Child Neuropsychology

A Journal on Normal and Abnormal Development in Childhood and

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Cognitive, behavioral and psychological

functioning in children with metopic synostosis:
a meta-analysis examining the impact of surgical
status

A. J. Osborn, R. M. Roberts, J. L. Mathias, P. J. Anderson & W. J. Flapper

To cite this article: A. J. Osborn, R. M. Roberts, J. L. Mathias, P. J. Anderson & W. J.

Flapper (2018): Cognitive, behavioral and psychological functioning in children with metopic
synostosis: a meta-analysis examining the impact of surgical status, Child Neuropsychology, DOI:
10.1080/09297049.2018.1441821

To link to this article: https://doi.org/10.1080/09297049.2018.1441821

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CHILD NEUROPSYCHOLOGY, 2018
https://doi.org/10.1080/09297049.2018.1441821

ARTICLE

Cognitive, behavioral and psychological functioning in

children with metopic synostosis: a meta-analysis examining
the impact of surgical status
A. J. Osborn a, R. M. Roberts a
, J. L. Mathias a
, P. J. Andersonb
and W. J. Flapper b
a
School of Psychology, University of Adelaide, Adelaide, Australia; bThe Australian Craniofacial Unit,
Women’s and Children’s Hospital, North Adelaide, Australia

ABSTRACT ARTICLE HISTORY

Neurodevelopmental delays are known to occur in children with Received 20 December 2017
metopic synostosis, but it is presently unclear whether the cognitive, Accepted 10 February 2018
behavioral and psychological outcomes of children with metopic KEYWORDS
synostosis differ to those of their healthy peers. This meta-analysis Metopic synostosis; surgical
consolidated data from 17 studies (published prior to August 2017) status; cognitive;
that examined the cognitive, behavioral and psychological outcomes psychological; behavioral;
of children (n = 666; aged ≤19 yrs) with metopic synostosis. Hedges’g outcome
(gw) effect sizes compared the outcomes of samples with metopic
synostosis (unoperated, operated) to healthy controls or normative
data and, where available, the prevalence of problems/disorders was
calculated. Children with unoperated metopic synostosis performed
significantly worse than their healthy peers on measures of: general
cognition (gw = −.38), motor functioning, (gw = −.81), and verbal
(gw = −.82) and visuospatial (gw = −.92) abilities. Children with oper-
ated metopic synostosis performed significantly worse on measures of
motor functioning (gw = −.45), visuospatial skills (gw = −.32), attention
(gw = −.50), executive functioning (gw = −.36), arithmetic ability
(gw = −.37), and behavior (gw = −.34). Cognitive, behavioral, and
psychological problems were prevalent, but variable. Overall, the cog-
nitive, behavioral, and psychological outcomes of children with meto-
pic synostosis are generally worse than their healthy peers, regardless
of surgical status. However, research is sparse, samples small, controls
are rarely recruited, and the severity of metopic synostosis often not
stated. Nevertheless, the findings suggest that children with metopic
synostosis are likely to experience a variety of negative outcomes and
should therefore receive ongoing monitoring and support.

Metopic synostosis (MS), also referred to as “trigonocephaly” due to changes in cranial

shape (see van der Meulen, 2012 for a review), involves a deformation of the frontal
skull due to premature fusion of the metopic suture (Lajeunie, Le Merrer, Marchac, &
Renier, 1998). MS can be mild, with only a slight bone ridge visible, or more severe,
with the forehead having a triangular wedge-shape when viewed from above.

CONTACT R. M. Roberts rachel.roberts@adelaide.edu.au School of Psychology, University of Adelaide,

Adelaide, South Australia 5005 Australia
Supplemental data for this article can be accessed here.
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. J. OSBORN ET AL.

Furthermore, the condition may be categorized as non-syndromic (isolated), complex

