SSC, A Review of Neurobehavioral Research and Theory

Journal of Pediatric Psychology () pp. –, doi:./jpepsy/jsh

Journal of Pediatric Psychology vol. no. © Society of Pediatric Psychology ; all rights reserved.

Single-Suture Craniosynostosis: A Review of Neurobehavioral Research and Theory

Matthew L. Speltz,1 PHD, Kathleen A. Kapp-Simon,2 PHD, Michael Cunningham,3 MD, PHD, Jeffrey Marsh,4 MD, and Geraldine Dawson,5 PHD1Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; 2Department of Surgery, Northwestern University, Chicago; 3Department of Pediatrics, University

of Washington, Seattle; 4Department of Plastic and Reconstructive Surgery, Washington University,

St. Louis, Missouri; 5Department of Psychology, University of Washington, Seattle

Objective To review research and theory regarding the neurobehavioral correlates and

outcomes of single-suture, or isolated, craniosynostosis in children. Methods A critical

review of 17 studies of the hypothesized association between isolated craniosynostosis and

neurodevelopment. Results Isolated craniosynostosis is associated with a three- to fivefold

increase in risk for cognitive deficits or learning/language disabilities. The causal basis for this

association is unclear. No particular calvarial suture (sagittal, metopic, left or right unilateral

coronal) has been associated with higher risk of problems. There is little evidence from quasi-

experimental studies that cranioplastic surgery prevents or reduces risk of neurobehavioral

impairment. Conclusions Future studies would benefit from larger samples and larger con-

trol groups; measures of specific neuropsychological functions (in addition to global cognition);

analyses of neuropsychological status in relation to the severity and cortical impact of synosto-

sis; and an examination of interactions between synostosis and social/family risk factors on

neurodevelopment. Routine neurodevelopmental screening of young children with isolated

craniosynostosis is recommended.

Key words craniosynostosis; neuropsychology; cranioplasty.

Craniosynostosis refers to the premature fusion of one ormore of the fibrous joints (sutures) that normally sepa-rate the bony plates of the infant’s skull. In typicallydeveloping infants, open sutures allow the skull to expandas the brain grows, producing relatively normal headshape. If one or more sutures are prematurely fused,there is restricted growth perpendicular to the fusedsuture(s) and compensatory growth in the skull’s unfusedbony plates, producing abnormal head shape. The etiologyand pathogenesis of craniosynostosis are unclear. Multiplefactors have been implicated, including genetic processes(monogenic disorders and chromosomal aberrations),teratogens (e.g., nicotine and nitrosatable medications),fetal head constraint, and metabolic and hematologic

disorders (Cohen, 1991). Multiple-suture fusions areassociated with several well-described genetic syn-dromes—including Apert, Crouzon, Pfeiffer, SaethreChotzen, and Carpenter syndromes—which have beenassociated with elevated rates of mental retardation andlearning disabilities (Cohen, 1991).

Single-suture synostosis includes isolated fusions ofthe sagittal, metopic, and left or right coronal or lamb-doid sutures. In Figure 1 (Panel A) these sutures areshown on a three-dimensional CT (computerized tomog-raphy) scan of a normal skull. Metopic synostosis (Figure 1,Panel B) produces a triangular head shape (trigonoceph-aly) that features a forehead midline ridge, frontotempo-ral narrowing on both sides of the head, and a broad

All correspondence concerning this article should be addressed to Matthew L. Speltz, CHRMC, 4800 Sand Point Way, N.E., MS CL-08, Seattle, WA 98105. E-mail: [email protected].

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Speltz, Kapp-Simon, Cunningham, Marsh, and Dawson

parietal-occiput. Unilateral coronal synostosis (Figure 1,Panel C) is characterized by an asymmetrically skewedhead (plagiocephaly) with retrusion of the forehead andbrow on the same side as the fused suture and with com-pensatory “bossing” (bulging) of the forehead on the sideopposite of the fused suture. Plagiocephalic head shape isalso found in cases of unilateral lambdoid synostosis, char-acterized by occipital retrusion on the fused side and bybossing in the occipital and frontal areas on the oppositeside. Plagiocephaly associated with unilateral coronal or

lambdoid synostosis can be distinguished clinically fromthe relatively common “positional” or “deformational”plagiocephaly, which is believed to result from externalforces shaping the infant’s malleable skull (e.g., invariantsleeping position; see Mulliken, Van Der Woude, Hansen,LaBrie, & Scott, 1999). Sagittal synostosis (Figure 1, PanelD) is manifest at birth as a long, narrow head shape(scaphocephaly) with bifrontal and occipital bossing.

The incidence of an isolated suture fusion is about 1in 2,000 live births (Shuper, Merlob, Grunebaum, &

Figure 1. Examples of single-suture craniosynostosis: (a) normal skull 3D CT scan with pseudocolored sutures: red-metopic = M, blue-coronal = C, green-sagittal = S, and orange-lambdoid = L; (b) metopic synostosis-red arrowheads in position of prematurely fused suture; (c) unilateral right coronal synostosis, with blue arrowheads in position of prematurely fused suture; (d) sagittal synostosis-green arrowheads in position of prematurely fused suture. Note the changes in skull shape with reduced growth perpendicular to the fused suture.



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Single-Suture Craniosynostosis

Reisner, 1985; Singer, Bower, Southall, & Goldblatt,1999). Sagittal synostosis is believed to be the mostcommon (e.g., 1 in 4,000 births; Lajeunie, LeMerrer,Bonaiti-Pellie, Marchac, & Renier, 1996), although inci-dence figures for each of the specific suture fusions havevaried tremendously (Singer et al., 1999). The majorityof single-fusion cases are sporadic, although mutationsin the fibroblast growth factor receptor genes have beenfound in some cases (e.g., Moloney et al., 1997). Mostcases of isolated synostosis require a single surgery(cranioplasty) to release the fused suture and reshape thedeformed calvaria. Surgery is preferentially performedwithin the first year of life (typically 3–6 months of age),which capitalizes on the malleability and rapid growthof the infant’s brain and minimizes secondary facialdeformation (Marsh, Jenny, Galic, Picker, & Vannier,1991; Marsh & Vannier, 1986). Surgery before 1 or 2months of age is rare, due to concerns about blood loss andother survivability factors (Jimenez, Barone, Cartwright,& Baker, 2002).

