Craniosynostosis (CS) refers to the premature fusion of one or more of the cranial sutures, leading to abnormalcranial and facial shapes and function. We propose to investigate the hypotheses that CS risk is associatedwith maternal nutrient intake and factors related to thyroid dysfunction. We propose to study intake of nutrientsinvolved in methylation, glycemic control and oxidative stress because folate-responsive neural crest cellscontribute to the development of the skull and because glycemic control and hypoxia may contribute to CS.We propose to study factors related to thyroid dysfunction because several case-only studies have reportedCS among women and neonates with thyroid disorders. The contribution of the proposed exposures to CSetiologies has either not been evaluated or has largely been investigated with studies that have numerouslimitations. We will address our hypotheses by accomplishing the following Specific Aims:
Aim 1. Intake of nutrients. We will determine whether maternal intakes of nutrients from the diet or supplements that are involved in methylation, glycemic control or oxidative stress are associated with risk of CS among offspring, including folate/folic acid, choline, betaine, methionine, vitamin B12, vitamin B6, riboflavin, glycemic load, -carotene, vitamin E, and vitamin C.
Aim 2. Factors related to thyroid dysfunction. We will determine whether factors that are predictive ofthyroid dysfunction are associated with risk of CS among offspring, including maternal hypertension, intakeof iron, race-ethnicity, age, number of previous live births, miscarriages and fetal deaths, intra-uterinegrowth retardation, preterm delivery, smoking, alcohol, body mass index, diabetes, use of anti-depressants,and sub-fertility.
The aims will be achieved by using existing data from a large, multi-state, population-based case-control studyof birth defects, the National Birth Defects Prevention Study (NBDPS), which includes high quality clinical datathat were collected using rigorous case ascertainment and classification criteria and detailed data onexposures that were collected by maternal interview. The proposed research represents the first large-scalestudy to explore the proposed exposures and CS. This research will fill an important data gap by launchingforward our knowledge regarding etiologies of CS and providing direction for the next generation of studies ofCS.

Public Health Relevance

The goal of this research program is to contribute to the prediction and prevention of craniosynostosis. The medical costs of craniosynostosis are huge and of course the emotional costs to families of the affected children are immeasurable. This proposal will improve our understanding of the causes of craniosynostosis, so that ultimately we will be able to prevent it and/or detect it as early as possible.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Research Grants (R03)
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Special Emphasis Panel (ZDE1-JH (20))
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Harris, Emily L
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Stanford University
Schools of Medicine
United States
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Carmichael, S L; Ma, C; Rasmussen, S A et al. (2015) Craniosynostosis and risk factors related to thyroid dysfunction. Am J Med Genet A 167A:701-7
Carmichael, Suzan L; Rasmussen, Sonja A; Lammer, Edward J et al. (2010) Craniosynostosis and nutrient intake during pregnancy. Birth Defects Res A Clin Mol Teratol 88:1032-9
Ma, Chen; Carmichael, Suzan L; Scheuerle, Angela E et al. (2010) Association of microtia with maternal obesity and periconceptional folic acid use. Am J Med Genet A 152A:2756-61