(multiple fused sutures) or syndromic (other birth defects also evident) (Mathijssen,
2015). MS occurs in approximately 1 in 5,200 births, making it the second most
common form of cranial synostosis (van der Meulen, 2012); with twice as many boys
being affected, although this ratio varies (Kolar, 2011; Lajeunie et al., 1998; Selber et al.,
2008). MS is an heterogeneous condition that is ubiquitous worldwide, with rates
increasing globally; but little is known about either the underlying pathological pro-
cesses or the reasons for the increasing incidence (Kini et al., 2010; Mathijssen, 2015).
Although intrauterine constraint, maternal smoking, the use of valproic acid during
pregnancy and chromosomal abnormalities have all been linked to the development of
MS (see Tahiri, Bartlett, & Gilardino, 2017 for a review), defects of the FREM1 gene are
the only single-point mutations that are known to increase the risk of MS (Vissers et al.,
2011).
Treatment for MS usually involves surgery to release the constricted skull and
correct the distorted skull vault (Shim, Park, Kim, Kim, & Kim, 2016) and increase
intracranial volume (Anderson, Netherway, Abbott, & David, 2004), with the aim of
optimizing the child’s cognitive functioning, esthetic outcomes and associated quality
of life (Wong, Forrest, Goodacre, & Klassen, 2013). Given the metopic suture
normally closes between the ages of 3 and 9 months (Fearon, 2014), clinicians
must consider whether, and how, the natural course of the condition would change
as a result of surgery. Thus, the decision to operate is complex and usually made in
conjunction with parents. Although surgical rates differ, unoperated MS is often
assumed to be a less severe condition; an assumption that is challenged by Scheuerle,
Guilford, and Habal's (2004) finding that a high proportion of unoperated children
had cognitive and behavioral problems.
Neurodevelopmental delays are known to occur in some children with MS (Bottero,
Lajeunie, Arnaud, Marchac, & Renier, 1998; Sidoti, Marsh, Marty-Grames, & Noetzel,
1996), but estimates of the prevalence of general cognitive problems vary enormously
(1–50%; Kapp-Simon, 1998; Lajeunie et al., 1998). The same is true for verbal and
language skills, with the prevalence of problems variously estimated to be 6% (Kunz
et al., 2014), 15% (Kini et al., 2010), 30% (Mendonca et al., 2009) and 99% (Shimoji,
Tominaga, Shimoji, Miyajima, & Tasato, 2015), and the reasons for such discrepancies
(e.g., children recruited because they displayed cognitive/behavioral problems) often
not clear. Similarly, global development delays (multiple cognitive, learning & beha-
vioral problems) have been reported in 26% (Bottero et al., 1998), 57% (Becker et al.,
2005), and 90% (Kapp-Simon, 1998) of children with MS. Many school-aged children
also experience problems that require an assessment by a school psychologist (33%) or
additional learning assistance (47%) (Kelleher et al., 2006), possibly because learning
and cognitive problems become more apparent in this setting (Kapp-Simon et al.,
2016). Added to this is the fact that children’s concerns with their appearance may
lead to social isolation and anxiety, which can impact on their psychological well-being;
however, research is limited and has often examined a variety of suture types (Cloonan,
Collett, Speltz, Anderka, & Werler, 2013; van der Vlugt et al., 2009) or syndromes
(Bannink, Maliepaard, Raat, Joosten, & Mathijssen, 2010; de Jong et al., 2010), making
it difficult to determine the specific impact of MS on psychological well-being.
 CHILD NEUROPSYCHOLOGY 3

There are a number of factors that may have contributed to these disparate findings,
including differences in: the children’s age, the outcomes that were assessed (e.g.,
general cognition, verbal or motor abilities), sample sizes, and whether or not they
had undergone surgery for their MS. In fact, most studies have evaluated children who
have undergone surgery, with fewer focusing on those who were treated conservatively
and did not have surgery. Others have not reported the surgical status of their sample
(Kini et al., 2010) or failed to separate their findings according to surgical status
(operated vs. unoperated) (Kelleher et al., 2006; Lajeunie et al., 1998). Moreover,
many researchers (Alperovich, Golinko, Lee, Runyan, & Staffenberg, 2016; Cloonan
et al., 2013; Korpilahti, Saarinen, & Hukki, 2012; van der Vlugt et al., 2009) combine
data from multiple suture types (e.g., sagittal, lambdoidal, metopic), rather than exam-
ining MS alone. This has made it difficult to determine whether, and to what extent,
children’s outcomes differ by suture type. Additionally, those studies that have focused
solely on MS have yielded mixed results.
It is not yet clear whether, or to what extent, the different surgical groups – children
with MS who have been treated conservatively (unoperated) or surgically (operated) –
are having problems compared to their healthy peers. The current study therefore meta-
analyzed research that has assessed the cognitive, behavioral and psychological out-
comes of children who were diagnosed with non-syndromal MS, with results separated
according to surgical status (unoperated, operated), cognitive domains (general cogni-
tion, motor functioning, verbal ability, visuospatial ability, attention, executive function,
arithmetic and memory) and, where possible, developmental stage (infants <12 mths,
toddlers 18–24 mths, young children 3–6 yrs, older children >7 yrs) in order to examine
the extent of difficulties experienced by children with MS.