Relevance for Pediatric Psychology

Single-suture craniosynostosis and its associated neuro-behavioral features represent an important area of studyand clinical intervention for pediatric psychologists. Sin-gle-suture synostoses are relatively common birthdefects that present frequently in hospital-based cranio-facial programs and neurodevelopmental centers, eitheralone or with other developmental disorders. Communitypediatric practices are often faced with the differentialdiagnosis of isolated synostosis versus the relatively fre-quent presentation of positional plagiocephaly (Mullikenet al., 1999). As this review demonstrates, there is grow-ing evidence that single-suture craniosynostosis is asso-ciated with neurobehavioral problems, including learningdisabilities and behavior problems (e.g., Kapp-Simon,1998; Magge, Westerveld, Pruzinsky, & Persing, 2002).Although the causal relation between this condition andneurodevelopment is uncertain, it would appear thatcalvarial abnormality is at the very least a visible andeasily diagnosed marker for elevated risk of neurodevel-opmental problems. This creates opportunities withinsystems of pediatric care for early detection of neurobe-havioral difficulties and preventative interventions.Moreover, congenital defects involving an infant’s faceand skull seem to evoke particularly strong emotionalresponses from parents, who must contend with a hostof potentially stressful events and circumstances, includ-ing the infant’s unusual appearance, potentially life-threatening surgeries and other medical procedures, and

the possibility of future neuropsychological and educa-tional problems (Endriga & Kapp-Simon, 1999). All ofthese factors can potentially affect parents’ responsive-ness and adaptation to the infant with craniofacialabnormality (Speltz, Greenberg, Endriga, & Galbreath,1994). Hospital- or clinic-based psychological inter-ventions for parents experiencing extraordinary levels ofstress or belonging to certain high-risk categories (e.g.,young, single, primiparous mothers; Endriga, Speltz,Maris, & Jones, 1998) may have beneficial effects oninfants’ neurobehavioral development.

In recognition of the many psychosocial factorsaffecting the physical and psychological developmentof infants and children with craniosynostosis andother craniofacial conditions, the practice parametersof the American Cleft Palate-Craniofacial Associationrequire the provision of psychological assessment andintervention services by hospital-based craniofacialteams (American Cleft Palate-Craniofacial Associa-tion, 1993, 1996). It is therefore important that pedi-atric psychologists become familiar with emergingresearch on this type of craniofacial anomaly and itsimplications for neurodevelopmental theory and clini-cal practice.

Before reviewing specific neurobehavioral findings,we first discuss theoretical complexities and measure-ment issues surrounding the investigation of interrela-tionships between the brain and cranium, focusing onthe potential mechanisms by which calvarial suturefusions might affect neurodevelopment. After reviewingspecific neurobehavioral findings, we provide a method-ological critique of this research and offer suggestionsfor future studies of isolated synostoses.

Interrelated Growth of Brain and Cranium

Until recently there has been little study or theoreticaldiscussion of the interrelations between the developingbrain and cranium (Kjaer, 1995). Clinical formulationsof the relation between calvarial suture fusion and neu-rodevelopment (e.g., Cohen, 1986) have typicallyassumed a linear causal pathway in which suture fusionadversely affects brain development. Two specific path-ways, operating alone or in combination, have been pro-posed in this regard: elevated intracranial pressure withhypovascularity (e.g., Renier, Sainte-Rose, Marchac, &Hirsch, 1982) and secondary cerebral deformation result-ing from brain growth in an abnormally shaped skull(Fernbach & Feinstein, 1991). Another causal pathwayis also possible in which primary brain malformationcould lead to both synostosis and neurodevelopmental



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difficulties. We next discuss the details of, and empiricalsupport for, each of these possibilities.

Intracranial Pressure (ICP)

Elevated ICP is the most frequently cited mediator of thepresumed negative effect of suture fusions on braindevelopment (Cohen & Persing, 1998). Elevated ICP isbelieved to promote hypovascularity in the approximateregion of the fused suture, leading to hypoplasia ofunderlying brain tissue. Clinical formulations often referto the reduction or prevention of elevated ICP as one ofthe primary reasons why cranioplastic surgery mayreduce the probability of neurodevelopmental delay ordeficits in infants with craniosynostosis (e.g., Renier &Marchac, 1988). This hypothesis has been widely com-municated to parents, mostly via websites that suggest acausal relation between ICP and subsequent neurobe-havioral problems and that surgery may relieve ICP andtherefore prevent or lower the risk for “brain damage”and associated neurobehavioral deficits. What is theempirical evidence for such claims, particularly for chil-dren having single-suture synostosis?

Thompson et al. (1995) monitored the subduralICP of 74 children with sagittal, metopic, or unilateralcoronal synostosis while they slept. Using a standard cri-terion for “elevated” ICP (readings above 15 mmHg),they found that nearly half of their sample had normalICP, over a third had “borderline” readings, and lessthan 20% had clearly elevated ICP. Among the differenttypes of synostosis, the metopic and sagittal groups hadthe highest proportions of elevated cases (38% and 24%,respectively). Renier et al. (1982) reported similar find-ings in their sample of children with single-suturesynostosis, using the same criterion for elevation. Fewstudies have examined associations between ICP andneurobehavioral status. Renier and Marchac (1988)compared the ICP values of children with developmen-tal quotients above and below 90 on standardized cogni-tive measures. Among the single-suture anomaliesincluded in these analyses (sagittal and unilateral coro-nal), only those with unilateral coronal synostosisshowed the hypothesized inverse relation between cog-nitive status and ICP; however, it is unclear whether thisassociation was statistically significant (no details ofthese analyses were reported). Neither Arnaud, Renier,and Marchac (1995) nor Gewalli et al. (2001) found sig-nificant associations between ICP and developmentaltest scores in independent samples of infants with sagit-tal synostosis.

Cohen and Persing (1998) have discussed the manyproblems in interpreting ICP data, including the use of

differing measurement techniques and patient selectioncriteria among investigators; and the complete lack ofnormative data, which are unlikely to become availableuntil there are reliable methods of noninvasive measure-ment (Mouradian, 1998). In the absence of normativedata, the precise threshold for “abnormal” readings isunclear. ICP is also difficult to quantify, as it is a chang-ing value that covaries with an individual’s activities(e.g., coughing or sneezing can produce rapid increasesup to 50 or 60 mmHg). ICP therefore needs to be mea-sured over an extended period to obtain a stable repre-sentation. The metric most reflective of clinicallymeaningful intracranial hypertension is still a matter ofdebate (e.g., mean values or number of elevations abovethreshold; see Eide, Helseth, Due-Tonnessen, & Lundar,2002). Cohen and Persing noted the relative infrequencyof clinical indicators of increased ICP in cases of single-suture synostosis (e.g., irritability, head banging, retinalchanges), even among those with elevated readings. Theconsequences of elevated ICP in the absence of clinicalsymptoms are unclear.

Overall, it would appear that the elevated ICPhypothesis is at best modestly supported by availabledata, with uncertain implications for the causal relationbetween synostosis and brain growth.

