Fetal constraint as a potential risk factor for craniosynostosis.
ABSTRACT Non-syndromic craniosynostosis is multifactorial, and fetal head constraint has been hypothesized as one factor thought to play a role. Data from the National Birth Defects Prevention Study (NBDPS), a large multi-site case-control study of birth defects, were used to evaluate associations between four selected factors related to fetal constraint and craniosynostosis: plurality (twins or higher), macrosomia (birth weight >4,000 g), post-term gestational age (> or =42 weeks), and nulliparity (no previous live births). Case infants (n = 675) had craniosynostosis documented either by radiographic evidence or by surgical intervention. Infants with a recognized or strongly suspected single-gene conditions or chromosomal abnormalities were excluded. Control infants (n = 5,958) had no major birth defects and were randomly selected from the same population as case infants. Logistic regression was used to estimate odds ratios for the association between these four factors and craniosynostosis, while adjusting for several covariates. We found that plurality and nulliparity were associated with a twofold increased risk for metopic craniosynostosis, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were also associated with craniosynostosis. In conclusion, these four constraint-related factors were not found to be associated with craniosynostosis when all suture types were combined, though some types of craniosynostosis were associated with individual constraint-related factors.
- [Show abstract] [Hide abstract]
ABSTRACT: We report on a young child with intellectual disability and unilateral coronal craniosynostosis leading to craniofacial malformations. Standard karyotype showed an apparently balanced translocation between chromosomes 2 and 15 [t(2;15)(q21;q21.3)], inherited from his mother. Interestingly, array-CGH 180K showed a 3.64 Mb de novo deletion on chromosome 15 in the region 15q21.3q22.2, close to the chromosome 15 translocation breakpoints. This deletion leads to haploinsufficiency of TCF12 gene that can explain the coronal craniosynostosis described in the patient. Additional FISH analyses showed a complex balanced maternal chromosomal rearrangement combining the reciprocal translocation t(2;15)(q21;q21.3), and an insertion of the 15q22.1 segment into the telomeric region of the translocated 15q fragment. The genomic imbalance in the patient is likely caused by a crossing-over that occurs in the recombination loop formed during the maternal meiosis resulting in the deletion of the inserted fragment. This original case of a genomic microdeletion of TCF12 exemplifies the importance of array-CGH in the clinical investigation of apparently balanced rearrangements but also the importance of FISH analysis to identify the chromosomal mechanism causing the genomic imbalance. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 06/2014; 164(6). · 2.30 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Purpose:Craniosynostosis is a common cranial malformation occurring in 1 per 2,000-2,500 births. Isolated defects (nonsyndromic) occur in ~75% of cases and are thought to have multifactorial etiology. It is believed that each suture synostosis is a distinct disease, with varying phenotypes and recurrence rates.Methods:We analyzed family histories of 660 mutation-negative nonsyndromic craniosynostosis patients and symptoms in 189 of these patients.Results:The incidence rate of craniosynostosis was highest for first-degree relatives of probands with metopic craniosynostosis (6.4%), followed by those with complex craniosynostosis (4.9%), sagittal craniosynostosis (3.8%), lambdoid craniosynostosis (3.9%), and coronal craniosynostosis (0.7%). Across all suture types, siblings had a greater craniosynostosis incidence rate than parents (7.5 vs. 2.3%). In phenotype comparisons, patients with complex craniosynostosis had the highest frequency of reported symptoms and those with sagittal craniosynostosis had the lowest. Ear infections, palate abnormalities, and hearing problems were more common in complex craniosynostosis patients. Visual problems were more common in coronal craniosynostosis, and metopic craniosynostosis patients noted increased frequency of chronic cough.Conclusion:Our data suggest that the genetic component of nonsyndromic craniosynostosis appears to be suture specific. The incidence rate of craniosynostosis among first-degree relatives varies by suture and family member. Additionally, the phenotype of each suture synostosis shows both unique and shared features.Genet Med advance online publication 26 September 2013Genetics in Medicine (2013); doi:10.1038/gim.2013.134.Genetics in medicine: official journal of the American College of Medical Genetics 09/2013; · 3.92 Impact Factor
