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The craniofacial morphology of the parents of children with orofacial clefting: a systematic review of cephalometric studies

¹ Glasgow Dental Hospital & School, UK
² University of Dundee, UK

Address for correspondence:
Grant T. McIntyre, Orthodontic Department, Glasgow Dental Hospital and School, 378 Sauchiehall Street, Glasgow G2 3JZ, UK. E-mail:
grant{at}mcintyreg.freeserve.co.uk

Abstract

Objective To systematically review the cephalometric studies investigating the craniofacial morphology of the parents of children with orofacial clefting (OFC).

Search strategy The search strategy was based on the keywords ‘parent‘, cephalometry', and ‘cleft‘, identifying 17 studies, of which 15 ‘case/control’ studies met the inclusion criteria

Statistically significant clinically relevant cephalometric variables from univariate statistical tests and multivariate results were collated and presented unweighted.

Results/Conclusions The parental craniofacial complex in OFC is distinctive in comparison to the non-cleft population. However, there is insufficient consistency in study designs and results to accurately characterize the parents of children with OFC. Although the craniofacial morphology of the parents of children with CL(P) differs to the parents of children with CP, there is insufficient information to accurately localize these differences.

Introduction

It is widely recognized that craniofacial form of individuals with orofacial clefting (OFC) is distinctive in comparison to that of unaffected people,¹ and that craniofacial form is influenced by hereditary factors.² As a result, it could be suggested that the craniofacial morphology of the biological parents of children with OFC could be different to the general population.

The identification of the parental craniofacial form in the aetiopathogenesis of OFC may be important for several reasons:

1. The parental craniofacial form (the phenotype) represents the hereditary influences on the craniofacial form of their offspring (the genotype). The craniofacial form in OFC is considered to be a predisposing factor in the development of OFC; for example, increased head and facial widths would logically mitigate against the palatal shelves from making contact.³
   
2. The identification of microform features in the relatives of subjects with OFC (e.g. craniofacial form) will assist in the elucidation of the interaction of genes, both with other genes and their products, and with environmental factors.
   
3. The identification of craniofacial features that are similar in several biological relationships (features that may not seem directly related to the aetiopathogenesis of OFC, e.g. dental or auricular anomalies) may assist in the identification of the genes involved in the aetiopathogenesis of OFC.
   

However, at present, both researchers and clinicians are unsure of which parental cephalometric features are pathognomic for OFC. We, therefore, carried out a systematic literature review to answer the following ‘key questions’:

1. Does the parental craniofacial morphology in OFC differ to that of the population?
   
2. Which features of the craniofacial skeleton characterize the parents of children with OFC?
   
3. Are the differences in the parental craniofacial morphology in OFC dependent on the OFC subtype possessed by their offspring?
   

Methods

Search strategy
The search strategy was formulated to identify any previous systematic reviews and meta-analyses in addition to all the published cohort studies (with appropriate comparison groups), case/control studies and case reports. The Cochrane, Medline (via PubMed, Internet Grateful Med, OVID, and Knowledgefinder), HealthSTAR, POPLINE, SDILINE, SPACELINE, Embase, OLDMEDLINE, CINAHL, and ASKSAM Orthodontic Reference Database (1950–1997, European Orthodontic Society, London) databases were searched using a combination of the following keywords: ‘parent’, ‘cephalometry’, and ‘cleft’. A ‘grey literature’ search was carried out via the ECHHSR (European Clearing House on Health Systems Reform) web site (www.leeds.ac.uk/nuffield/inforservices/ECHHSR/dbase.html) and the UK National Research Register Database was consulted to identify any ongoing and unpublished relevant studies. The Cleft Palate Craniofacial Journal (formerly the Cleft Palate Journal) was hand searched, and the reference lists and bibliographies of all previous publications were consulted to identify any publications, not already identified using the electronic search strategy.

Selection criteria
The selection criteria applied to the study abstracts to select reports for inclusion within this systematic review were inclusion of reports in any language, and exclusion of case-reports and case series (a case-series was defined as including less than 25 subjects).