Secondary Cerebral Deformation

Radiographic studies of craniosynostosis have revealedabnormalities in the subarachnoid space beneath theregion of suture fusion (i.e., a scalloped, or “hammeredsilver,” appearance apparent on CT scans) and compres-sion of the neighboring ventricular system (e.g., Carmel,Luken, & Aschere, 1981). These observations suggestthat cortical or even subcortical brain tissue is com-pressed or “redirected” in the process of growing withina skull that has limited capacity to accommodate suchgrowth. For example, metopic and sagittal synostosesimpose midline restrictions that potentially affect frontallobe development. In metopic synostosis, the ventraldevelopment of the brain may be limited by severelyrestricted ventral expansion of the anterior cranial fossaand frontal bones. In sagittal synostosis, there are frontalprominences that seem to result from excessive pressureof the growing frontal lobes, presumably due to theinability of the skull to expand sufficiently bi-tempo-rally; in other words, there may be redirection of braingrowth toward the frontal lobes because lateral growthis restricted. In unilateral coronal synostosis, the frontalbone ipsilateral to the synostosis is retruded, and theunderlying frontal lobe could therefore be compressedand/or hypoplastic.



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Evidence for these hypothesized secondary deforma-tions is just beginning to emerge. In a recent study usingthree-dimensional MRI (magnetic resonance imaging),Marsh and colleagues (Aldridge, Marsh, Govier, &Richtsmeier, 2002) examined preoperative infants withisolated sagittal, metopic, and unilateral coronal or lamb-doid synostosis and compared them with unaffectedinfants. Significant differences in subcortical morphologywere found. Sagittal patients displayed anteriorly dis-placed lateral ventricles (LV) and rostrum of the corpuscallosum relative to the unaffected group. In unilateralcoronal patients, the anterior LV on the affected side wasdisplaced toward the midline, and the anterior corpus cal-losum was compressed. In metopic patients, the posteriorLV were truncated, and there was midline constriction inthe area between the left and right caudate nuclei.

The effects of these observed secondary cerebraldeformations on children’s measurable functional abili-ties are unclear. One complication is the lack of one-to-one correspondence between particular sutures and sub-cortical brain structures. For example, the sagittal,metopic, and unilateral coronal sutures may all poten-tially affect frontal lobe growth to some degree. Never-theless, tentative functional hypotheses can be tendered.If metopic, sagittal, or coronal synostoses have detri-mental effects on frontal lobe development, executivefunctions (e.g., attention, inhibition, working memory,and flexibility) could be more problematic for these chil-dren than other neuropsychological functions, as hasbeen hypothesized by Persing, Magge, Westerveld, andPruzinsky (1999). Similarly, children with unilateralcoronal synostosis might experience problems in inter-hemispheric functions, due to the compression of thecorpus callosum, observed by Marsh and colleagues.However, it is important to also consider that neuropsy-chological functions may have limited relation to theaffected suture and associated structural deficits, due tothe effects of neural plasticity, compensatory processes,behavioral adaptation and environmental factors. All ofthese factors are likely to moderate the effects of com-pression or hypoplasia on brain structures occurring inthe early months or years of life (Johnson, Halit, Grice, &Karmiloff-Smith, 2002; Spreen, 1989).

Primary Malformation

Assumed deformations of the brain (secondary to synos-tosis) might actually reflect a primary malformation ofthe central nervous system, which also leads to synosto-sis. In other words, synostosis and the types of subcorti-cal anomalies observed by Aldridge et al. (2002) may becausally unrelated, with both attributable to underlying

neuropathology, perhaps originating early in the courseof embryonic development (Kjaer, 1995). This idea isconsistent with emerging evidence that elevated risk ofcraniosynostosis is associated with genetic defects and inutero exposure to environmental toxins such as nicotineor nitrosatable medications (Honein & Rasmussen,2000; Johnston & Bronsky, 1995). Mutations in thefibroblast growth factor receptor genes have been impli-cated in most cases of multiple-suture, syndromic synos-tosis (Gripp, Zackai, & Stolle, 2000; Kan et al., 2002),and mutations in these genes may account for a signifi-cant minority of single-suture cases as well. Current datapoint to isolated unilateral coronal synostosis as themost likely candidate (e.g., Moloney et al., 1997; Schin-dler, Friedrich, Wagener, Lorenz, & Preising, 2002).This finding has important implications for the study ofneurobehavioral outcomes in children with craniosynos-tosis, as the fibroblast growth factor receptor genesappear to play a role in the early development of the cen-tral nervous system (Belluardo et al., 1997; Oh et al.,2003; Sleptsova-Friedrich et al., 2001, Soo et al., 2002;Wilke, Gubbels, Schwartz, & Richman, 1997).

Summary

Clinical formulations of the potential linkage betweensynostosis and neurobehavioral functioning have usu-ally assumed a direct, linear pathway in which suturefusion leads to brain deformation and, consequently,neuropsychological impairment (e.g., Arnaud et al.,1995; Renier & Marchac, 1988). However, there areinsufficient data and limited theory with which tohypothesize any particular causal pathway. It is not clearwhether synostosis is a cause or correlate of neuropa-thology. Even if single-suture synostosis were shown todirectly and independently affect brain structureadversely, compensatory mechanisms and adaptive pro-cesses could significantly alter the form and severity ofassociated functional characteristics. Nevertheless, anecessary first step in the investigative process is toexamine whether a measurable association betweensynostosis and neurobehavioral status exists, under-standing that association does not imply causality.

Measurement Limitations

In addition to previously noted problems in measuringICP, the investigation of associations between synostosisand neuropsychological status is complicated by prob-lems and uncertainties in the measurement of both vari-ables. Although the presence and specific location ofsuture fusions are easily established by clinical diagnosis



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(physical examination confirmed by CT scan), the sever-ity of synostosis and its impact on brain tissue is not soeasily assessed. Several aspects of synostosis are poten-tially quantifiable, including the extent to which thesuture is fused or patent (open) and the degree of com-pression of extraxial cerebrospinal fluid (CSF) spaces inproximity to the fused suture (effacement). Both can beobserved on CT scans, but there are no generallyaccepted or standardized methods of quantifying thesepotential indicators of severity.

The measurement of neurobehavioral variables iscomplicated by the early developmental period in whichsynostosis is initially diagnosed, surgically treated, andfollowed (typically the first 2 years of life). As we showin the review of neurobehavioral findings, most studieshave assessed infants and toddlers before, and at varyingintervals after, surgery in large part because surgery isbelieved to modulate the presumed negative effects ofsynostosis on neurodevelopment (e.g., reduction ofICP). There are relatively few standardized and well-researched measures of infancy neurodevelopment.Most instruments for this age group focus on globalfunctioning (e.g., the Mental Development index fromthe Bayley Scales of Infant Development; Bayley, 1969,1993), with limited assessment of the more specific neu-ropsychological functions of relevance to hypothesizedsuture–brain–behavior relations (e.g., executive func-tion deficits). Given the rapidity of brain growth duringinfancy (Chugani, 1992; Huttenlocher, 1998), the reli-ability and predictability of scores from infancy assess-ments have varied depending on the specific functionsmeasured, age of measurement, and the neurodevelop-mental status of the child (Aylward, 1997; Hauser-Cram,Warfield, Shonkoff, & Krauss, 2001; Shonkoff &Meisels, 2000). For infants with craniosynostosis, reli-able and valid assessment may be further limited byenvironmental stress and instability associated with thediagnostic process and subsequent hospitalization forand recovery from a potentially life-threatening surgery(e.g., negative effects on the caregiving environment dueto parental anxiety; Endriga & Kapp-Simon, 1999).