Article: Birth Defects Epidemiology[Show abstract] [Hide abstract]
ABSTRACT: This article provides background information about epidemiologic methods and how they can be used to further our understanding of what causes birth defects. It briefly describes basic study designs and advantages and disadvantages of each, provides examples of how epidemiologic studies contribute to our current understanding of the etiologies of birth defects, and makes recommendations for future research.European journal of medical genetics 08/2014; · 1.57 Impact Factor
Fetal Constraint as a Potential Risk
Factor for Craniosynostosis
Pedro A. Sanchez-Lara,1* Suzan L. Carmichael,2John M. Graham Jr.,3Edward J. Lammer,4
Gary M. Shaw,2,5Chen Ma,2Sonja A. Rasmussen6
and the National Birth Defects Prevention Study
1Children’s Hospital Los Angeles, Keck School of Medicine at the University of Southern California, Los Angeles, California
2California Research Division, March of Dimes Foundation, Oakland, California
3Medical Genetics Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California
4Children’s Hospital Oakland Research Institute, Oakland, California
5Stanford University School of Medicine, Stanford, California
6Centers for Disease Control and Prevention, Atlanta, Georgia
Received 1 June 2009; Accepted 7 November 2009
Non-syndromic craniosynostosis is multifactorial, and fetal
head constraint has been hypothesized as one factor thought to
play a role. Data from the National Birth Defects Prevention
Study (NBDPS), a large multi-site case–control study of
birth defects, were used to evaluate associations between four
selected factors related to fetal constraint and craniosynostosis:
post-term gestational age (?42 weeks), and nulliparity (no
documented either by radiographic evidence or by surgical
intervention. Infants with a recognized or strongly suspected
single-gene conditions or chromosomal abnormalities were
and were randomly selected from the same population as
case infants. Logistic regression was used to estimate odds
ratios for the association between these four factors and cranio-
synostosis, while adjusting for several covariates. We found
that plurality and nulliparity were associated with a twofold
increased risk for metopic craniosynostosis, and macrosomia
Contrary to our hypothesis, prematurity and low birth
these four constraint-related factors were not found to be
associated with craniosynostosis when all suture types were
combined, though some types of craniosynostosis were asso-
ciated with individual constraint-related factors.
? 2010 Wiley-Liss, Inc.
Key words: craniosynostosis; fetal constraint; plurality; twin-
ning; macrosomia; prolonged gestation; low birth weight; calvarial
morphogenesis; skull deformation; sagittal synostosis; metopic
sutures between adjacent calvaria. It is most often an isolated
Grant sponsor: Centers for Disease Control and Prevention Centers of
Excellence Award; Grant number: 1U01DD000489-01; Grant sponsor:
Robert Wood Johnson Foundation; Grant sponsor: CHLA-USC Child
HealthResearch Career Development Program; Grant number: NIH K12-
HD05954; Grant sponsor: SHARE’s Childhood Disability Center; Grant
Medical Genetics NIH/NIGMS Training Program Grant; Grant number:
Pedro A. Sanchez-Lara, M.D., USC Keck School of Medicine, Children’s
MS-90, Los Angeles, CA 90027. E-mail: firstname.lastname@example.org
Published online 22 January 2010 in Wiley InterScience
How to Cite this Article:
Jr., Lammer EJ, Shaw GM, Ma C, Rasmussen
SA, the National Birth Defects Prevention
factor for craniosynostosis.
Am J Med Genet Part A 152A:394–400.
? 2010 Wiley-Liss, Inc.
finding in an otherwise normal child. In non-syndromic cranio-
premature suture fusion. Several risk factors have been implicated
in craniosynostosis including fertility treatments [Reefhuis et al.,
altitude of residence [Alderman et al., 1995], maternal thyroid
1995], and teratogenic exposures such as heavy maternal smoking
that continued into the second trimester [Carmichael et al., 2008]
and sodium valproate [Lajeunie et al., 2001].
Case reports and retrospective series led previous investigators
to hypothesize that fetal head constraint might reduce dural
growth stretch and thereby increase the risk of non-syndromic
craniosynostosis [Graham et al., 1979, 1980; Graham and Smith,
1980; Higginbottom etal., 1980].Proposed constraint factors have
included early descent of the fetal cranium into the lower uterine
segment, breech presentation, maternal uterine malformation,
nulliparity, oligohydramnios, multiple gestation (twins or higher),
macrosomia, and prolonged gestation.