Method
Literature search and inclusion criteria
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA
guidelines; Moher, Liberati, Tetzlaff, & Altman, 2009) were used in the design and
reporting of this meta-analysis. Comprehensive searches of the PubMed, Scopus,
Embase, and PsycINFO electronic databases for literature published before August
2017 were undertaken under the guidance of an expert research librarian (see
Supplementary Table 1, for detailed search strategies). The reference lists of all meta-
analyzed studies were also examined for other relevant research.
All studies had to meet the following criteria: (1) participants were diagnosed with
single-suture (isolated/non-syndromic) MS/trigonocephaly, (2) cognitive (e.g., memory,
attention), behavioral (e.g., attention deficit disorder, difficulties at school) and/or
psychological (e.g., depression, anxiety, satisfaction with appearance) outcomes were
assessed, (3) data (test scores or prevalence rates) enabling the calculation of effect sizes
were provided, (4) it was published in a peer-reviewed journal (“gray” literature
excluded) in English, and (5) it was original research with n > 1 participants (excludes
reviews & case-studies). Cases of syndromic MS (e.g., with Apert, Crouzon, Muenke,
Saethre-Chotzen & Opitz C syndromes) or with multiple sutures were excluded, due to
differences in the outcomes for these other conditions (Mathijssen, 2015). Participants
4 A. J. OSBORN ET AL.

who were identified for study inclusion because they had cognitive/behavioral problems
were also excluded.
The literature search initially identified 10,289 articles, 5,050 of which were dupli-
cates. The titles and abstracts of the remaining 5,239 articles were all screened by the
first author (AJO), after which full-text versions of 277 studies were retrieved for
detailed screening. Re-application of the inclusion criteria reduced the number of
eligible studies to 29 (see Supplementary Figure 1, for details of the review & selection
process); equating to 17 independent studies when papers with non-independent
samples were combined (Rosenthal, 1995) (for details see Supplementary Table 2).
Of these, 8 examined MS (alone) and 9 examined multiple suture types (e.g.,
sagittal, lambdoid), from which MS data could be extracted. Two studies examined
unoperated MS only, 6 studies examined operated MS, 1 study examined both
unoperated and operated groups (separate samples), 5 studies examined pre-post
surgery outcomes (longitudinal study) and 3 studies examined mixed samples
(unoperated & operated) MS. AJO (1st author), RMR (2nd author) and JLM (3rd
author) independently assessed all studies where eligibility was ambiguous, after
which a consensus decision was made.

Data collection and preparation

Background demographic information (age, sex), MS details (surgical status: unoper-
ated, operated, mixed), study design (single MS group or MS and control groups), and
details of the outcomes (cognitive, behavioral, psychological) and measures (test name;
score/variable type: continuous or categorical) were extracted from each study. For
surgical status, “unoperated” refers to children who had not undergone surgery at the
time of their assessment. For some studies (Nstudies = 6), these data comprised baseline
assessments of children who were scheduled for surgery, however other studies did not
state whether or not children were likely to undergo surgery at a later date (Nstudies = 2).
A variety of tests were used to assess cognitive outcomes: these were classified into eight
domains (Lezak, Howieson, Bigler, & Tranel, 2012) in order to organize the data
(general cognition, motor functioning, verbal ability, visuospatial ability, attention,
executive function, arithmetic, memory).
The data were standardized before being analyzed: standard errors (SE) were trans-
formed into SDs (Hedges, 1982); age at assessment was converted to months; and data
from subgroups that were not relevant to this study were combined (e.g., groups
differentiated by age at surgery). Comprehensive Meta-Analysis (CMA, version 2;
©2006, Biostat, Inc., Englewood, NJ) software was used for all analyses. All plots were
generated using Forest Plot Viewer (Boyles, Harris, Rooney, & Thayer, 2011).