Results of search strategy
Seventeen cephalometric studies investigating the parental craniofacial morphology in OFC were identified. These were published in peer-reviewed journals. Two of the identified studies were excluded at this stage because one examined one family⁴ and the other was a case series.⁵ Thus, 15 study reports met the inclusion criteria for this systematic review. Table 1 includes details of these studies and full references are included on the Journal website (http://ortho.oupjournals.org/).

Evaluation of methodological quality
The methodological quality of the selected studies was then evaluated using a checklist (Figure 1). All were retrospective case/control studies. None of the included studies were methodologically ideal, with several differences between these studies. All the included studies stated the cleft types possessed by the offspring of the parents; however, only Mossey et al. ^6–8 stated the relative proportions of the parents belonging to their respective cleft subtypes from a completely ascertained sample. No study stated an attempt to contact subjects who defaulted for record collection.

View larger version (45K): [in this window] [in a new window]   Fig. 1 Methodological quality checklist.

Synthesis of univariate statistical data
The statistically significant variables from univariate statistics were evaluated for clinical significance using the criteria set out in Table 2 and are included in Table 3. As the methodological quality of all the study reports is similar, the data abstracted from them is presented unweighted.

View this table: [in this window] [in a new window]   Table 3 Parental cephalometric variables of clinical significance in OFC (study numbers as per Table 2)

Cluster analysis. Cluster analysis was used by Ward et al. to identify groups of subjects demonstrating similar cephalometric features in their sample of parents of children with clefts.⁹ They identified three major clusters, two demonstrating cephalometric similarities to individuals with clefts and one with similar dimensions to published cephalometric values. Another study produced a series of male and female values, above or below which a potential parent could be classified as ‘at risk’.¹⁰

Mahalanobis distance analysis. Mahalanobis distance analysis measures the degree of deviation of an individual from the mean of the group when multiple variables are evaluated simultaneously. Using this technique, Nakasima and Ichinose found that the face shape of the parents of children with cleft lip and palate (CLP), cleft lip (CL), or cleft palate (CP), and the combined experimental group were highly distinguishable from the control group.¹¹ Similarly, Mossey et al. identified a highly significant difference between the craniofacial morphology of their parental sample and controls. One significantly different parameter between the paternal and control groups was mandibular length (Cd–Gn). The Mahalanobis distance was greater for females than males.⁷

Discriminant analysis. Discriminant analysis has been used to identify the parameters that could be used to classify an individual into the correct experimental group. Nakasima and Ichinose identified seven ratios that played an important role in the discrimination between parents and controls, all from PA cephalograms; however, they were unable to classify the three experimental groups according to craniofacial morphology.¹¹ In their study, the probabilities of misdiscrimination ranged from 13.0 to 17.4 per cent. Mossey et al. investigated the morphometric features that predispose to OFC (between parents of CL, CLP and CP).⁶ Their whole group analysis and couples analysis yielded no significant differences. Their discriminant analysis indicated that for the maternal group, ramus height, and cranial height are reliable discriminators for CLP (80 per cent) and CP (75 per cent). Mossey et al. (parents/ controls) found that for male parents, the useful discriminators were cranial area, parietal chord length, cranial base length, total anterior facial height, ramus length, and the horizontal distance between condyle and sella.⁷ A Jack-knifed classification found that 83.3 per cent of parents and 82.6 per cent of controls were correctly classified. For females, the useful discriminators were cranial area, cranial height, parietal chord length, and parietal and occipital subtenuce measurements. A Jack-knifed classification found that 92.7 per cent of parents and 98 per cent of controls were correctly classified. Other investigators identified the features that classified their parents in comparison to their control group as follows: a larger inter-orbital distance, larger nasal cavity width and larger inter-coronoid distance relative to the maximum head width, and shorter mandibular length relative to the anterior cranial base length.¹² This correctly classified the pooled experimental and control subjects in 67.9 per cent of cases and on the pooled test group in 61.8. Finally, AlEmran et al. produced two models using stepwise logistic regression, one for males and one for females.¹³ The male model selected increased nasal width and decreased alveolar width for correctly classifying an individual at risk 74.36 per cent, whereas for females the model selected only a decreased head width for a 76.92 per cent correct classification.

