Int. J. Oral Maxillofac. Surg.

2007; 36: 200206

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: 200206.
# 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
Students t-test. Seven linear, two angular and five triangular cephalometric
variables were measured. Mandibular body length (GoGn) 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 individuals68,13,1721.
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 Students 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

2248
33.45

1846
30.41

2348
32.85

2246
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
GoGn
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

Zandi, and Miresmaeili

Table 2. Mean and standard deviation values of the lateral cephalometric measurements

202

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
(GoGn) 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 clefting4,5,10,12,14,2224. 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 2545%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 studies68,13,1721, 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
(GoGn), 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 (GoGn) 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 (GoGn) 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 conflicting68,13,17,18,20,21.

204

Zandi, and Miresmaeili

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
cellcell 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 (GoGn) 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) GoGn 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: 129134.
2. Altemus LA. A comparison of cephalofacial relationships. Angle Orthod 1960:
30: 223239.
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: 1319.
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: 143153.
5. Cobourne MT. The complex genetics of
cleft lip and palate. Eur J Orthod 2004:
26: 716.

6. Coccaro PJ, DAmico R, Chavoor A.

Craniofacial morphology of parents with
and without cleft lip and palate children.
Cleft Palate J 1972: 9: 2838.
7. Cronin DG, Hunter SW. Craniofacial
morphology in twins discordant for cleft
lip and/or palate. Cleft Palate J 1980: 17:
116126.
8. Dahl E. Craniofacial morphology in
clefts of lip and palate. Acta Odontol
Scand 1970: 28(Suppl.):1167.
9. Davoody PR, Sassouni V. Dentofacial
pattern differences between Iranians and
American caucasians. Am J Orthod 1978:
73: 667675.
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: 463465.
11. Figalova P, Hajnis K, Smahel Z. The
interocular distance in children with cleft
before the operation. Acta Chir Plast
1974: 16: 6577.
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: 11291136.
13. Kurisu K, Niswander JD, Johnston
MC, Mazaheri M. Facial morphology

206

14.

15.

16.

17.

18.

Zandi, and Miresmaeili

as an indicator of genetic predisposition

to cleft lip and palate. Am J Hum Genet
1974: 26: 702714.
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: 557568.
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: 2329.
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: 371378.
Mossey PA, McColl J, OHara M.
Cephalometric features in the parents of
children with orofacial clefting. Br J Oral
Maxillofac Surg 1998: 36: 202212.
Nakasima A, Ichinose M. Characteristics of craniofacial structures in parents of

19.

20.

21.
22.

23.

children with cleft lip and/or palate. Am J

Orthod 1983: 84: 140146.
Prochazkova J, Vinsova J. Craniofacial morphology as a marker of predisposition to isolated cleft palate. J
Craniofac Genet Dev Biol 1995: 15:
162168.
Raghavan R, Sidhu SS, Kharbanda
OP. Craniofacial pattern of parents of
children having cleft lip and/or cleft
palate anomaly. Angle Orthod 1994:
64: 137144.
Sato T. Craniofacial morphology of parents with cleft lip and palate children.
Shikwa Gakuho 1989: 89: 14791506.
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: 427430.

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:
769780.
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: zandi88m@yahoo.com