Statistical analyses and interpretation

The outcomes of unoperated, operated and mixed (unoperated + operated) MS were
each examined separately, with the findings grouped into cognitive (general cognition,
motor functioning, verbal & visuospatial ability, attention, executive function, arith-
metic & memory), behavioral and psychological outcomes. Outcomes were also exam-
ined according to the child’s developmental stage (infants <12 mths, toddlers
 CHILD NEUROPSYCHOLOGY 5

18–24 mths, young children 3–6 yrs, older children >7 yrs) at assessment, where
sufficient data were available.
A conservative random-effects model was used to calculate effect sizes (Lipsey &
Wilson, 2001), with two types of effect sizes being calculated. First, Hedges’ g was used
to measure the standardized mean difference between the outcomes of two groups
(Nstudies = 8): MS and healthy controls or normative data. Only one study (comprising
data drawn from 11 publications) recruited healthy controls, thus published normative
data were used for the remaining comparisons (Nstudies = 7). Weighted (inverse variance
method) mean effect sizes (gw) were calculated for each outcome. A negative gw (g if
Nstudies = 1) indicates that children with MS had poorer functioning (lower scores/more
errors/slower performance) than the comparison group (healthy controls or normative
data). Similarly, a positive gw indicates that MS patients had better functioning (higher
scores/fewer errors/faster performance), with g = .2, .5 and .8 equating to small,
medium and large effects, respectively (Cohen, 1992). Probability values (p) were
used to assess statistical significance. Orwin’s (1983) Fail Safe N (Nfs) statistics were
additionally calculated in order to assess the potential bias caused by the tendency for
journals to favor statistically significant results (publication bias) (Rosenthal, 1995) and
the fact that unpublished/non peer-reviewed papers (gray literature) were excluded
from our analyses. The Nfs estimates the number of unpublished studies needed to
reduce a finding to a small effect (g = .2): the larger the Nfs, the more confident we can
be in a finding.
Second, proportions were used to examine the prevalence of cognitive, behavioral
and psychological problems in those with MS (Nstudies = 9). It should be noted that the
studies that reported these data often used different criteria to determine the presence
of problems; thus the data reported here reflect the original published findings.
Moreover, 95% confidence intervals (95% CIs) were calculated to provide the upper
and lower bounds within which we can be 95% confident that the actual population rate
for problems following MS lies.

Results
Participants
The 17 studies that were meta-analyzed provided data for a total of 666 MS patients (see
Table 1 for summary data and Supplementary Table 2, for study-specific information).
Overall, the samples were quite small (mean = 35, range = 3–127) and participants were
generally young (mean = 4 years) boys who were largely (71%) recruited within Europe;
although ethnicity was rarely reported.

Unoperated metopic synostosis

Eight studies examined the cognitive, behavioral and/or psychological functioning of
children with unoperated MS: 5 of these reported test scores, 2 provided prevalence
data, and 1 reported both types of data (see Table 2). General cognition (Nstudies = 7)
was the most frequently examined outcome, followed by verbal ability (Nstudies = 5),
motor functioning (Nstudies = 4), with visuospatial abilities and global developmental
6 A. J. OSBORN ET AL.

Table 1. Summary details for the 17 independent studies included in the meta-analysis.
Nstudies Nparticipants Mean SD
Sample size 17 666 35.1 34.6
Age (months) 13 446 45.6 44.7
Surgical statusa
Unoperated 8 140 14.0 15.0
Operated 12 353 27.2 27.3
Mixed (unoperated + operated) 3 262 87.3 34.6
%
Sex (male) 11 311 77.5
Suture types of patientsb
Metopic synostosis only 9 533 80.0
Combined suture types 9 182 27.3
Control group used
Yes 1 51 7.7%
No 16 615 92.3%
Origin of study
Europe 8 475 71.3%
US 7 167 25.1%
Australia 2 24 3.6%
Sample ethnicity reported
Yes 1 49 7.4%
No 16 617 92.6%
Nstudies and Nparticipants refer to the total number of studies and participants for which data were available.
a
Some studies reported data for multiple groups
b
One study published papers examining both “metopic synostosis only” and “combined suture type” samples.

Table 2. Outcomes of children with unoperateda metopic synostosis.