Review of Neurobehavioral Findings

Table I summarizes the methods and results of 17 stud-ies examining the neurocognitive and/or behavioraldevelopment of children with single-suture craniosynos-tosis. Collectively, these studies have examined wellover 1,000 infants, children, or adolescents with single-suture fusions. Despite this relatively large number,most studies have examined relatively small samples,

the exception being two very large studies conducted inFrance that collected patients over several years (Arnaudet al., 1995; Renier & Marchac, 1988). The ages atwhich cases have been assessed have ranged from 3months to 16 years, with most cases having participants8 years or younger at the time of assessment.

Neurocognitive Findings

The results of studies in Table I can be summarized inrelation to how outcomes were assessed: either member-ship in a specific category of adverse outcome (e.g.,learning disability, language impairment, “behavioral orcognitive abnormality,” test scores below a definedthreshold) or between-group comparisons of averagescores on a test or symptom checklist. Among theformer, most studies found some type of adverse neu-rocognitive outcome in about 35–40% of assessed cases(Bottero, Lajeunie, Arnaud, Marchac, & Renier, 1998;Rozzelle, Marty-Grames, & Marsh, 1995; Shimoji,Shimabukuro, Sugama, & Ochiai, 2002; Shipster et al.,2003; Sidoti, Marsh, Marty-Grames, & Noetzel, 1996),although some reports were as high as 50% (classifica-tions of learning disability by Kapp-Simon, 1998; andMagge et al., 2002). As the prevalence of outcomes suchas learning disability and behavior problems in the gen-eral population of children and adolescents is roughly10% (at least in the United States; Nietzel, Speltz,McCauley, & Bernstein, 1998), these findings suggestthat the risk of poor neurobehavioral outcome in chil-dren with single-suture synostosis may be three-to-fivetimes higher than average. This conclusion is temperedby the fact that some studies used imprecisely definedcategorical outcomes and/or did not directly assess chil-dren but rather relied on clinicians’ reviews of medicalor school records. Exceptions include Magge and col-leagues’ study (2002) of children with sagittal synostosis(in which learning disability was defined by directlymeasured IQ–achievement discrepancy scores) andShipster et al. (2003), who rigorously defined speech andlanguage impairment in terms of standard scores onexpressive and receptive language measures and a dis-crepancy greater than 20 standard score points betweenlanguage and nonverbal IQ scores. The Magge et al.analysis (2002) revealed one of the highest reported lev-els of learning disability among cases with synostosis(50%). These investigators also found that verbal IQ wassignificantly higher than nonverbal IQ, which couldindicate specific problems in learning tasks that requirevisual–spatial abilities or related nonverbal abilities(e.g., perceptual organization and reasoning, visualattention and memory).



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Table I. Summary of Studies

AuthorsNumber of cases

by diagnosisAge at

evaluationNeurobehavioral

measuresControl group? Summary

of results

Barritt, Brooksbank, &

Simpson (1981)

44 sagittal

(31 without

surgical correction)

1–16 yrs Unspecified

psychological

assessment and

chart review

No 10% with developmental

deficits, 7% with learning

disability. High psychological

distress related to head

shape in no surgery group

Muke (1972; cited in

Camfield &

Camfield, 1986)

14 sagittal

1 unilateral coronal

7–12 yrs Unspecified battery

of psychological

tests

Yes Group differences favoring

control group on each

psychological test:

synostosis: mean IQ = 79

control: mean IQ = 104

Hunter & Rudd

(1976, 1977)

205 sagittal


13 metopic

23 bicoronal

16 lambdoid

64 multisuture

Not provided Unspecified

intelligence

tests given at

unknown ages

No Only retardation rates

reported: sagittal: 8.9%

unilateral coronal: .096%

bicoronal: 26%

metopic: not reported

multisuture: 26%

Renier & Marchac

(1988)

90 sagittal

18 metopic


28 bilateral coronal

105 other multisuture

synostoses

Not provided Unspecified

developmental/

intelligence test

given at widely

varying ages

No Inferential statistics not

reported. For single-suture

diagnoses, normal IQ score

distribution.

Kapp-Simon (1994,

1997, 1998;

Kapp-Simon et al.

(1993)

30 sagittal

19 metopic


Mean age at

T1 = 8.1 mo

T2 = 18.4 mo

T3 = 50.2 mo

BSIDa or BSID-II at T1

and T2, MSCAb at T3,

LD determined by

direct assessment

and/or chart

review at school

age

No Pre- and postsurgery MDIc

scores unrelated to surgery

age (T1 mean = 100,

SD = 13; T2 mean = 95,

SD = 15) (N = 53). Mental

retardation rate: 6.5%;

learning disorders rate:

47% (N = 34).

Arnaud, Renier, &

Marchac (1995)

396 sagittal

100 were tested twice

(41 without

surgical correction)

Mean age at

1st testing =

1 yr

2nd testing =

6.4 yr

Brunet-Lezine scale

for children “and

younger” 3. Revised

Binet-Simon

IQ test for older

children

No No group differences by

surgery status: No surgery:

T1 DQ mean = 105, SD = 8,

range = 80–125; T2 IQ

mean = 106, SD = 12,

range = 76–136; Surgery T1

DQ mean = 101, SD = 12

Rozzelle, Marty-Grames,

& Marsh (1995)

38 sagittal Preschool to

Grade 12

Retrospective chart

review focusing

on results of speech

and language

evaluations

No 37% classified as “impaired”

in language, articulation,

and/or phonology

Sidoti, Marsh,

Marty-Games, &

Noetzel (1996)

32 metopic 8 yr 3 mo on

average

Combination of parent

questionnaire and

medical chart review

targeting behavior,

language, and learning

problems

No 37.5% identified as having

one or more behavioral or

cognitive abnormalities

Speltz, Endriga, &

Mouradian (1997)

19 sagittal Presurgery,

12 mo,

24 mo

BSID given

longitudinally

at 3, 12, and 24 mo

Yes:

19 matched

for age,

gender, SES

No group differences at any

age. MDI scores and

surgery age inversely

correlated (r = –.30).



