Risk Of Craniosynostosis Research Articles

Serum nickel is associated with craniosynostosis risk: Evidence from humans and mice

BackgroundTo date, few studies have explored the effects of exposure to metal mixtures on adverse developmental outcomes, and no reported studies have linked metal exposure to craniosynostosis (CS). The purpose of this study is to investigate the association between metal exposure and the risk of CS by conducting epidemiological and experimental studies. MethodsInductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentrations of 6 metals (chromium [Cr], nickel [Ni], tin [Sn], arsenic [As], thallium [Tl], and lead [Pb]) in serum samples from 174 CS patients and 85 control individuals. Non-syndromic patients with isolated sagittal suture closure were selected as the case group, and healthy children matched by sex and age were selected as controls. Bayesian kernel machine regression (BKMR) models were used to account for joint metal effects. Multiple logistic regression analysis was used to explore the association between metal concentration and CS occurrence, with adjustment for potential confounders. During pregnancy, mice were exposed to Ni (0, 0.05, or 0.1 g/kg/day) until weaning, and the widths of the sutures and shapes of the skull were analysed by micro-CT 3D imaging and histological analysis. MC3T3-E1 cells were treated with Ni (0, 0.005, or 0.05 μg/mL) for 72 h. Alkaline phosphate (ALP) staining and Alizarin red staining were performed to observe the development of osteoblasts. The expression levels of osteoblast-related genes were also detected. ResultsA positive association between the metal mixture and CS risk was observed based on population data; the Ni group had the highest conditional posterior inclusion probability (PIP), at 0.8416, and in the fully adjusted model, the highest Ni exposure level had a more significant association with CS (coefficient = 2.65, 95% CI: 0.29, 5.02) than the lowest Ni exposure level. The mean widths of the sagittal sutures in mice were 8.8 ± 0.6 mm in the control group, 8.0 ± 0.8 mm in the 0.05 g/kg/day group and 6.8 ± 0.4 mm in the 0.1 g/kg/day group. After Ni exposure, ALP gene expression in skull tissue was increased, and ALP activity was increased in MC3T3-E1 cells. Moreover, increased collagen content in mouse skull sections and elevated osteocalcin (OCN) expression in MC3T3-E1 cells were observed in the Ni-treated groups compared to the control group. ConclusionsThis study is the first to provide evidence that increased serum Ni was associated with an increased risk of CS. Early life exposure to Ni promoted osteogenesis during skull growth, which may contribute to the development of CS.

Craniosynostosis and risk factors related to thyroid dysfunction.

Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6-0.9, for <25 years versus 25-29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2-0.4 and AOR 0.6, 95% CI 0.4-0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2-2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7-0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable.

Methylenetetrahydrofolate reductase C677T variant in Indian children with craniosynostosis: Its role in the pathogenesis, risk of craniosynostosis.

BACKGROUND:677C to T allele in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene has been implicated in the etiology of various syndromes and nonsyndromic diseases but till date no direct studies have been reported with craniosynostosis.OBJECTIVES:The aim was to study the family-based association of MTHFR polymorphism in different categories of craniosynostosis patients.MATERIALS AND METHODS:This was a cross-sectional study in which 30 patients classified as Apert syndrome, Pfeiffr syndrome and nonsyndromic craniosynostosis patients with their family were recruited. A sample of 3 ml intravenous blood was taken from patients and from their family members (father and mother) in ethylenediaminetetraacetic acid-anticoagulated vacutainer for the purpose of the study. Genomic DNA was extracted from peripheral blood lymphocytes by phenol chloroform extraction method. Primers for MTHFR gene were designed. The polymerase chain reaction was carried out. After successful amplification, a small aliquot (5 μl) of the MTHFR reaction mixture was treated with 1 units of Hinf I restriction enzyme (NEB). Results were obtained and compiled.RESULTS:A total of 30 patients/participants with craniosynostosis of Indian descent and their parents formed the study group. The genotyping did not confirm an association between the MTHFR 677C to T polymorphism and between different categories of craniosynostosis. When comparing the offspring of mothers statistically significant differences were found.CONCLUSION:C667T polymorphism of the MTHFR gene is unlikely to play a role in the pathogenesis of craniosynostosis though maternal MTHFR C677T polymorphism may be a genetic risk factor.