It is well accepted that primary microcephaly or aggressively
can each result in secondary premature sutural fusion. One sug-
gested mechanism for craniosynostosis involves altered dural me-
chanical signaling, which is proposed to lead to premature fusion
when dural growth stretch is decreased [Cohen, 1991]. Given the
above examples of post-natal influences on premature suture
fusion, it is plausible that a deformational influence on the fetal
calvaria in late gestation may account for a subset of craniosynos-
tosis cases. Supporting evidence from animal models has shown
that in vivo constraint-induced suture fusion causes changes in
expression of genes involved in cranial ossification [Heller et al.,
2007; Jacob et al., 2007]. Not only is there an induction of suture
obliteration but also an induced expression of osteogenic bone
growth factors (such as TGF beta) in fetal calvarial bone and the
underlying dura, suggesting that mechanical factors might influ-
ence the expression of genes involved in cranial ossification and
To date, no population-based study has directly assessed the
association between factors affecting fetal constraint and non-
syndromic craniosynostosis. With a goal to clarify the role of fetal
constraint for craniosynostosis risk, we assessed four available
factors (birth weight, gestational age, multiple gestation, and
parity) as proxies for potential fetal constraint.
We used data from the National Birth Defects Prevention Study
(NBDPS). Eligible subjects had estimated dates of delivery (EDDs)
ongoing, multi-site case–control study of over 30 major birth
defects conducted in 10 states within the United States. Detailed
study methods have been published [Yoon et al., 2001]. Each state
randomly selects between 125 and 150 liveborn infants without
major birth defects (controls)per studyyearfrombirth certificates
hospitals (AR 1997–1999, CA, GA 1997–2000, NY, TX) with the
which cases were derived. Clinical diagnostic information was
abstracted from medical records and entered into a standardized
information to determine study eligibility of each case infant
[Rasmussen et al., 2003]. For this analysis, case infants had a
diagnosis of craniosynostosis documented by either radiographic
confirmation or by surgical intervention, excluding those with
known or suspected chromosomal abnormalities or recognizable
all study sites were subsequently reviewed by a single clinical
each case aseither ‘‘isolated’’ (if there was no other majordefect or
only minor defects) or as ‘‘multiple’’ (if there was one or more
additional major, unrelated defect) [Rasmussen et al., 2003]. For
each case infant, the specific synostotic suture involved was cate-
gorized as sagittal, coronal, metopic, lambdoid, unknown, or
were categorized as multiple sutures.
Maternal interviews were conducted primarily by telephone (in
English or Spanish) using a standardized, computer-based ques-
if unknown, EDD was estimated from information in the medical
of 675 cases (74% of eligible subjects) and 5,958 controls (69% of
eligible subjects). The mean time from delivery to interview was
14 months for case mothers and 9 months for control mothers.
Factors considered as potentially conferring fetal constraint
?4,000g), prolonged gestational age (?42 weeks), and nulliparity
(no previous live births). Covariates included maternal and pater-
nal age (in years), maternal race–ethnicity (Caucasian, African
American, Hispanic, Other), education (<12 years, 12 years, or
>12 years), prepregnancy body mass index (calculated as prepreg-
nancy weight in kilograms divided by height in meters squared),
infant sex, maternal smoking (during the month before pregnancy
or the first trimester), gestational diabetes, and fertility treatment.
Fertility treatment was defined as an affirmative answer to the
following question: ‘‘Did you or [baby’s name]’s father take any
We excluded infants whose mothers had prepregnancy diabetes
from all analyses (5 cases and 30 controls) because of the strong
association between maternal diabetes and birth defects [Correa
et al., 2008]. In addition, we excluded infants from multiple
gestations from all analyses (32 cases and 141 controls), except the
analyses of plurality, because infants born as part of a multiple
and craniosynostosis. We examined crude odds ratios and odds
ratios adjusted for the covariates listed above. In addition, we
examined the association of plurality with craniosynostosis after
excluding women who had fertility treatments. We estimated odds
SANCHEZ-LARA ET AL.
ratios and corresponding 95% confidence intervals using SAS
(version 9.1, 2003, SAS Institute, Cary, NC). In addition, we also
performed the analyses restricted to isolated cases and to subjects
with no first-degree relative (i.e., a parent or sibling) with
After exclusion of subjects whose mothers had prepregnancy
diabetes, there were 670 case infants and 5,928 control infants
available for analysis. A summary of characteristics of the infants
with craniosynostosis and control infants is provided in Tables I
and II. Cases were more likely than controls to be male (66% vs.
