, with an interval of approximately 40 days between replicate tracings. The intra-observer and inter-observers errors were insignificant for purposes of statistical analysis. Landmarks for lateral cephalograms used in this study are shown in (Fig. 1). Seven linear, two angular and five triangular lateral cephalometric variables were measured (Table 2). Some of these variables that are not commonly used are as follows: anterior maxillary triangle (S.N.A): a triangle constructed by joining the points S, N and A (Fig. 2); posterior maxillary triangle (S.N.Pns): a triangle constructed by joining the points S, N and Pns (Fig. 3); mandibular triangle (Co.Gn.Go): a triangle constructed by joining the points Co, Gn and Go (Fig. 4); cranial base triangle (S.N.Ba): a triangle constructed by joining the points S, N and Ba (Fig. 5); nasopharyngeal triangle (S.Pns.Ba): a triangle constructed by joining the points S, Pns and Ba (Fig. 6).
Fig. 1. Landmarks: N,nasion; S,sella; A,subspinale; Ans,anterior nasal spine; Pns,posterior nasal spine; Go,gonion; Gn, gnathion; Co,condylion; Ba,basion.
Fig. 2. Anterior maxillary triangle.
With all variables, the mean values obtained for mothers, fathers and parents in the study group were compared with the mean values of their counterparts in the
control group. These were subjected to statistical evaluation using Student’s t-test and the statistically significant differences between the groups evaluated by calculating the P-value.
Table 1. Age of parents in years Study group Range Mean
Control group
Fathers
Mothers
Fathers
Mothers
22–48 33.45
18–46 30.41
23–48 32.85
22–46 31.04
Results
The mean and standard deviation values of the cephalometric variables of the
Asterisks indicate a significant difference between corresponding values in study and control groups. * P < 0.01.
Control group (N = 22)
80.72 3.92 129.93 6 55.73 3.93 122.4 8.37 47.46 3.73 54.22 4.28 47.98 3.57 80.23 5.72 110.25 6.15 2207.53 217.83* 1716.68 194.14 2479.8 445.87 1334.9 198.1 962.91 133.73 81.13 3.99 131.71 5.83 56.97 4.04 123.77 8.23 47.58 4.28 54.7 3.89 49.25 3.68 81.02 4.73 111.18 5.71 2297.41 208.58* 1794.52 193.18 2470.64 432.57 1319.8 236.1 984.44 144.26 82.15 3.83 128.87 5.35 57.55 3.29 128.42 6.32 49.82 2.63* 55.6 4.29 50.4 2.59 83.95 4.57 113.65 5.37 2314.67 211.96 1845.81 162.19 2782.38 345.6 1454.56 154.9 1051.43 104.21 79.5 4.14 130.89 6.36 54.33 3.86 116.58 5.95 45.37 3.1 52.77 4.45 45.85 2.78 76.22 4.76* 106.79 4.67 2087.27 196.2 1581.31 117.1* 2145.62 316.16 1210.07 155.25 871.56 88.93 SNA NSBa Ans-Pns Co-Gn SBa N-Ans S-Pns Go–Gn N-Ba Anterior maxillary triangle Posterior maxillary triangle Mandibular. triangle Cranial base triangle Nasopharyngeal triangle
79.45 3.95 123.6 5.81 55.12 3.01 117.52 5.92 44.85 3.38 53.5 3.86 46.81 2.07 78.79 4.13* 108.6 4.78 2173.44 174.96 1655.75 124.1* 2250.84 345.78 1168.17 150.16 890.21 104.21
82.47 3.34 129.22 5.11 58.80 4.09 129.57 5.89 49.5 4.5* 55.75 4.23 51.65 3.29 83.6 5 113.92 5.82 2402.87 208.8 1921.82 161.5 2732.63 418.7 1456.16 226.8 1065.51 132.2
Study group (N = 22) Control group (N = 22)
Fathers
Study group (N = 22) Control group (N = 22)
Mothers
Study group (N = 22) Measurements
Midparents
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Table 2. Mean and standard deviation values of the lateral cephalometric measurements
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experimental and control groups are presented in Table 2. The most significant differences in craniofacial morphology between mothers of affected and normal children were mainly expressed in mandibular body length (Go– Gn) and posterior maxillary triangle (S.N.Pns). The mandibular body length (Go–Gn) and the posterior maxillary triangle (S.N.Pns) were significantly larger in mothers of children having cleft anomalies (P < 0.01). All the other measurements were almost the same in mothers of the study and control groups. Only the length of posterior cranial base (S-Ba) proved to be significantly different for fathers of affected children as compared to fathers of normal children. The fathers in the study group had a significantly shorter posterior cranial base (SBa) than those in the control group (P < 0.01). All the other measurements were not significantly different between fathers of affected and normal children. A significant difference between parents of affected and normal children was noted in the anterior maxillary triangle (S.N.A), which was larger in experimental group parents than in those of the control group (P < 0.01). None of the other measurements showed any significant difference between parents of affected and normal children. Discussion