Study details Hedges’ g Prevalence

Authors MS Hedges’ g p Nfs Hedges’ g and 95% CI Prevalence Prevalence and 95% CI
participants -2.00 -1.00 0.00 1.00 2.00 0% 50% 100%
Objective measures
General cognition MS outcomes worse MS outcomes better → increasing prevalence

Kapp-Simon et al., 1993^ 7 .25 .52

Da Costa et al., 2012/2013^ 21 -.06 .79
ILP study^‡ 49 -.38 .07
Warschausky et al., 2005^ 22 -.48 .04
Kapp-Simon et al., 1998^ 7 -.78 .07 50%
Bellew & Chumas, 2015^ 8 -.99 .01
Kunz et al., 2014 22 5%
Overall 136 -.38 .01 17 18%
Motor functioning
Da Costa et al., 2012/2013^ 21 -.66 .01
ILP study^‡ 49 -.83 .00
Warschausky et al., 2005^ 22 -.94 .00
Kunz et al., 2014 22 36%
Overall 114 -.81 .00 15
Verbal abilities / language
ILP study^‡ 49 -.31 .10
Bellew & Chumas, 2015^ 8 -.81 .03
Warschausky et al., 2005^ 22 -1.39 .00
Scheuerle, 2004 3 33%
Kunz, 2014 22 18%
Overall 104 -.82 .03 15 20%
Visuospatial abilities
Bellew & Chumas, 2015^ 8 -.92 .01
Global developmental delay
Kapp-Simon et al., 1998^ 6 90%

Hedges’ g results for the unoperated metopic synostosis group compared to published norms (^) or study healthy
controls (‡);
MS: metopic synostosis, CI: confidence intervals, Nfs: Failsafe N.
a
these children had not undergone surgery for their MS prior to being assessed, but some may have undergone
surgery at a later date
 CHILD NEUROPSYCHOLOGY 7

delay each only examined by a single study (see Supplementary Table 3, for details of
the measures used to assess these domains).
Overall, the findings revealed that children with unoperated MS performed signifi-
cantly more poorly than their healthy peers (controls or age-matched normative data)
in all domains that were assessed, with motor functioning (gw = -.81), verbal skills
(gw = -.82) and visuospatial abilities (gw = -.92) all equating to large effects (see Table 2).
A high percentage (prevalence data Table 2) of children with unoperated MS also had
problems (as defined by the study authors), particularly in the areas of global develop-
mental delay (90%) and motor functioning (36%), with verbal (20%) and general
cognitive (18%) problems also relatively common.
Overall, significantly poorer test performance, combined with a high frequency of pro-
blems, suggests that children with unoperated MS are lagging behind their healthy peers;
particularly with respect to motor and verbal abilities. Although based on limited data, there
is some suggestion that they may also be experiencing visuospatial problems. Notably, no
studies examined behavioral or psychological outcomes in children with unoperated MS.

Operated metopic synostosis

There were 12 studies that examined the outcomes of children with operated MS; 3 of
which reported test scores (means, SDs), 6 reported prevalence rates and 3 provided
both forms of data. The findings from these studies are summarized in Table 3, with the
data obtained from objective assessments (e.g., cognitive tests) shown in the top half
and subjective assessments (e.g., questionnaire measures, parent/teacher reports) shown
in the bottom half. General cognitive functioning was examined most frequently
(Nstudies = 8), followed by verbal ability (Nstudies = 6), motor functioning and behavioral
problems (Nstudies = 3), global development (Nstudies = 3), and visuospatial abilities
(Nstudies = 2), with single studies assessing attention, executive function, arithmetic,
memory and autistic tendencies (see Supplementary Table 3, for the measures used to
assess each domain).
As seen in Table 3, the Hedges’ g effect sizes revealed that children who had
undergone surgery for their MS had significantly poorer outcomes than healthy chil-
dren (healthy peers/test norms), based on objective assessments of motor functioning
(gw = −.45), visuospatial abilities (gw = −.32), arithmetic ability (gw = −.37) and
behavioral problems (gw = −.34); as well as subjective (parent/teacher) ratings of
attention (gw = −.50) and executive function (gw = −.36). Each of these findings equated
to low-moderate-to-moderate differences. When the prevalence rates for objectively
assessed problems were examined, it was found that verbal/language problems (27%),
global developmental delays (43%) and behavioral problems (27%) were common. In
addition, parents/teachers reported high rates of global developmental delays (40%) and
behavioral problems (37%), with autistic tendencies being fewer, but still concern-
ing (13%).

Metopic synostosis, surgical status not specified

Our goal was to summarize all available published research, consequently the data for
three studies that examined mixed MS samples (operated + unoperated) were
8 A. J. OSBORN ET AL.