50%, P-value <0.001) and case mothers were more likely than
control mothers to be non-Hispanic white (74% vs. 60%, P-value
were adjusted for covariates, none of the constraint-related factors
as preterm delivery, were associated with increased risk (see
Suture-specific analyses indicated that plurality and nulliparity
that macrosomia was associated with coronal craniosynostosis
(Table IV). Of note, low birth weight was associated with risk of
sagittal and metopic craniosynostosis. There were too few cases of
lambdoidal or multiple suture synostosis to separately assess risks
for constraint-related factors. Adjusted ORs for twins or higher
for sagittal cases and 1.8 (95% CI 0.5–5.9) for metopic cases.
Of note, after this exclusion, all coronal cases were of singleton
gestation; thus, no additional OR was calculated for this group. Of
65 infants in whom craniosynostosis was associated with other
intrauterine constraint [Graham, 2007]. These included two with
hip dislocation with associated malformations (cleft lip and palate
in one and diaphragmatic hernia in the other), three with talipes
equinovarus with craniosynostosis (two sagittal cases and one
metopic case), and one infant with metopic craniosynostosis, who
had a unilateral non-functioning kidney, bilateral hydronephrosis,
and arytenoid hypertrophy. The remaining 59 infants with cranio-
to occur early in pregnancy. Furthermore, when analyses were
performed excluding infants with craniosynostosis and associated
defects, or infants with a family history of craniosynostosis, results
were similar to those for all infants with craniosynostosis.
Although no constraint-related factor had a large overall influence
on craniosynostosis and some data were too sparse to allow for a
well grounded scientific inference, our study found that plurality
and nulliparity were both associated with a twofold increased risk
for metopic craniosynostosis, plurality was associated with sagittal
synostosis only when including cases with fertility treatments, and
macrosomia had almost twice the risk of developing coronal
birth weight were associated with craniosynostosis, rather than
macrosomia and post-term gestation. Although the four hypothe-
sized constraint-related factors were not associated with cranio-
synostosis when all suture types were combined, some types of
incomplete penetrance and variable expressivity. Familial types
account for 14.4% of coronal synostosis, 6% of sagittal synostosis,
and 5.6% of metopic synostosis, while lambdoidal synostosis is
compared with coronal synostosis may suggest a greater environ-
Published results have been mixed regarding associations be-
tween constraint-related factors and non-syndromic craniosynos-
Boulet et al., 2008]. A study by Alderman et al.  of 173
children with craniosynostosis and 759 control infants showed an
association between multiple gestation and craniosynostosis (OR
3.0, 95% CI 1.2–7.1), but no association with parity. A study from
Western Australia of 170 case infants and 522 control infants
examinedconstraint-related factorsincluding prolonged gestation
>42 weeks, plurality, and macrosomia, and none of these were
significantly associated with craniosynostosis [Singer et al., 1999].
Similar to our findings, these investigators found an association
between preterm delivery (<37 weeks) and craniosynostosis (OR
2.9;95%CI1.8–4.8)[Singeretal.,1999].K€ all? enetal.conductedan
investigation using Swedish health registries and found an associa-
all forms of craniosynostosis, but no significant linear trend except
TABLE I. Characteristics of Infants With Craniosynostosis (Cases)
and Infants With No Major Birth Defects (Controls), the National
Birth Defects Prevention Study, 1997–2004
Maternal education (years)
Maternal race or ethnicity
Non-Hispanic African American
Asian or Pacific Islander
Native American/Alaskan native
66.1% (443) 50.3% (2,982)
33.9% (227) 49.6% (2,941)
23.7% (159) 24.7% (1,464)
63.6% (426) 57.2% (3,389)
74.2% (497) 59.5% (3,524)
16.0% (107) 22.3% (1,323)
396 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
for sagittal synostosis (P for linear trend¼0.01). Reefhuis et al.
 found no association between multiple births nor primi-
gravidity and craniosynostosis. Most recently Boulet et al. 
showed an increased prevalence of craniosynostosis among multi-
ple births and infants with a birth weight >4,000g.