The etiology of facial clefting is complex and has been extensively investigated. There are both major and minor genetic influences involved, with variable interactions from environmental factors. The relative contribution of each factor for an individual case is unknown, and even in those individuals whose genetic backgrounds verify familial tendencies for facial clefting, the mode of inheritance is complex and not completely understood. Some important findings have recently come from studies of syndromic forms of facial clefting. These include several genes that have been shown to have a major effect in the etiology of clefting4,5,10,12,14,22–24. For example, it has recently been demonstrated that the interferon regulatory factor-6 (IRF6) gene plays a role in causing Van der Woude syndrome, the most common of the syndromic conditions5,22,24. These genes have been used to demonstrate a significant overlap between syndromic and non-syndromic forms of orofacial clefts. As several hundred different genetic causes of cleft lip and palate may be
Cephalometric features of parents of children with cleft deformities
Fig. 3. Posterior maxillary triangle.
underlined by different changes in the basic DNA structure, understanding the genetic component of each individual form of the condition is extremely difficult. Environmental factors and a variety of unknown causes that play some role in producing cleft deformities make the problem even more complicated. For example, the concordance rate in monozygotic twins is approximately 25–45%5. This lack of total concordance illustrates the importance of environmental factors in the etiology of orofacial clefting.
Fig. 4. Mandibular triangle.
Orofacial clefting arises as a complex multifactorial trait, being a myriad of Mendelian patterns exhibiting varying levels of penetrance, sex differences and environmental overlays, with the result that identification of the individuals at risk for producing a child with a cleft using only a genetic approach is very difficult at the present time. In this study, based on the results of many other studies6–8,13,17–21, a supplementary approach of craniofacial data analysis was investigated to identify ’at-risk’ individuals.
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In order to compare the craniofacial morphology of parents of children with cleft anomalies and parents of non-cleft children, 14 lateral cephalometric variables were measured. The main significant differences between the two groups were with regard to mandibular body length (Go–Gn), posterior cranial base (S-Ba), anterior maxillary triangle (S.N.A) and posterior maxillary triangle (S.N.Pns), as shown in (Fig. 7). One of the most consistent findings concerning the craniofacial morphology of parents of cleft children was the increase in mandibular body length. The mandibular body length (Go–Gn) in mothers in the study group was larger than in mothers in the control group (P < 0.01) (Fig. 7B). Similarly, MOSSEY et al. observed a significant increase in mandibular body length (Go–Gn) in mothers of children with cleft anomalies17. PROCHAZKOVA & VINSOVA in their Czech study found that the fathers of children with cleft anomalies have a larger mandible19. RAGHAVAN et al. did not observe a significant difference in mandibular body length between their study and control groups, but they had not segregated fathers and mothers in their investigation20. The fathers in the study group had a shorter posterior cranial base (S-Ba) than those in the control group (P < 0.01) (Fig. 7A). This finding is in contrast to the findings of MOSSEY et al.17 who found a larger posterior cranial base in their study group. As some information may be lost when craniofacial morphology is assessed with traditional linear and angular measurements, five triangular variables were also used, and two were found to be significantly different between the study and control groups. These triangular variables have not been used in previous studies. The anterior maxillary triangle (S.N.A) in parents of the study group was larger than in those of the control group (P < 0.01) and the posterior maxillary triangle (S.N.Pns) in mothers of the study group was larger than in those of the control group (P < 0.01) (Fig. 7C and D). These findings may indicate that the parents of children with cleft anomalies have a larger nasomaxillary complex, but further studies are required for confirmation. In this study the cranial base angle, upper anterior facial height and palatal length did not show any significant differences between the two groups. Other investigators found that these three measurements differed between study and control groups, but their results were conflicting6–8,13,17,18,20,21.