Table 3. Outcomes of children who had previously undergone surgery for their metopic
synostosis.
Study details Hedges’ g Prevalence

Authors MS Hedges’ g p Nfs Hedges’ g and 95% CI Prevalence Prevalence and 95% CI
participants -2.00 -1.00 0.00 1.00 2.00 0% 50% 100%
Objective measures
General cognition MS outcomes worse MS outcomes better increasing prevalence
Da Costa et al., 2006^ 3 .69 .24
van der Vlugt et al., 2012/2017^ 82 .07 .61 8%
Kapp-Simon et al., 1998^ 11 -.17 .72 14%
Bellew & Chumas, 2015^ 5 -.28 .54
ILP study^‡ 51 -.50 .00
Da Costa et al., 2012/2013^ 15 -.90 .00
Kunz et al., 2014 22 5%
Cradock et al., 2015# 48 44%
Overall 237 -.26 .20 2 15%
Motor functioning
ILP study^‡ 51 -.34 .04
Da Costa et al., 2012/2013^ 21 -.70 .01
Kunz et al., 2014 22 13%
Overall 94 -.45 .01 7
Verbal abilities / language
ILP study‡ 51 -.14 .40
Bellew & Chumas, 2015^ 5 -.26 .56
Naran et al., 2017 28 57%
Medonca et al., 2009 20 30%
Scheuerle et al., 2004 3 13%
Kunz et al., 2014 22 6%
Overall 129 -.15 .32 4 27%
Visuospatial abilities
Bellew & Chumas, 2015^ 5 -.27 .55
Wallace et al., 2016‡ 45 -.33 .05
Overall 50 -.32 .04 5
Orientation & attention
Collett et al., 2017‡ 45 -.17 .32
Executive function
Collett et al., 2017‡ 43 -.21 .21
Arithmetic
Speltz et al., 2015‡ 48 -.37 .02
Short-term memory
Kapp-Simon et al., 2016‡ 43 -.20 .24
Long-term memory
ILP study‡ 45 -.11 .53
Global developmental delay
Kapp-Simon et al., 1998^ 7 43%
Behaviour
Van der Vlugt et al., 2012 82 27%
Subjective measures
Verbal abilities / language
Kapp-Simon et al., 2016‡ 51 .04 .82
Orientation & attention
Collett et al., 2017‡ 42 -.50 .01
Executive function
Collett et al., 2017‡ 40 -.36 .05
Global developmental delay
Becker et al., 2005 37 57%
Bottero et al., 1998 62 26%
Overall 99 40%
Behaviour
Toth et al., 2008‡ 51 -.34 .04
Speltz et al., 2016 44 37%
Overall 242
Autistic tendencies
Van der Vlugt et al., 2012 47 13%

Hedges’ g results for the unoperated metopic synostosis group compared to published norms (^) or study
healthy controls (‡);
MS: metopic synostosis, CI: confidence intervals, Nfs: Failsafe N, ILP: Infant Learning Project
b
Cradock et al. (2015) is part of the ILP study, however as the only ILP paper contributing prevalence data to
the general cognition domain, it has been listed separately.
 CHILD NEUROPSYCHOLOGY 9

Table 4. Summary findings for those outcomes that were assessed in studies of both
unoperated and operated metopic synostosisa.
Hedges’ g and 95% CI
Nstudies Nparticipants Hedges’ g p Nfs Study references –2.00 –1.00 0.00 1.00 2.00
MS outcomes worse MS outcomes better
General cognition
unoperated 4 43 –.50 .04 6 1,4,5,6
operated 6 167 –.26 .20 2 2,3,5,6,7,8

Motor functioning
unoperated 1 22 –.94 .00 4 4
operated 2 72 –.45 .01 7 2,3

Verbal abilities / language

unoperated 2 30 –1.16 .00 10 4,6
operated 2 56 –.15 .32 4 3,6

Visuospatial abilities
unoperated 1 8 –.92 .01 4 6
operated 2 50 –.32 .04 5 6,9

MS: metopic synostosis, CI: confidence intervals, Nfs: Failsafe N, ILP: Infant Learning Project
a
presurgical assessments from 2 longitudinal studies of children with MS were excluded in order to ensure each
child’s data was only analyzed once
Included studies: (1) Kapp-Simon et al. (1993); (2) Da Costa et al. (2012), (2013); (3) ILP study; (4) Warschausky
et al. (2005); (5) Kapp-Simon (1998); (6) Bellew and Chumas (2015); (7) Da Costa et al. (2006); (8) van der Vlugt
et al. (2012), (2017); (9) Wallace et al. (2016)

additionally analyzed (see Supplementary Table 4). One study (Nparticipants = 127)
assessing the general cognitive abilities of their MS sample did not differ from norma-
tive data. The prevalence data from all three studies revealed minimal problems with
general cognition, motor functioning and global developmental delay (1%), although
more children were found to have verbal/language problems (15%). In addition, a large
percentage of children reported required remedial assistance at school (47%), had
problems with reading/writing (37%), or were assessed by a school psychologist (33%).