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Table I. Summary of Studies (Continued)

Abbreviations: BSID = Bayley Scales of Infant Development; BSID-II = Bayley Scales of Infant Development, 2nd edition; CELF-R = Clinical Evaluation of Language

Fundamentals–revised; DQ = developmental quotient; (BSID-II); ICP = intracranial pressure; LD = learning disability; MDI = Mental Development index (from the BSID);

MSCA = McCarthy Scales of Children’s Abilities; PDI = Psychomotor Development index (from the BSID); PIQ = Performance IQ; PLS-3 = Preschool Language Scale, 3rd

edition; SES = socioeconomic status; VIQ = Verbal IQ; WISC-III = Wechsler Intelligence Scale for Children–third edition; WISC-R = Wechsler Intelligence Scale for

Children–revised; WPPSI-R = Wechsler Preschool and Primary Scale of Intelligence, revised.

AuthorsNumber of cases

by diagnosisAge at

evaluationNeurobehavioral

measuresControl group? Summary

of results

Bottero, Lajeunie,

Arnaud, Marchac,

& Renier (1998)

76 metopic Presurgery

(before age 3 yr)

and “most recent

assessment”

(mean age

6.5 yr)

Testing same as Arnaud

et al., 1995, plus reports

from parents, teachers,

and clinic team to

determine presence/

absence of “developmen-

tal problems”

No 32% of sample with reported or

observed developmental problem.

Problem status associated with

severity of frontal stenosis, surgery

> 1 yr of age, extracranial

abnormality.

Virtanen, Korhonen,

Fagerholm, &

Viljanto (1999)

18 sagittal 7.8–16.3 yr

(mean age

12.2 yr)

Test battery measuring

fine motor/visual–spatial

skills, reading, language

and memory

Teacher ratings of

achievement, parent

ratings of behavior

Yes:

18 matched

for age,

gender

Group differences favoring the control

group found on 3 WISC-R subtests

(Similarities, Comprehension, and

Digit Span)

DeLeon, Speltz, &

Cunningham

(2000)

37 sagittal Presurgery

(before

12 mo) and up

to 6 mo

postsurgery

BSID No Presurgery PDI,d but not MDI, scores

were significantly lower than test

norms. No significant pre- or

postsurgery change in scores. No

relation found between BSID

scores and age at surgery.

Panchal et al. (2001) 21 synostosis

(11 sagittal,

5 metopic,

3 unilateral coronal,

2 bilateral coronal)

42 plagiocephaly

without synostosis

Presurgery

(mean age =

11 mo) or

prehelmet

therapy (mean

age = 8.4 mo)

BSID-II No Synostosis group: PDI, but not MDI,

scores lower than test norms.

Plagiocephaly group: Both PDI and

MDI scores lower than test norms.

Gewalli et al. (2001) 26 sagittal 4–16 mo

presurgery;

9–40 mo

postsurgery

Griffiths’s Mental

Development Scales

No No association between DQ and ICP or

pre- and postsurgical status.

Magge Westerveld,

Pruzinsky, &

Persing (2002)

16 sagittal 6.4–16 yr

(mean =

10.3 yr)

Test battery measuring IQ

(WISC-R), achievement,

attention, and vigilance,

executive functions,

visual-motor skills, and

behavior

No Full scale IQ in normal range but VIQ

significantly higher than PIQ. 50%

rate of learning disability as defined

by IQ–achievement discrepancy

scores (approximately 1 SD)

Shimoji,

Shimabukuro,

Sugama, & Ochiai

(2002)

65 “mild”

metopic

Less than 1 yr

to 9 yr. Assessed

before surgery

and 6 mo later

K-Form Developmental

Test (yields a

developmental quotient)

and Japan Child

Behavioral Checklist

Neurological exam

No 94% with language delay before

surgery. Some improvement in

language following surgery; most

remain significantly delayed

(37% DQ < 60); behavior improved

after surgery. No significant changes

in nonsurgery group.

Shipster et al. (2003) 76 sagittal 9 mo−15 yr BSID-II, PLS-3, WPPSI-R

UK, WISC-III UK,

CELF-Re, other tests

No 38% with speech and/or language

impairment, primarily expressive

language problems. No increased rate

of global IQ deficit.



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Few studies have reported actual rates of mentalretardation (typically defined as standardized test scoresbelow 70). Hunter and Rudd (1976, 1977), Kapp-Simon(1998), and Sidoti et al. (1996) reported slightly increasedrates of mental retardation (from 6.5 to 12%). This com-pares to an expected rate of approximately 2.2% in thepopulation.

Among studies that focused on or included analysesof average group performance, two used a matchedcontrol group, and the others compared the perfor-mance of cases with test norms (i.e., essentially compar-ison with the test’s standardization group). One of thetwo control-group studies found that children withsagittal synostosis scored significantly lower thancontrols on 3 subtests of the WISC-R (Wechsler Intelli-gence Scale for Children–revised; Virtanen, Korhonen,Fagerholm, & Viljanto, 1999), although these differ-ences might not have reached statistical significance hadthe data been analyzed more conservatively (i.e.,controlling for the number and intercorrelation ofvariables analyzed). The other study using a matchedcontrol group (Speltz, Endriga, & Mouradian, 1997)found no differences between infants with and withoutsagittal synostosis tested at three age points (3, 12, and24 months).

Nearly all studies comparing average test scores totest norms examined infants and toddlers with the well-known Bayley Scales of Infant Development (BSID;Bayley, 1969), using the BSID Mental Development index(MDI) and Psychomotor Developmental index (PDI).Kapp-Simon’s studies (1994, 1997, 1998; Kapp-Simon,Figueroa et al. (1993)) did not find that cases performedworse than test norms on average. However, Kapp-Simondid not administer the PDI, which in two other studiesrevealed lower-than-average scores among cases than didthe mean of the BSID standardization group (DeLeon,Speltz, & Cunningham, 2000; Panchal et al., 2001). Inboth studies, MDI scores did not distinguish cases fromtest norms. Although it is therefore tempting to speculatethat motor functions are more affected by synostosis thanpurely cognitive functions, this is an unreliable distinc-tion during infancy, given the highly integrated andreciprocal development of cognition and motor skills atthis age (Bremner, 1993). However, the PDI findings mayhave some importance, as studies involving other high-risk groups (e.g., premature infants) have found thatinfancy PDI scores are more predictive of children’s sub-sequent language and intellectual abilities than are MDIscores (Siegel, 1989) and are therefore believed by someinvestigators to better index central nervous systemintegrity (Aylward, Verhulst, Bell, & Guyrke, 1995).