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Fig. 5. Cranial base triangle.
Craniofacial development is a highly complex phenomenon that is largely determined genetically and is dependent on a spectrum of signaling molecules, transcription factors, growth factors and cell–cell interactions. Any disturbance of this coordinated process can result in a facial anomaly such as clefting. The craniofacial morphology that is characteristic of parents of children with nonsyndromic facial clefting is not inherited following Mendelian rules (autosomal
Fig. 6. Nasopharyngeal triangle.
dominant or recessive and X-linked dominant or recessive) and is different from the morphologic features of the cleft-affected children. One widely accepted model to explain the genetic basis of non-syndromic cleft anomaly is the multifactorial threshold model. According to this model, the risk of cleft anomaly is assumed to be continuously distributed in the population and to be determined by multiple factors, some genetic and others environmental, with a
threshold dividing the population into unaffected and affected groups. The hypothesis to be tested by this study is that the parents of children with facial clefting are characterized by some cephalometric features that can be used as a marker of predisposition for having a child with a cleft deformity. The individuals who have more of these landmarks are more at risk of having a cleft-affected child, and their children are nearer to the threshold point. If enough of the predisposing factors (genetic and environmental) are present, the embryo of such parents is pushed over the threshold and becomes affected by a cleft deformity. So, a parent with cephalometric features characteristic of at-risk individuals may have an affected child with cephalometric features characteristic of cleft patients. Comparing the results of this investigation with other cephalometric studies, it can be concluded that the craniofacial morphology of the parents of children with cleft anomalies differs from that of the parents of normal children, but the results are not sufficiently consistent to accurately localize these differences. These conflicting results may be due to: (a) methodological differences between various studies; (b) sex and age differences between samples of parents studied; (c) wrong assumption that both parents have equal role in contributing predisposing factors to an affected child; (d) geographic and ethnic variability in craniofacial morphology. Considering (c), there is an accumulation of evidence suggesting that the predisposing factors are unevenly distributed within parental pairs and may be heavily weighted to one parent15,17. Many previous studies investigating the cephalometric features of the parents of children with orofacial clefting have not segregated males and females in their analysis, but have compared the parents en masse, and this method does not allow for one parent to confer more of a predisposing factor on an affected child. MOSSEY et al. segregated the fathers and mothers in their study and observed a significant increase in mandibular body length (Go–Gn) in mothers of children with cleft anomalies17. Similarly, FIGALOVA et al.11 and BLANCO et al.3 found that only the mothers of children with orofacial clefting have differences in certain cephalometric measurements. PROCHAZKOVA & VINSOVA in their study found that the fathers of children with cleft anomaly have a larger mandible19. The results of these investigations indicate the importance of segregating males and females in cephalometric studies.
Cephalometric features of parents of children with cleft deformities
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Fig. 7. Histograms showing main significant differences in lateral cephalometric variables between study and control groups: (A) SBa in fathers, (B) Go–Gn in mothers, (C) Posterior maxillary triangle in mothers, (D) Anterior maxillary triangle in parents.