We found that the association of craniosynostosis with
constraint-related factors varied by suture type and that these
covariates were difficult to disentangle, despite having access to a
large number of subjects. Fertility treatments and plurality are
strongly associated with each other [Aston et al., 2008; Hoekstra
et al., 2008], and fertility treatments may be associated with
craniosynostosis [Reefhuis et al., 2003]. When we excluded
subjects with fertility treatments, however, results for plurality
were essentially unchanged for all suture types.
Gestational age and size at birth are highly correlated with each
other and for analytic completeness our study and others have
assessed the opposite ends of each factor. For low birth weight, it is
important to distinguish between intrauterine growth restriction,
which often demonstrates catch-up growth, and fetal growth
deficiency that continues after birth is associated with numerous
syndromes and other problems [Rimoin and Graham, 1989;
Snijders et al., 1993]. It is possible that one of the many risk factors
we cannot determine the impact of fetal constraint on preterm
delivery. Longitudinal studies have demonstrated evidence that
constrained infants from multiple births are commonly born
preterm with a low birth weight and typically show prompt
post-natal catch-up growth [Ijzerman et al., 2001; Dubois et al.,
infants with late fetal growth restriction [Harvey et al., 1979].
On the opposite end of the spectrum, post-maturity, or pro-
longed gestation is associated with large for gestational infants
[Chervenak, 1992] and has a higher incidence of birth complica-
tions [Shea et al., 1998]. Although our study did not demonstrate
evidence for an association between prolonged gestation and
craniosynostosis, prolonged gestation has been associated with
craniosynostosis in an animal model. In a murine study where
fetal constraint was generated using a cervical clip and by delaying
birth by 2–3 days, 88% of the 26 treated pregnant mice had
evidence of craniosynostosis [Koskinen-Moffett, 1986]. However,
not all animal studies demonstrate such a strong association with
craniosynostosis. Some hypothesize that a murine model is not an
ideal system to study constraint, given that multiple gestation
pregnancies are typical and the gestational period results in the
birth of offspring that are significantly less developed.
TABLE III. Summary of Constraint-Related Factors for all Suture Types Combined, the National Birth Defects Prevention Study, 1997–2004*
Twin or higher order
Low birth weight
No prior birth
2 or more
No. cases No. controls OR (95% CI) crude No. casesNo. controls OR (95% CI) adjusteda
aAll analyses excluded mothers with prepregnancy diabetes and all analyses except those of plurality also excluded multiple births.
bAll adjusted models included maternal body mass index, education, race–ethnicity, age, fertility treatments, infant sex, gestational diabetes, and smoking.
TABLE II. Type of Craniosynostosis Among Case Infants in the
National Birth Defects Prevention Study, 1997–2004
Type of suture involved
aInfants with no other unrelated major birth defects.
bInfants with one or more unrelated major birth defects.
SANCHEZ-LARA ET AL.
and found to be associated with the risk of developing craniosyn-
ostosis. Although speculative, it is possible that late gestational
constraint could lead to early delivery of a fetus that is small in size
due to premature delivery. Because of a consistent relationship
between craniosynostosis and low birth weight/preterm delivery,
factors involving preterm labor and delivery should be explored in
more detail. Size at birth may potentially be more influenced by
[Brooks et al., 1995; Drooger et al., 2005]. Many factors contribute
to the occurrence of low birth weight, including genetic and
environmental factors such as parity, pregnancy spacing, maternal
age and size, blood pressure, race, health, smoking, alcohol intake,
twinning, and intrauterine constraint [Opitz et al., 1985; Cogswell
and Yip, 1995; Drooger et al., 2005]. The influence of fetal con-
straint on size at birth has been studied in animal models, with the
Shire horses (large) with the much smaller Shetland ponies and
varied only the maternal breed (size). Birth weight correlated with
maternal breed and size. This suggests that late-gestational growth
natal catch-up growth. Human studies reported similar observa-
tions for babies born after ovum donation, and their size at birth
correlated more strongly with the ovum recipients than the ovum
of interest to know in this cohort if low birth weight/preterm
mothers with tall partners, and whether or not such fetuses show
prompt post-natal catch-up growth, as is frequently seen with
multiple gestation infants carried to near term.