Unoperated versus operated MS

The aforementioned analyses separately examined the outcomes of unoperated, oper-
ated and mixed MS samples, but most did not directly compare unoperated with
operated MS samples with only a single study providing the requisite data to do this.
However, one of the benefits of calculating effect sizes is that the data is standardized;
enabling the findings from studies of unoperated MS to be directly compared with those
of operated MS. When the 95% confidence intervals for the effects sizes that are being
compared do not overlap, it suggests that the outcomes of the unoperated and operated
MS groups differ significantly.
Of all the outcomes summarized in Tables 2 (unoperated MS) and 3 (operated MS),
only general cognition, motor functioning, verbal skills and visuospatial ability data
were examined in both unoperated and operated children, thus limiting our compar-
ison to these cognitive domains. However, before doing so, we revisited the data that
were extracted from longitudinal studies (Da Costa 2012/2013 & the Infant Learning
Project), which reported pre-surgical data for children with unoperated MS, who later
went on to have surgery and were, therefore, also included in the operated MS findings.
10 A. J. OSBORN ET AL.

Given that these findings were not from independent samples, we removed the pre-
surgical data for children with unoperated MS (but retained the post-surgical/operated
data) and re-calculated the relevant effect sizes. As seen in Table 4, verbal ability was the
only domain where those with unoperated MS (gw = −1.16) performed significantly
worse than those with operated MS (gw = −.15).

General cognitive functioning: surgical status and age

It is possible that outcomes differed according to the age of the sample; particularly
given that the children ranged in age from infancy to 19 years. Thus, we used subgroup
analyses to examine age more closely. Unfortunately, general cognition was the only
domain that was examined by a sufficient number of studies; thereby limiting our
analyses to this one outcome. Studies were grouped according to the developmental
stage of their sample: infants (<12 mths), toddlers (18–24 mths), young children (3–
6 yrs) and older children (>7 yrs) (see Supplementary Table 5). Participant and study
numbers were small, consequently the findings can only be considered tentative. At
most, there appears to be a trend toward unoperated children having poorer outcomes
as they grow older (>7 yrs; gw = −.99), compared with operated children whose general
cognitive abilities more closely resemble their healthy peers/norms as they grow older
(>7 yrs; gw = −.21, n.s.).

Discussion
The current study analyzed data from 17 independent studies that examined a total of 666
individuals in order to determine whether, and to what extent, unoperated and operated
children with MS experience poorer outcomes, when compared to their healthy peers.
Overall, relative to their healthy peers, children who had not undergone surgery for their
MS (Table 2) performed significantly more poorly than their healthy peers in all cognitive
domains that were evaluated: namely, general cognition (e.g., Wechsler Intelligence Scale
for Children – fourth edition [WISC-IV], full-scale IQ), motor functioning (e.g., Purdue
Pegboard Test), verbal (e.g., Wide Range Achievement Test: Word Reading, Spelling
subtests) and visuospatial (e.g., WISC-IV, Performance IQ index) abilities. Similarly, a
high proportion of children (90%) were found to have global development delays and
motor functioning problems (36%). Surprisingly, no studies examined behavioral problems,
depression and anxiety, or satisfaction with appearance in those with unoperated MS,
indicating that future research is needed to identify whether, and to what extent, children
with unoperated MS are experiencing behavioral and psychological difficulties.
In contrast, when children had undergone surgical treatment for their MS (Table 3),
findings were less conclusive. Although a large number of cognitive domains were
assessed, only objective measures of motor functioning, visuospatial abilities, arithmetic
and the subjective measures of attention, executive function and arithmetic differed
significantly from healthy individuals (norms). Nevertheless, sample sizes were small
and most domains only assessed by a few studies, rendering it difficult to draw
conclusions, and highlighting the need for additional data in order to assess the extent
to which children who have received surgical treatment for their MS differ from their
healthy peers.
 CHILD NEUROPSYCHOLOGY 11