Nickel ENMs Activate HIF-1α

The health record of nickel, a known carcinogen, is far from shiny. Now the metal’s reputation has been further tarnished with the discovery that nano-scale nickel triggers a cellular pathway linked to cancer much more effectively than larger particles do.1 Engineered nanomaterials (ENMs) typically measure less than 100 nm in at least one dimension. Their minuscule size gives them novel physical and biological properties, and, being manufactured in a wide range of chemical compounds and shapes, they have applications in numerous fields.2 Nickel nanoparticles are used in catalysts, sensors, energy storage devices, and other products, although they are not yet made in great quantity. “It’s essential to study the toxicological properties so we understand them before they become widely used,” says Jodie Pietruska, a postdoctoral researcher at Brown University in Providence, Rhode Island, who led the new study. Nickel is a well-known occupational hazard.3 In rodent studies, nickel nanoparticles instilled in the trachea and lung caused greater toxicity and inflammation than larger particles,4,5,6 and inhaled nickel nanoparticles caused signs of vascular disease.7,8 Brown University pathologist Agnes Kane coauthored a 2007 paper showing that, compared with larger micron-scale nickel, nickel nanoparticles release nickel ions more rapidly, a mechanism characteristic of carcinogenic nickel compounds.9 To further connect the dots, Kane, Pietruska, and colleagues conducted a series of experiments comparing the behavior in human lung epithelial cells of nickel oxide and pure metallic-nickel nanoparticles with larger metallic-nickel microparticles.1 They detected nickel ions inside lung epithelial cells exposed to nickel nanoparticles but not to nickel microparticles. And they showed that exposure to the nanoparticles, but not the microparticles, activated the HIF-1α cellular pathway, which is thought to be involved in carcinogenesis and tumor progression. The researchers also found differences in overt toxicity of the various forms of nickel, with the nanoparticles killing the lung epithelial cells quickly and the microparticles having little effect. Intriguingly, in toxicity as well as in ion release and activation of the HIF-1α〈 pathway, nickel oxide was much more active than metallic nickel. Pietruska and Kane speculate that metallic nickel may be the more carcinogenic nanoparticle, because it seems more likely to let cells survive long enough to develop cancer. More research is needed, ultimately in live animals, before nickel nanoparticles can definitively be said to cause cancer. Vincent Castranova, coordinator of nanotoxicology research at the National Institute for Occupational Safety and Health, says the finding has implications for agents besides nickel and reinforces the prediction that many ENMs will have greater biological effects than their larger-form counterparts. “It’s an important finding, but it’s not a surprising finding,” he says. “It confirms what would have been our suspicions.”

First-Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects

About 10% of pregnant women experience symptoms of clinical depression. Many of them receive antidepressants, particularly selective serotonin-reuptake inhibitors (SSRIs). While SSRIs are not major teratogens, recent reports cite an increased risk of birth defects in general and of congenital heart defects, craniosynostosis, and omphalocele in connection with SSRI treatment. The investigators examined associations between maternal SSRI treatment in the first trimester of pregnancy and the risk of birth defects in mothers of 9849 infants with, and 5860 without birth defects who participated in the Slone Epidemiology Center Birth Defects Study. Participants completed a standardized interview in person or by phone within 6 months after delivery. This analysis was limited to women who conceived in the years 1993 to 2004. Infants with chromosomal defects or metabolic disorders were excluded. In contrast to other reported studies, taking SSRIs was not associated with a significantly increased risk of craniosynostosis, omphalocele, or heart defects. The odds ratio (OR) for cardiac defects overall was 1.2, with a 95% confidence interval (CI) of 0.9 to 1.6. Maternal use of sertraline was significantly associated with omphalocele (OR, 5.7; 95% CI, 1.6-20.7) and septal cardiac defects (OR, 2.0; 95% CI, 1.2-4.0). Taking paroxetine carried a significantly increased risk of right ventricular outflow tract obstruction defects (OR, 3.3; 95% CI, 1.3-8.8). No increase in risk was noted when pregnant women took other SSRIs or other types of antidepressants. Maternal use of SSRIs in early gestation was not associated with an overall increase in risk of cardiac defects in this study. While individual drugs of this class may confer an increased risk of specific defects, these abnormalities are rare and the absolute risk level is small.

Prenatal ultrasound diagnosis of fetal craniosynostosis.

Craniosynostosis is defined as the premature closure of the calvarial sutures. The prevalence of this heterogeneous condition is 1 in 2000 and approximately 100 different forms have been described with an established genetic transmission in half of them. Prenatal diagnosis of craniosynostosis relies mainly on identification of associated anomalies and molecular analysis of fetal DNA, which is only feasible in some syndromic forms and in well-documented families. The objective of this study was to investigate the value of prenatal ultrasound examination of cranial sutures in fetuses at risk for craniosynostosis. Forty fetuses at risk for craniosynostosis on the basis of either a family history (Group 1, n = 16) or skull deformity suspected on a first-level fetal ultrasound examination (Group 2, n = 24) were retrospectively investigated. Craniosynostosis was suspected on the basis of skull deformities when present, however the diagnosis was only made in cases where there was a loss of hypoechogenicity of the normal sutures. All infants had both clinical and radiological investigations performed postnatally. In Group 1, serial ultrasound examination from 12 weeks' gestation onwards led to accurate prenatal diagnosis in all 16 cases. Dysmorphism and skull deformity preceded closure of the sutures by 4 to 16 weeks. In Group 2, prenatal diagnosis was correct in 23/24 cases. There were no false-negative results in either group. This series questions further the uncertain genetic determinism of craniosynostosis and seems to rule out the hypothesis of a deformation sequence following primary closure of the cranial sutures. It also suggests that ultrasound examination is useful to demonstrate closure of the sutures in the third trimester of pregnancy in most affected cases.