Behavior and Social Adjustment

Few studies of craniosynostosis have included measuresof children’s behavior and social–emotional characteris-tics. Speltz, Morton, Goodell, and Clarren (1993) foundthat children with various craniofacial anomalies—including those with craniosynostosis—were more thantwice as likely as children in a matched control group tohave teacher- and parent-reported behavior problems atschool entry. However, small numbers precluded analy-sis by craniofacial diagnosis.

The Bottero et al. study (1998) of metopic synosto-sis used a categorical outcome measure based in part onclinicians’ judgments regarding the presence or absenceof “behavior problems”; however, there was no specifi-cation of the nature of these problems or how they wereassessed. Investigators of three other studies in Table Iincluded a concurrent measure of behavioral adjustmentor conducted follow-ups of their samples that includedassessment of children’s behavioral–social status. In theFinnish sample of school-age sagittal cases studied byVirtanen et al. (1999), no significant differencesbetween cases and controls in maternal ratings of childbehavioral adjustment were found. Subsequent analysesof the infants with sagittal synostosis examined by Speltzet al. (1997) indicated that these children at 7 years oldshowed higher levels of parent- and teacher-reportedbehavior problems than did a matched group of normalchildren. Using a normed behavior checklist, Kapp-Simon and Dawson (1998) examined the behavior andsocial adjustment of 29 children with single-suturesynostoses at age 7 and found that parental ratings ofproblem behavior were roughly equivalent to thoseobtained in the standardization sample.

Surgery and Neurobehavioral Status

The assertion that cranioplastic surgery prevents or mit-igates neurobehavioral delays or deficits (e.g., Arnaudet al., 1995) has provoked considerable controversy,raising the question of whether the effects of surgery are“merely” aesthetic or functional as well (Hayward,Jones, & Evans, 1999; Kapp-Simon, 1994, 1998; Pos-nick, 1998; Rozelle et al., 1995). To our knowledge,there have been no randomized trials of cranioplasty forcraniosynostosis, given the ethical constraints of thisapproach. Investigators have therefore been forced torely on quasi-experimental designs and measures ofassociation to draw inferences about the effects of sur-gery on neurodevelopment. As noted, age of surgery andneurobehavioral status are hypothesized to show aninverse relation because increased ICP in the absence of



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surgery is expected to affect brain developmentadversely (Arnaud et al., 1995). Several studies havetherefore examined the developmental scores of infantgroups distinguished by surgery before or after a speci-fied age point, or they simply computed correlationsbetween surgery age and outcome measures amongoperated children. Most of these studies have been con-ducted in Europe. In a French cohort, Renier andMarchac (1988) found that 88% of children havingsurgery before 1 year of age (with various synostoses)scored above 90 on a standardized test of infancy devel-opment, whereas only 76% of children having surgeryafter 1 year exceeded this criterion. The investigatorsconcluded that surgery lowered ICP and therefore pre-vented cognitive decline. The same investigative groupfound in a later study (Arnaud et al., 1995) that ICPamong cases of sagittal synostosis was unrelated to cog-nitive functioning, although age of surgery was never-theless correlated inversely with mental function. Thisfinding is difficult to interpret, as ICP is believed to bethe primary mediator of the relation between surgeryage and neurodevelopment. In yet another study bythese investigators, Bottero et al. (1998) found that ageof surgery was one of four variables in a multifactorialmodel accounting for about half of the variance inneurobehavioral measures of children with metopicsynostosis (in order of contribution, the predictors wereseverity of frontal stenosis, family environment, age ofsurgery, and extracranial malformations).

Virtanen et al. (1999) compared cases of sagittalsynostosis having surgery after 1 month of age withthose having surgery at or before 1 month of age.Although no significant differences emerged, the direc-tion of mean group differences favored the early surgerygroup on most measures, and the investigators con-cluded that “an early operation seems to be justified notonly for correction of the skull shape but also to allowunrestricted development for the brain” (p. 791). In aSwedish sample, Gewalli et al. (2001) evaluated the cog-nitive effects of cranioplasty on 26 infants with sagittalsynostosis. No significant pre- or postsurgery differencesin developmental scores were observed, and there wasno association between developmental scores andincreased cranial pressure.

The few studies conducted in the United States havegenerated less-positive findings regarding surgery effects.Speltz et al. (1997) found that MDI scores (based on theBSID) and surgery ages inversely correlated (r = –.30) ina small sample of infants with sagittal synostosis, but nopresurgery-to-postsurgery change in scores was evidentwhen assessed twice and up to a year following surgery.

In subsequent analyses of a larger cohort of infants withsagittal synostosis drawn from the same hospital pro-gram (DeLeon et al., 2000), the correlations betweenBSID scores (MDI and PDI) and surgery age were nearzero. Similarly, there were no significant relations foundbetween MDI scores and surgery age in Kapp-Simon’s(1994, 1997, 1998; Kapp-Simon, Figueroa et al. (1993))samples of infants with various single-suture synostoses.

Methodological Critique

In the interpretation of data regarding surgery age, it isimportant to consider two methodological vulnerabili-ties that commonly limit the inference of causality fromcorrelational data. Correlation is sensitive to the range ofvalues of the variables measured in a particular sample(e.g., restricted range produces lower correlation in thesample than in the general population). The range ofsurgery ages included in studies of craniosynostosis maybe affected by factors unrelated to the etiology of synos-tosis and its neurobehavioral correlates (e.g., regionalpractice parameters, study duration, and subject enroll-ment procedures). Second, age of surgery may be con-founded with other variables that affect neurobehavioralstatus. For example, infants with synostosis who firstcome to the attention of a craniofacial specialist wellinto their second year of life may represent a somewhatdifferent sample of infants from those first diagnosed inearly life; for example, early-diagnosed infants may havebetter medical care, closer proximity to services, morevigilant or concerned parents, parents less ambivalentabout surgery, and so on. Factors such as these couldaffect neurobehavioral development in subtle ways. Weare unaware of studies that have been able to disentanglethe effects of age of detection (i.e., diagnosis) from ageof surgery, as this would require varying intervals oftime between initial testing and surgery—typically,cases have been tested at the time of their initial diagno-sis, with surgery immediately following. It is also possi-ble that surgical timing could have an effect oncognition that is independent of ICP or synostosis (e.g.,early surgeries might be better tolerated by infants interms of initial trauma or recovery). Other reviewershave noted similar problems in the ascertainment andsegregation of cases based on surgery age or occurrence,and they have urged caution in the interpretation ofthese data (Hayward et al., 1999; Kapp-Simon, 1994;Posnick, 1998).