When the cognitive functioning of unoperated and operated children were compared
(Table 4), there was a trend for unoperated children to have poorer outcomes than
those who had received surgical treatment. Surgical decisions are often primarily based
on the appearance of the forehead (i.e., the extent of the visible deformity)(Forrest &
Hopper, 2013). However, appearance may be influenced by the severity of the condition
– which varies from a barely palpable/visible ridge to fulminant trigonocephaly
(Mathijssen, 2015) – and the age at which the metopic suture closes, because the earlier
it fuses, the more severe the changes to appearance (Yee et al., 2015). It is possible
though, that the degree of visible deformity does not necessarily correlate with the
degree of disturbance to the underlying structure/function of the brain (Yang et al.,
2017), with a mild deformity actually indicative of a failure of compensatory growth.
We also wanted to explore the functioning of unoperated and operated children at
various developmental stages, in order to determine whether the outcomes of children with
MS differed compared to their healthy peers at different ages. However, the data were
limited and, thus, it is difficult to draw firm conclusions. Nevertheless, there was a trend
toward poorer general cognitive functioning in unoperated children who had reached
kindergarten/school-age compared to their healthy peers, possibly indicating that deficits
become more evident as children reach an age where they are faced with greater intellectual
demands (Yang et al., 2017). Although preliminary, these findings suggest that additional
research should be undertaken with older children who have unoperated MS in order to
ascertain the long-term impact of MS on cognitive functioning.
The current meta-analysis was unable to determine why those who had undergone
surgery often had better outcomes than those who had not. It is possible that reduced
mechanical pressure on the brain improved blood flow, leading to better cognitive perfor-
mance (see Mathijssen, 2015 for a review). Alternatively, patients who had undergone
surgery may have had more frequent follow-up and, consequently, greater access to support
services, such as speech therapy, occupational therapy, physiotherapy, psychology; poten-
tially leading to better outcomes (Cole & Ball, 2013). Furthermore, the comparability of the
unoperated and operated groups prior to decisions being made about surgery was not able
to be addressed by the current meta-analysis. For example, the decision not to operate may
have been made in some cases based on other conditions or comorbidities, which may
themselves be associated with developmental delay.
Overall, the results suggest that all patients with MS should undergo ongoing
developmental and cognitive assessments, with referral to support services as needed.
Moreover, the high number of problems seen in children with unoperated MS suggests
that, indeed, more children diagnosed with MS may benefit from surgical treatment,
which could have implications for current clinical protocols.
Finally, there are a number of limitations that warrant consideration. First, some of
the “unoperated” studies recruited infants who, in some cases, were patients in pre/
post-surgery outcome studies but, in others, it is not known whether infants received
surgical treatment at a later date. Thus, the current study was unable to determine
whether there were other important differences between these groups, which may have
influenced their functioning. Second, samples were often small and a matched control
group was rarely recruited, however test-norms were used to partly address this
problem. Third, some data were excluded because, on occasion, studies reported
findings from measures that were not standardized or objective (e.g., parent’s opinions
12 A. J. OSBORN ET AL.

of their child’s problems) or the participants were known to be experiencing develop-

mental difficulties. In addition, the exact criteria used to identify children with pro-
blems differed between studies and, moreover, in the case of infant assessments, the
measures used to assess cognitive functioning have lower reliability and may not
accurately predict later performance (Sattler, 2014). Fourth, many studies did not
provide important data, such as age, sex, surgical status or, on occasion, details of the
outcome measure, thus limiting our ability to perform moderator analyses. Finally,
there were frequently only a small number of studies examining each domain, which
may limit the reliability of our findings.

Conclusions
Overall, despite the limited research that has been undertaken, it appears that indivi-
duals with MS experience deficits in cognitive functioning, with behavioral and psy-
chological problems also common. Of particular note, is the fact that children who are
treated conservatively appear to experience more difficulties than both their healthy
peers and the children with MS who receive surgery. For this reason, all children with
MS should be monitored from infancy on an on-going basis in order to ensure they
receive appropriate access to support services. The limited data available in the current
meta-analysis – particularly in domains other than general cognition – highlights the
importance of undertaking further research into the long-term outcomes of both
unoperated and operated metopic synostosis. Importantly, wherever possible, these
studies should use larger sample sizes and include a control/comparison group in
order to enhance the conclusions that can be drawn.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
This work was supported by the Australian Cranio-maxillo Facial Foundation.

ORCID
A. J. Osborn http://orcid.org/0000-0002-9720-7117
R. M. Roberts http://orcid.org/0000-0002-9547-9995
J. L. Mathias http://orcid.org/0000-0001-8957-8594
W. J. Flapper http://orcid.org/0000-0001-5960-4595

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