As has been documented in other studies of craniosynostosis,
[Singer et al., 1999; Boulet et al., 2008], we also noted a male and
non-Hispanic white predominance among the cases, compared to
controls. Both of these variables could be associated with larger
head size at birth, and this might suggest a role for fetal head
constraint [Madan et al., 2002]. The association between macro-
somia and preexisting maternal diabetes is well accepted [Spellacy
et al., 1985]. Because preexisting diabetes is also associated with an
increased riskformalformations, thisfactorwasconsidered tobea
criterion for exclusion of both cases and controls, even though
isolated craniosynostosis is not a diabetes-related malformation
[Correa et al., 2008]. Although we used an accepted definition
of macrosomia (birth weight >4,000g) as a surrogate for
(unmeasured) large size in late gestational development, it is still
unclear when in gestation premature suture fusion occurs, thus
size on fetal head constraint.
As the largest population-based study completed to date, our
factors. Not only were we able to assess an appropriate control
population, we also have the statistical power to adjust for the
available confounders. Also, all cases were clearly identified and
reviewed by a clinical geneticist to ensure the study’s inclusion
criteria were met. However, our study also had several limitations.
Attempts were made to exclude infants with craniosynostosis of
known etiology (e.g., single-gene disorders and chromosome
abnormalities) through careful review of information abstracted
from medical records. However, infants mildly affected with these
conditions and infants with Muenke syndrome were quite likely to
routinely performed on these infants. If molecular testing was
pursued clinically and found to be abnormal, then these infants
were excluded from the study. We assumed that syndromic cases
might be more frequent among infants with coronal involvement;
thus we analyzed infants with sagittal, metopic, and coronal in-
TABLE IV. Summary of Constraint-Related Factors by Affected Sutures, the National Birth Defects Prevention Study, 1997–2004*
Twin or higher order
Low birth weight
No prior birth
2 or more
adjusted OR (95% CI)
adjusted OR (95% CI)
OR (95% CI)
6 1.7 (0.7–3.9)
37 1.7 (1.2–2.5)
9 1.1 (0.5–2.2)
aAll analyses excluded mothers with prepregnancy diabetes and all analyses except those of plurality also excluded multiple births; odds ratios were calculated only if all cells had at least two
bAll adjusted models included maternal body mass index, education, race–ethnicity, age, fertility treatments, infant sex, gestational diabetes, and smoking.
398 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
involvement or lambdoid involvement to perform a meaningful
analysis, so these groups were not analyzed separately from infants
with either sagittal, coronal, or metopic involvement.
post-dates, and nulliparity are relatively easy to ascertain using a
maternal questionnaire and though they are good measures of
is the issue in question. The four factors we chose are either poor
proxies for fetal head constraint or not major factors in the overall
cause of non-syndromic craniosynostosis, which is likely a multi-
factorial defect of heterogeneous etiology. Yet these were the
variables available in this very large data set that systematically
ascertained data using one of the most comprehensive question-
naires administered to both case and control mothers. Another
limitation isthattheNBDPS doesnotroutinely ascertaininforma-
tion on in utero positioning or amniotic fluid status (e.g.,
oligohydramnios) across all sites. The risk of recall bias, for exam-
ple, relying on parental recall of use of fertility treatment instead of
abstracting data from all medical records, was another weakness.
