Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one of 5,000 newborns. We conducted the first genome-wide association study (GWAS) for non-syndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic white (NHW) case-parent trios. Robust associations were observed in a 120 kb region downstream of BMP2, flanked by rs1884302 (P = 1.13 × 10−14; odds ratio [OR] = 4.58) and rs6140226 (P = 3.40 × 10−11; OR = 0.24) and within a 167 kb region of BBS9 between rs10262453 (P = 1.61 × 10−10; OR=0.19) and rs17724206 (P = 1.50 × 10−8; OR = 0.22). We replicated the associations to both loci [rs1884302 (P = 4.39 × 10−31); rs10262453 (P = 3.50 × 10−14)] in an independent NHW population of 172 unrelated sNSC probands and 548 controls. Both BMP2 and BBS9 are genes with a role in skeletal development warranting functional studies to further understand the etiology of sNSC.

Craniosynostosis, a condition that includes the premature fusion of one or multiple cranial sutures, is a relatively common birth defect in humans and the second most common craniofacial anomaly after orofacial clefts. There is a significant clinical variation among different sutural synostoses as well as significant variation within any given single-suture synostosis. Craniosynostosis can be isolated (i.e., nonsyndromic) or occurs as part of a genetic syndrome (e.g., Crouzon, Pfeiffer, Apert, Muenke, and Saethre-Chotzen syndromes). Approximately 85 % of all cases of craniosynostosis are nonsyndromic. Several recent genomic discoveries are elucidating the genetic basis for nonsyndromic cases and implicate the newly identified genes in signaling pathways previously found in syndromic craniosynostosis. Published epidemiologic and phenotypic studies clearly demonstrate that nonsyndromic craniosynostosis is a complex and heterogeneous condition supporting a strong genetic component accompanied by environmental factors that contribute to the pathogenetic network of this birth defect. Large population, rather than single-clinic or hospital-based studies is required with phenotypically homogeneous subsets of patients to further understand the complex genetic, maternal, environmental, and stochastic factors contributing to nonsyndromic craniosynostosis. Learning about these variables is a key in formulating the basis of multidisciplinary and lifelong care for patients with these conditions.

This study focuses on the evaluation of factors influencing the quality (accuracy and reliability) of non-adult dental age assessment from radiographic stages of permanent teeth (excluding the third molar). We used four distinct cross-sectional samples of 1,528 healthy children: 3 of known geographic origin (Ivory Coast, Iran and France) and 1 additional sample of children whose grandparents originated from a different continent. Two different methods of calculations are compared: the correspondence analysis combined with linear regression (CAR) and Bayesian predictions (with no independence assumption). Our results indicate that the quality of age assessment does not seem to depend predominantly on the use of geographic-specific standards. In the case of Bayesian predictions, we observed a clear trend in favour of significantly higher accuracy and reliability levels when using non-geographic-specific standards. One of the main advantage of Bayesian predictions over maximum likelihood methods of estimation is an overall increase in accuracy with high levels of reliability on a fraction of the test sample and, importantly, across all age categories (contrary to methods based on regression analysis). Importantly, in the case of Bayesian non-adult predictions, and contrary to age estimation techniques based on regression, a better quality does not depend on age.

FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.