Genetic and Environmental Risk Factors for Sagittal Craniosynostosis
Abstract
The authors investigated whether genetic and environmental factors influence risk for sagittal craniosynostosis. Cases were ascertained from craniofacial clinics in the Baltimore-Washington metropolitan region. Controls were recruited from the Johns Hopkins newborn nursery and a large pediatric practice in Baltimore County. Forty-two probands with isolated, nonsyndromic sagittal craniosynostosis born in the mid-Atlantic region were included in this analysis. Controls are infants born in Maryland without any known birth defects (n = 182). Odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated. Cases were genotyped at several loci implicated in malformation syndromes including craniosynostosis. There were no elevated risks for craniosynostosis related to maternal or paternal smoking or maternal vitamin usage. Case mothers consumed less alcohol (OR = 0.38, 95% CI = 0.17-0.85) and had less education than control mothers ( < 0.001). All cases that were sequenced were negative for mutations at the following genes: exon IIIa 755C->G, (exons IIIa and IIIc,), exon IIIa, and exon 1. These findings suggest that whereas TWIST and the genes are important for syndromic craniosynostosis, they are unlikely to be involved in isolated sagittal craniosynostosis. Parental education and alcohol consumption were associated with sagittal craniosynostosis in this study.
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Epidemiological studies have identified demographic and environmental associations with sCS, including male sex, advanced maternal age, and specific prenatal exposures such as maternal smoking, hypoxia-related conditions, sodium valproate, retinoic acid, antidepressants, and assisted reproductive technologies.
“Epidemiological studies have identified several demographic and environmental associations, such as male sex, advanced maternal age, and specific prenatal exposures including maternal smoking, hypoxia-related conditions, sodium valproate, retinoic acid, antidepressants, and assisted reproductive technologies [15, 26–35].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [26]
The majority of studies reported an odds ratio of male occurring CS ranging from 1.46 to 4.5, with a geometric mean of ~2.7.
“The majority of the studies studied the odds ratio of male occurring CS with an OR ranging from 1.46 to 4.5 (with geometric mean of ~ 2.7) [2, 3, 15, 26, 50, 53, 74, 80, 82, 86, 96–98, 102, 103, 117].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [26]
Higher parental educational level (≥15 years) is associated with increased risk of sCS, with reported odds ratios ranging from 1.6 to 3.3 for maternal education and up to 4.4 for paternal education.
“Interestingly, higher parental educational level (≥ 15 years of education) has been associated with an increased risk of sCS, with reported odds ratios ranging from 1.6 to 3.3 for maternal education [15] and up to 4.4 for paternal education [26].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [26]
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References 20 · Cited by 66
- Authors
- Zeiger, J. S., Beaty, T. H., Hetmanski, J. B., Wang, H., Scott, A. F., Kasch, L., Raymond, G., Jabs, E. W., & VanderKolk, C.
- Affiliations
- Johns Hopkins University (US)
- Peking University (CN)
- Corresponding author
- Zeiger, Joanna S.
- Beaty, Terri H.
- Hetmanski, Jacqueline B.
- ORCID
- Venue
- Journal of Craniofacial Surgery
- Published
- 2002-09
- Volume
- 13
- Issue
- 5
- Pages
- 602-606
- ISSN
- 1049-2275 (ISSN-L)
- OpenAlex
- W2056428350
- Cited by
- 66
- References
- 20
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Craniofacial Surgery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1p50de011131-01, 5r01de011441-04)
- National Institute of Dental and Craniofacial Research (R01 DE11441, P60 DE13078, P60DE013078, P5- DE11131)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Health Sciences › Medicine › Surgery › Pectus Deformity Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Keywords
- sagittal craniosynostosis, nonsyndromic craniosynostosis, genetic risk factors, environmental risk factors, maternal alcohol consumption, maternal education, parental smoking, twist gene, congenital malformations
- MeSH terms
- Alcohol Drinking, Craniosynostoses, Educational Status, Environment, Exons, Fathers, Female, Fibroblast Growth Factors, Gestational Age, Humans, Infant, Newborn, Male, Mothers, Mutation, Nuclear Proteins, Parietal Bone, Protein-Tyrosine Kinases, Risk Factors, Smoking, Transcription Factors, Vitamins, Confidence Intervals, Logistic Models, Odds Ratio, Case-Control Studies, Receptors, Fibroblast Growth Factor, Helix-Loop-Helix Motifs, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 3, Twist-Related Protein 1
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