Also, information was collected by telephone several months after
different between the cases and controls. Although fetal head
constraint cannot be directly measured, we were unable to study
studies of non-syndromic craniosynostosis. These unavailable and
therefore unstudied factors included the sensation of early descent
of the fetal head into the lower uterine segment [Graham et al.,
1979], abnormal birth presentation which has an increased rate of
preterm birth [Higginbottom et al., 1980], and the presence of
uterine malformations which may also be associated with preterm
birth, malpresentation, and craniosynostosis [Graham and Smith,
1980]. Such factors could potentially limit fetal movement and
of factors leading to fetal head constraint might have synergistic
effects that increase the risk of craniosynostosis. And finally, it was
unfortunate that this study had no post-natal follow-up data to
weight ultimately caught up in growth, which might suggest they
delivered early because of fetal constraint in late gestation.
Although uncertainties remain regarding the influence of fetal
head constraint, we conclude that no single constraint-related
factor assessed in this study contributed greatly to the risk of
craniosynostosis. Here we have demonstrated some evidence of
suture-specific environmental influences, but these constraint-
related factors and others will need further investigation in order
to increase our understanding of the underlying causes of
The authors are grateful to all of the participating families which
made this research possible. We would also like to thank the staff,
contributions. This work was made possible by funding from the
Centers for Disease Control and Prevention Centers of Excellence
FacultyDevelopment ProgramthroughtheRobert WoodJohnson
Foundation and the CHLA-USC Child Health Research Career
SHARE’s Childhood Disability Center, the Steven Spielberg
Pediatric Research Center, the NIH/NICHD Program Project
Grant (HD22657), and the Medical Genetics NIH/NIGMS Train-
ing Program Grant (5-T32-GM08243). We thank the California
Department of Public Health, Maternal Child and Adolescent
Health Division for providing surveillance data from California
ofthe authorsanddo not necessarilyrepresent theofficial position
of the Centers for Disease Control and Prevention, the National
Institute of Child Health and Human Development, the National
Alderman BW, Lammer EJ, Joshua SC, Cordero JF, Ouimette DR, Wilson
MJ, Ferguson SW. 1988. An epidemiologic study of craniosynostosis:
Risk indicators for the occurrence of craniosynostosis in Colorado. Am
J Epidemiol 128:431–438.
Alderman BW, Zamudio S, Baron AE, Joshua SC, Fernbach SK, Greene C,
Mangione EJ. 1995. Increased risk of craniosynostosis with higher
antenatal maternal altitude. Int J Epidemiol 24:420–426.
Aston KI, Peterson CM, Carrell DT. 2008. Monozygotic twinning associ-
ated with assisted reproductive technologies: A review. Reproduction
craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet
Part A 146A:984–991.
Bradley CM, Alderman BW, Williams MA, Checkoway H, Fernbach SK,
Greene C, Bigelow PL, Reif JS. 1995. Parental occupations as risk factors
for craniosynostosis in offspring. Epidemiology 6:306–310.
Brooks AA, Johnson MR, Steer PJ, Pawson ME, Abdalla HI. 1995. Birth
weight: Nature or nurture? Early Hum Dev 42:29–35.
2008. Craniosynostosis and maternal smoking. Birth Defects Res A Clin
Mol Teratol 82:78–85.
Chervenak JL. 1992. Macrosomia in the postdates pregnancy. Clin Obstet
Cinalli G, Sainte-Rose C, Kollar EM, Zerah M, Brunelle F, Chumas P,
Arnaud E, Marchac D, Pierre-Kahn A, Renier D. 1998. Hydrocephalus
and craniosynostosis. J Neurosurg 88:209–214.
distribution of birthweight. Semin Perinatol 19:222–240.
N Am 2:507–513.
Correa A, Gilboa SM, Besser LM, Botto LD, Moore CA, Hobbs CA, Cleves
MA, Riehle-Colarusso TJ, Waller DK, Reece EA. 2008. Diabetes mellitus
and birth defects. Am J Obstet Gynecol 199:237. e1-9.
Snijders RJ, Verhulst FC, Witteman JC, Steegers EA, Joung IM. 2005.
Ethnic differences in prenatal growth and the association with
maternal and fetal characteristics. Ultrasound Obstet Gynecol 26:
Dubois L, Girard M, Girard A, Tremblay R, Boivin M, Perusse D. 2007.
twin birth-cohort study. Twin Res Hum Genet 10:479–485.
SANCHEZ-LARA ET AL.
register-based study. Hum Reprod 23:1306–1311.