In addition to these issues specific to the study ofsurgical effects, nearly all the studies in Table I havebeen limited by the methodological problems commonly



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found in studies of rare disorders. Sample sizes havebeen typically small, limiting statistical power and pre-cluding analyses of outcome by specific sutural diagno-sis. Little is known therefore about the effects ofdifferent synostoses on neurodevelopment (e.g., sagittalvs. metopic), comparisons that are critical to a betterunderstanding of specific suture–brain–behavior associ-ations. Another problem is the use of nonstandardizedage and assessment points in case series. Cases havebeen initially tested at widely differing ages (this hasusually been necessary to recruit a large enough sam-ple), with extremely variable follow-up assessmentintervals that likely reflect various clinical care exigen-cies (e.g., surgical dates, scheduling convenience). Sel-dom has the selection of assessment ages reflectedinvestigators’ consideration of critical developmentalmilestones or the optimal ages at which certain func-tions can be assessed. Widely differing assessment agescan also introduce unwanted test score variation due tovarying levels of reliability and validity in assessmentinstruments across age periods. For example, Aylward(1992) has noted that standard scores from the BSIDtend to decline with age. To our knowledge, only one ofthe longitudinal studies in this area (Speltz et al., 1997)assessed all cases at the same age points (3, 12, and 24months), but this study had one of the smallest samplesreviewed (n = 19), reflecting the logistical difficulty ofrecruiting a large sample of cases and assessing them allat the same age points.

Another methodological issue is the inclusion/exclusion criteria by which cases are selected, particu-larly with respect to the co-occurrence of associatedintracranial or extracranial anomalies. Bottero et al.(1998) found that nearly 20% of their sample of childrenwith metopic synostosis had one or more extracranialmalformations, including finger deviations and/or extradigits, ear anomalies, maxillofacial abnormalities, andcardiac defects. Such children had higher rates of devel-opmental problems (57%) than those without associatedanomalies (26%), and the relation between age of sur-gery and subsequent developmental outcome was medi-ated by this variable. In contrast, Kapp-Simon andcolleagues (1993) found no differences in mental devel-opment as a function of various risk factors, includingextracranial malformations. Although Posnick (1998)argues that the presence of associated anomalies in chil-dren with single-suture synostosis raises the probabilityof genetic defects and therefore may increase the proba-bility of neurodevelopmental problems, most studies inTable I have provided no information about the pres-ence or absence of associated anomalies.

Most studies in this area have ascertained casesstrictly through large hospital-based programs, anapproach that can introduce sample bias influencing therange and variance of neurobehavioral score distribu-tions. The sources of such bias include regional practiceparameters that may over- or undertarget urban or ruralfamilies, or families with particular socioeconomic back-grounds. Furthermore, hospital programs may be morelikely to see and retain more severe or complicatedpatients than community practices, especially if the sam-ple is recruited in relatively late childhood or adoles-cence. In the absence of population-based epidemiologicaldata, the extent is unknown to which any of the studysamples in Table I represents the larger population ofchildren with single-suture craniosynostosis. Ascertain-ment bias may compromise the external validity of theresearch—for example, to whom can the results of thestudy be appropriately generalized?—as well as internalvalidity, particularly when test scores or categoricaloutcomes are compared only to test norms or knownbase rates of particular outcomes—for instance, samplescontaining a disproportionate number of low-incomefamilies would produce spuriously low estimates ofneurodevelopmental status in the broader population ofcases.

Directions for Future ResearchMultisite Investigations

Two obvious directions for future research are to incor-porate control groups and to develop strategies forincreasing sample size. Larger samples would addressseveral of the methodological shortcomings listed here,including low statistical power, corresponding limita-tions on diagnostic subgroup comparisons, and prob-lems associated with extended case recruitment (e.g.,widely varying ages of assessment). Given the low prev-alence of isolated synostoses, multisite investigationswill almost certainly be necessary to recruit samples ofadequate size. Multisite studies also offer the advantagesof a broader range of surgery ages, greater demographicheterogeneity among cases, and some protection againstprogram-specific ascertainment bias.

Selection and Specificity of Neurobehavioral Measures

With few exceptions (e.g., Magge et al., 2002; Shipsteret al., 2003; Virtanen et al., 1999), the neurobehavioralassessment of craniosynostosis has been narrowlyfocused on a single index of global functioning (e.g., theBSID’s MDI and PDI). Global indexes are less likely to



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detect current and future aberrant development than isthe assessment of multiple domains of functioning,including expressive and receptive language, executivefunctioning and attention, memory, fine- and gross-motor functioning, and visual perception (Aylward,1997; Spreen, Risser, & Edgell, 1995). Although thereliable assessment of separate domains of function ininfants and very young children is challenging, futurestudies of craniosynostosis can benefit from recentdevelopments in standardized testing and experimentalparadigms for assessing fundamental processes. Reznick,Corley, and Robinson (1997), for example, have devel-oped a model for distinguishing theoretically relevantsubsets of BSID items pertaining to receptive language,expressive language, and nonverbal problem solving,which can be used to supplement or replace global indexscores (Speltz et al., 2000). Experimental tasks thatassess specific brain–behavior relations in primates andother animals have been recently adapted for use inyoung humans. One example is the A not B task, whichrequires both working memory and response inhibitionand has been consistently linked to the dorsolateral pre-frontal cortex in primates and humans as young as 18months (Braver et al., 1997; Diamond & Goldman-Rakic, 1986, 1989). Lesions to the medial temporal lobeand parietal cortex do not disrupt performance on thistask, suggesting relative specificity of linkage to the fron-tal lobe (Diamond & Goldman-Rakic, 1989; Diamond,Zola-Morgan, & Squire, 1989). Similar tasks—suitablefor infants and derived from animal studies—have beenassociated with the medial temporal lobe and parietalcortex and assess visual working memory (e.g., Bachevalier& Mishkin, 1986; Squire, Zola-Morgan, & Chen, 1988).

Another strategy for targeting relevant domains offunctioning in future studies is to identify the precursorsor emerging forms of later, fully developed skills. Oneexample of relevance to young children with cranio-synostosis is the well-demonstrated association betweenreading ability at school age and phonological process-ing skills in preschool children (e.g., Leitao, Hogben, &Fletcher, 1997; Webster, Plante, & Couvillion, 1997).Preschool phonological processing is in turn predictedby still earlier measures of rhyming and alliteration(Bryant, MacLean, Bradley, & Crossland, 1990; MacLean,Bryant, & Bradley, 1987). Simple rhyming tasks given tochildren as young as 3 years old have predicted effectiveword decoding at school age, after controlling for gen-eral IQ, receptive vocabulary, memory, and sociometricstatus (Whitehurst & Lonigan, 1998). In light of find-ings suggesting language and/or phonological deficits inschool-age children with isolated synostosis (Rozzelle

et al., 1995; Shipster et al., 2003), future longitudinalstudies should examine the use of these measures as pre-dictors of school-age verbal learning disabilities.