Which Misshapen Head Needs a Workup?

Radiology| October 01 2002 Which Misshapen Head Needs a Workup? AAP Grand Rounds (2002) 8 (4): 43–44. https://doi.org/10.1542/gr.8-4-43 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Which Misshapen Head Needs a Workup?. AAP Grand Rounds October 2002; 8 (4): 43–44. https://doi.org/10.1542/gr.8-4-43 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: craniosynostosis, cranium, plagiocephaly, synostosis, synostotic posterior plagiocephaly, well child, craniofacial abnormalities, sleep, radiologists, lambdoid suture Source: Medina LS, Richardson RR, Crone K. Children with suspected craniosynostosis: a cost-effectiveness analysis of diagnostic strategies. AJR. 2002;179:215–221. In this 2 1/2-year prospective study from Miami Children’s Hospital and Children’s Medical Center of Cincinnati of 115 infants presenting with unilateral posterior cranial . attening, only 1 child had synostotic posterior plagiocephaly secondary to lambdoid suture synostosis whereas 114 infants had deformation posterior plagiocephaly. This study was undertaken to evaluate the clinical and economic impact of 3 evaluation strategies in children who differed in their risk of craniosynostosis. Three evaluation strategies used were: no imaging, radiography (if abnormal, was followed by 3-dimensional CT [3D-CT]), and 3D-CT. Three risk groups were analyzed on the basis of the prevalence of disease: low (prevalence 34/100,000); intermediate (healthy children with head deformity, prevalence 1/115); and high risk (children with syndromic craniofacial disorders, prevalence 9–10/10). The results of the analysis were summarized in cost-effectiveness ratios showing the cost of achieving one quality-adjusted life year (QALY) gained for different risk groups and diagnostic strategies. In the low-risk group, the radiographic and 3D-CT strategies resulted in a cost per QALY gained of more than $560,000. In the intermediate-risk group, the radiographic strategy resulted in a cost per quality-adjusted life year gained of $54,600. Three-dimensional-CT was more effective than the other 2 strategies, but at a higher cost with a cost per QALY gained of $374,200. In the high-risk group, 3D-CT was the most effective strategy with a cost per QALY gained of $33,800. Less experienced radiologists and poor quality studies increased the evaluation cost per QALY gained for all of the risk groups. The outcome suggests that radiologic screening of healthy children at low risk for synostosis is unwarranted; in healthy children with a head deformity at intermediate risk, the radiographic strategy has a reasonable cost per QALY gained, with 3D-CT more effective but with higher cost per QALY. In children with syndromic craniofacial disorders who are at high-risk, 3D-CT is the most effective strategy and has a reasonable cost per QALY gained. Children with high-risk, syndrome-related craniosynostosis should be evaluated thoroughly with imaging performed and interpreted by experienced radiologists. This group will benefit from early intervention. Craniosynostosis, the early fusion of skull sutures, requires an accurate diagnosis before treatment. Both isolated and syndrome-related craniosynostosis contribute to the prevalence in the general population of 34 to 48 per 100,000 live births with nonsyndromic causes being the most common.1,2 Sagittal suture synostosis accounts for 56% of cases with coronal suture synostosis accounting for 22%.1 In the last 10 years there has been an exponential increase in infants with deformational posterior cranial plagiocephaly, likely related to the recommendation that infants sleep in the supine position and increased general awareness of plagiocephaly. Appropriate management of posterior plagiocephaly3 requires differentiation of occipitoparietal flattening caused by lambdoid synostosis from deformation due to external forces. In view of the very high costs of imaging required for early management of craniosynostosis, this cost-effectiveness analysis provides... You do not currently have access to this content.

Maternal exposure to prescription and non-prescription pharmaceuticals or drugs of abuse and risk of craniosynostosis.

The pre- and peri-natal drug exposures reported by women participating in a case-control study of children in Colorado were examined for association with infant craniosynostosis. Mothers of case and control children underwent a standardized telephone interview and obstetric and newborn medical record review. The interview included questions on the use of prescription and non-prescription drugs, nutritional supplements, recreational and drugs of abuse. The mother's obstetric record was abstracted for information about pharmacologic agents taken before and during the antepartum period. There were no statistically significant risk ratios associating craniosynostosis with prenatal exposure to hydantoin, valproic acid, or cocaine. Mothers of four case children and one control child reported specific exposure to retinoic acid. There were no statistically significant increases in the odds ratio (OR) for any suture type among children exposed to hypoxigenic agents, sympathomimetic or parasympatholytic agents, or metal-containing agents. The OR was 1.87 (lower bound of the two-sided 95% test-based confidence interval (CI): 1.08) among children with sagittal/lambdoid suture synostosis who were exposed to nitrosatable drugs chlorpheniramine, chlordiazepoxide, and nitrofurantoin compared to controls. Certain nitrosatable drugs may be associated with increased risk of infant sagittal/lambdoid craniosynostosis. A possible mechanism related to ischaemia/reperfusion injury is suggested.