Graham JM. 2007. Smith’s recognizable patterns of human deformation.
Philadelphia: Saunders. viii, 361 p.
Graham JM Jr, Smith DW. 1980. Metopic craniostenosis as a consequence
Graham JM Jr, deSaxe M, Smith DW. 1979. Sagittal craniostenosis:
Fetal head constraint as one possible cause. J Pediatr 95:747–750.
Graham JM Jr, Badura RJ, Smith DW. 1980. Coronal craniostenosis:
Fetal head constraint as one possible cause. Pediatrics 65:995–
Harvey MA, Smith DW, Skinner AL. 1979. Infant growth standards in
relation to parental stature. Clin Pediatr (Phila) 18:602–603, 606-7,
2007. Cranial suture response to stress: Expression patterns of Noggin
and Runx2. Plast Reconstr Surg 119:2037–2045.
craniosynostosis. Neurosurgery 6:39–44.
ma DI. 2008. Familial twinning and fertility in Dutch mothers of twins.
Am J Med Genet Part A 146A:3147–3156.
ma DI. 2001. Intra-uterine and genetic influences on the relationship
between size at birth and height in later life: Analysis in twins. Twin Res
Indian Hedgehog, BMP-4 and Noggin in craniosynostosis induced by
fetal constraint. Ann Plast Surg 58:215–221.
Kallen B, Robert-Gnansia E. 2005. Maternal drug use, fertility problems,
and infant craniostenosis. Cleft Palate Craniofac J 42:589–593.
Koskinen-Moffett L. 1986. In vitro experimental model for prenatal
craniosynostosis. J Dent Res 65:abstract 980.
Lajeunie E, Barcik U, Thorne JA, El Ghouzzi V, Bourgeois M, Renier D.
Lajeunie E, Crimmins DW, Arnaud E, Renier D. 2005. Genetic consid-
their families. J Neurosurg 103:353–356.
Madan A, Holland S, Humbert JE, Benitz WE. 2002. Racial differences in
birth weight of term infants in a northern California population.
J Perinatol 22:230–235.
Prog Clin Biol Res 200:33–63.
Prevention Study. Birth Defects Res A Clin Mol Teratol 67:193–201.
Rasmussen SA, Yazdy MM, Carmichael SL, Jamieson DJ, Canfield MA,
Honein MA. 2007. Maternal thyroid disease as a risk factor for cranio-
synostosis. Obstet Gynecol 110:369–377.
Reefhuis J, Honein MA, Shaw GM, Romitti PA. 2003. Fertility treatments
and craniosynostosis: California, Georgia, and Iowa, 1993–1997.
Rimoin DL, Graham JM Jr. 1989. Syndromes associated with growth
deficiency. Acta Paediatr Scand Suppl 349:3–10.
Shea KM, Wilcox AJ, Little RE. 1998. Postterm delivery: A challenge for
epidemiologic research. Epidemiology 9:199–204.
Singer S, Bower C, Southall P, Goldblatt J. 1999. Craniosynostosis in
Western Australia, 1980–1994: A population-based study. Am J Med
Snijders RJ, Sherrod C, Gosden CM, Nicolaides KH. 1993. Fetal growth
Am J Obstet Gynecol 168:547–555.
Spellacy WN, Miller S, Winegar A, Peterson PQ. 1985. Macrosomia–
Maternal characteristics and infant complications. Obstet Gynecol
aged 0–2.5 years. Acta Paediatr 97:1099–1104.
Walton A, Hammond J. 1938. The maternal effects on growth and
conformation in Shire horse—Shetland pony crosses. Proc R Soc Lond
B Biol Sci 124:311–335.
Weinzweig J, Bartlett SP, Chen JC, Losee J, Sutton L, Duhaime AC,
Whitaker LA. 2008. Cranial vault expansion in the management of
postshunt craniosynostosis and slit ventricle syndrome. Plast Reconstr
Yoon PW, Rasmussen SA, Lynberg MC, Moore CA, Anderka M, Carmi-
chael SL, Costa P, Druschel C, Hobbs CA, Romitti PA, Langlois PH,
Health Rep 116:32–40.
400AMERICAN JOURNAL OF MEDICAL GENETICS PART A