With regard to (d), many studies have demonstrated that there is ethnic and geographic variability in craniofacial morphology, and the norms and standards of one racial group cannot be used without modification for another racial group1,2. The race of the Iranians is Aryan. In a study, DAVOODY & SASSOUNI investigated the dentofacial pattern differences between Iranians and American Caucasians and concluded that the Iranians have a straighter profile, smaller anterior and posterior facial height and smaller interincisal angle9. The present study differs from previous similar investigations in the following ways. (1) In order to allow fathers and mothers to confer predisposing factors to the children separately, fathers were compared with a male control group, mothers with a female control group and midparents with midparents in the control group. It was found that some measurements differ only in the paternal or maternal group. (2) Five triangular variables were used that had not been used in previous cephalometric studies. It was found that two of these triangular variables were significantly different between the study and control groups. This indicates that some information may be lost when craniofacial morphology is assessed with simple linear and angular measurements, and there should be a trend toward assessing craniofacial structures three dimensionally. Further consistent cephalometric studies, particularly using postero-anterior cephalometry, are required to evaluate
the non-cleft parental craniofacial complex, and the information derived from conventional cephalometric studies should be supplemented with that obtained using 3-dimensional cephalometric analysis and morphometric measurements such as thin plate spline analysis and finite element morphometry. Craniofacial measurements are tools that in conjunction with genetic screening would allow more accurate identification of the individuals at risk of producing a child with a cleft anomaly. References 1. Alcalde RE, Jinno T, Pogrel MA, Matsumura T. Cephalometric norms in Japanese adults. J Oral Maxillofac Surg 1998: 56: 129–134. 2. Altemus LA. A comparison of cephalofacial relationships. Angle Orthod 1960: 30: 223–239. 3. Blanco R, Cifuentes L, Maldonado MJ, Rameaue MX, Munoz MA. Cleft lip and cleft palate, cephalometric features of affected individuals, their relatives and control population. Rev Med Chil 1992: 120: 13–19. 4. Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, NewburyEcob R, Hennekam RC, Van Buggenhout G, van Haeringen A, Woods CG, van Essen AJ, de Waal R, Vriend G, Haber DA, Yang A, McKeon F, Brunner HG, van Bokhoven H. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 1999: 99: 143–153. 5. Cobourne MT. The complex genetics of cleft lip and palate. Eur J Orthod 2004: 26: 7–16.
6. Coccaro PJ, D’Amico R, Chavoor A. Craniofacial morphology of parents with and without cleft lip and palate children. Cleft Palate J 1972: 9: 28–38. 7. Cronin DG, Hunter SW. Craniofacial morphology in twins discordant for cleft lip and/or palate. Cleft Palate J 1980: 17: 116–126. 8. Dahl E. Craniofacial morphology in clefts of lip and palate. Acta Odontol Scand 1970: 28(Suppl.):1–167. 9. Davoody PR, Sassouni V. Dentofacial pattern differences between Iranians and American caucasians. Am J Orthod 1978: 73: 667–675. 10. Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, SanchezFranco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet 2003: 33: 463–465. 11. Figalova P, Hajnis K, Smahel Z. The interocular distance in children with cleft before the operation. Acta Chir Plast 1974: 16: 65–77. 12. Gorski SM, Adams KJ, Birch PH, Friedman JM, Goodfellow PJ. The gene responsible for X-linked cleft palate (CPX) in a British Columbian native kindred is localized between PGK1 and DXYS1. Am J Hum Genet 1992: 50: 1129–1136. 13. Kurisu K, Niswander JD, Johnston MC, Mazaheri M. Facial morphology
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24. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 2004: 351: 769–780. Address: Mohammad Zandi Department of Oral and Maxillofacial Surgery Faculty of Dentistry Hamedan University of medical sciences Felestin square Hamedan Iran Tel: +98 811 8231322 Fax: +98 811 8231322 E-mail: [email protected]