Although ideal, it was not possible to synthesize the results from univariate and multivariate statistics together in addition to synthesizing the results obtained from univariate and multivariate statistics separately.

Analysis of synthesized data
These results confirm that the parental craniofacial morphology in OFC is distinctive compared to the population (Key question 1). However, there is insufficient evidence to accurately localize the anatomical regions (or parameters) that distinguish the parents of children with OFC from the population (Key question 2). Furthermore, there is insufficient evidence to accurately determine whether the parental craniofacial morphology in CL(P) differs to that of CP (Key question 3).

Discussion

The 15 study reports that were included report on retrospective case-‘control’ observational studies. Although all these reports refer to the use of controls, the term ‘comparison group’ is more appropriate: ‘control’ strictly refers to the situation where the subjects within the experimental and control groups are identical, save for the characteristic or intervention under investigation.

Clinical importance of the parental craniofacial morphology in OFC
It would be ideal to be able to collate a set of parental cephalometric variables specific to OFC that would facilitate the distinction between the parents of children with OFC and the non-OFC population. Additionally, this set of variables could be produced in template-form, and could, in the future, potentially become one of a battery of tests to be overlaid on the lateral and PA cephalograms of potential parents who are concerned about the possibility of having children with clefts, thereby allowing health care professionals to advise them appropriately. Both these goals might theoretically be achieved from a meta-analysis of data abstracted from previous parental cephalometric studies in OFC. However, in this systematic review, a meta-analysis of abstracted data was not possible, because of methodological differences between the included studies and, moreover, meta-analyses of non-RCT data are not well established yet.

The reasons for conflicting results from the previous studies investigating the parental craniofacial complex in OFC include:

• methodological differences between the various studies;
  
• ethnic and geographic variability in (a) the craniofacial morphology, (b) the incidence of OFC, and (c) the ratio of CL(P) to CP of OFC;
  
• the failure to account for sexual dimorphism in the craniofacial complex;
  
• the inappropriate use of conventional cephalometric analyses in the assessment of shape.
  

Further work required
Further cephalometric studies, particularly using PA cephalometry are required to evaluate the non-cleft parental craniofacial complex in the various subtypes of OFC using a combination of different cephalometric analyses. Ideally, the information derived from a conventional cephalometric analysis would be supplemented with that derived using morphometric tools (such as Procrustes superimposition, Euclidean Distance Matrix Analysis, Thin Plate Spline Analysis, and Finite Element Morphometry). This information would allow the identification of the regions that differentiate the parents of children with OFC from the non-cleft population and, when several studies are in agreement, lead to the identification of the morphogenes that code for these specific features. Only one study as yet has sought to examine both affected offspring and their parents.¹⁴ As a result more ‘triad’ or ‘parent and twin’ studies to investigate the heritability of craniofacial morphology in both cases and controls are required.

Conclusions

• The parental craniofacial complex in OFC is distinctive in comparison to the parents of children without cleft lip and palate.
  
• At present, there is insufficient consistency in study design and results to accurately localize the features that characterize the parents of children with OFC.
  
• Although there is evidence that the craniofacial morphology of the parents of children with CL(P) differs to the craniofacial morphology of the parents of children with CP, there is insufficient information to be able to accurately localize these differences.
  
• There are major problems with the quality of available data from parental cephalometric studies in OFC due to methodological shortcomings.
  

Acknowledgments

The authors would like to acknowledge financial support from the European Orthodontic Society (W. J. B. Houston Research Grant). The authors are indebted to Professor D. R. Stirrups for his invaluable advice and assistance.

References

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Received January 19, 2001; accepted August 2, 2001

This article has been cited by other articles:

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