Neurobehavioral Functioning and Severity of Synostosis

Most previous studies have examined neurobehavioralstatus in relation to the presence or absence of diagnosis,with little consideration of severity level or degree ofimpact on brain tissue. Analysis of the interrelationsamong measures of neurobehavioral functioning, sever-ity of synostosis, and degree of compression of brainstructures would help to clarify and refine causalhypotheses. For example, if severity (or degree of)suture fusion and compression of underlying brain tis-sue were highly intercorrelated and predictive of neu-robehavioral status, it would strengthen (although notprove) the hypothesis that these processes are causallyrelated to neurodevelopment. As noted, a limiting factorhas been the lack of standardized methods for assessingseverity and impact of synostosis from CT scans, whichare routinely given to infants with synostosis as part ofthe diagnostic process (MRI is rarely used at this age,due to the risks of sedation). However, future neurode-velopmental studies could develop relatively simplemeasures in this regard.

The percentage of suture patency could be obtainedfrom CT scan by linear measurement of the proportionof native suture remaining open, or “unfused” (i.e., theproportion of total suture length unobstructed). Severityof secondary calvarial deformation could be estimatedby measuring the deformation of skull shape that hasbeen produced by the fused suture. For fusions of thesagittal suture, skull deformation could be estimated bycalculating the ratio of the biparietal and sagittal dimen-sions of the skull. Severity of brain tissue compressioncould be rated or classified by examination of theamount and symmetry of extraxial (subarachnoid) CSFvisible on CT film. For example, it should be possible toreliably distinguish between subarachnoid space dimin-ished to the point of direct contact of the brain with theinner table of the skull—but still showing preserved gyriand sulci—versus complete absence of discernible gyriand sulci. Given large enough sample sizes, these mea-surements and ratings could be correlated with neurop-sychological data, both within and across groups ofchildren with different isolated synostoses.

Effects of Family Environment

There has been surprisingly little investigation of thepotential interaction between craniosynostosis and family



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risk factors on neurodevelopment. Only one studyamong those reviewed included a measure of family orother social risk factors (Bottero et al., 1998). Familyrisks such as single parenting, low socioeconomic status,family or marital conflict, and parenting stress mayexacerbate the adverse effects of synostosis on neurode-velopment—such factors have been shown to influencethe developmental trajectories of children with othertypes of chronic medical conditions or disability (e.g.,Britner, Morog, Pianta, & Marvin, 2003; Hauser-Cramet al., 1999; Kapp-Simon, 2002; Speltz et al., 1994).Parenting stress may be particularly influential, as fewevents are as devastating for parents as learning thattheir newborn has a serious or chronic medical condi-tion or disability that requires potentially life-threaten-ing surgery (Marvin & Pianta, 1996; McCubbin, 1988).In our clinical work with families of infants with cranio-synostosis, we have encountered many parents whoseem confused about the diagnosis and—for reasonsalready discussed—uncertain about the medical neces-sity of surgery, particularly with respect to surgery’s rolein preventing cognitive impairment (Speltz et al., 2003).The style and effectiveness of parental adaptation andcoping responses during this stressful period are likelyto vary widely but have been largely unstudied in thispopulation. Future studies of craniosynostosis wouldbenefit from assessment of the family environment,including measures of parental adjustment to the diag-nosis and its impact on infant-caregiving routines (e.g.,Parenting Stress Index, Abidin, 1995; Reaction to Diag-nosis Interview, Pianta & Marvin, 1992).

Facial Appearance

Infants with single-suture craniosynostosis have visiblyaltered craniofacial appearance, which varies in relationto the location and extent of suture involvement. Thepossibility of permanent abnormality in facial or cranialappearance seems to greatly affect parents’ decisions tohave their infant undergo cranioplastic surgery. Manysurgeons believe that the primary indication for cranio-plasty in isolated synostosis is cosmetic rather than func-tional (Hayward et al., 1999). Even after correctivesurgery, mild residual differences in appearance persistfor some children, particularly those with unilateral coro-nal synostosis. However, this is a clinical impression thathas not been studied empirically in this population. Asthere is clear evidence in other groups of children thateven mild deviations from typical facial appearance canhave significant impact on psychological adjustment(Endriga & Kapp-Simon, 1999; Macgregor, 1982, 1990;Richman, 1978), future studies of infants with single-

suture craniosynostosis should include ratings of appear-ance both before and after cranioplastic surgery, includ-ing comparisons with age- and gender-matched controls.

Summary and Conclusions

The majority of studies reviewed in this paper found atleast modestly elevated risk of neurobehavioral prob-lems among infants or children with single-suturesynostosis, as compared with standardized test norms,estimated population base rates of problems, or (rarely)control groups. This research suggests that the degree ofimpairment associated with synostosis is mild to moder-ate on average. Learning and language disorders andother categories of academic difficulty (“low average”)are the most anticipated problem areas. Quasi-experi-mental studies have found little support for the hypothe-sis that cranioplastic surgery prevents or reduces risk ofthese outcomes. Behavior and social problems may alsooccur at elevated levels among children with isolatedsynostosis, but there are too few studies of this issue tooffer even tentative conclusions.

It remains unclear whether single-suture cranio-synostosis is a cause or correlate of neurobehavioralimpairment. Future studies looking more closely at therelation between neurobehavioral status and the severityand cortical impact of synostosis are needed to clarifyetiological pathways. It is also possible that the probabil-ity of neurobehavioral impairment depends in part onthe co-occurrence and severity of other risk factors,including adversity and stress in the family environ-ment. This hypothesis has yet to be investigated.

Conclusions drawn from the reviewed literatureare tentative, given the methodological limitationsdescribed, which could either minimize or accentuatethe neurobehavioral differences between children withand without single-suture synostosis, particularly withinthe range of dysfunction suggested thus far. Further-more, the majority of studies in this area have examinedchildren during early childhood, when the reliableassessment of mild-to-moderate neurodevelopmentaldeficits is a challenge. The full range of deficits associ-ated with these disorders may not be revealed until thereis opportunity to assess a sizable number of children intheir middle-to-late elementary school years. Only atthis age can different types of learning disorders andsubtle patterns of neuropsychological deficit (e.g., verbalversus nonverbal, reading versus math or visual spatial)be unequivocally established.

From a clinical perspective, the studies reviewedsuggest that the outcomes of most children with isolated



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synostosis (slightly more than half) are indistinguish-able from those of typical children. However, a sizableminority (perhaps 30% to 40%) is likely to have prob-lems in need of intervention. This tentative estimate ofrisk suggests that routine neurodevelopmental screeningand referral would benefit children with synostosis,especially preschool-age children for whom the benefitsof early assessment and intervention have been welldemonstrated (Shonkoff & Meisels, 2000).

Acknowledgment

Dr. Marsh is now in private practice in St. Louis.

Received September 29, 2003; revisions received February 5,2004; accepted March 29, 2004.

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SSC, A Review of Neurobehavioral Research and Theory