Craniosynostoses

FGF23 is the cornerstone of phosphate / calcium / vitamin D metabolism: it is synthesized mainly by osteocytes and acts as a phosphaturizing agent, inhibitor of dihydroxyvitamin D, and inhibitor of synthesis and secretion of PTH in most tissues. The specific role of FGF23 on bone has yet to be demonstrated. In osteoblasts, overexpression of FGF23 in vitro suppresses not only osteoblastic differentiation but also the synthesis of the mineralized matrix independently of its systemic action on phosphate metabolism. In osteoblasts, FGF23 also regulates the secretion of osteopontin by directly suppressing transcription of alkaline phosphatase. In some diseases such as hypophosphatemic rickets (HR), the direct role of FGF23 on bone has not yet been studied to our knowledge, whereas these genetic hypophosphatemias are secondary to overexpression of FGF23, whether an activating mutation of FGF23 or inhibitory mutations of its inhibitors (DMP1 and PHEX). However, patients with X-linked hypophosphatemic rickets (XLH) have higher circulating FGF23 levels than healthy controls and these levels are higher in treated patients. Management of XLH consists primarily of correcting the native vitamin D defect by prescribing active vitamin D analogs as well as phosphate supplementation to improve bone mineralization and decrease dental complications, growth, and bone deformities. Recently, a new therapeutic option has been developed for XLH, burosumab, a human monoclonal antibody that binds and inhibits FGF23 activity. The use of burosumab is currently authorized in France in some pediatric patients with severe forms of XLH. Independently of the indirect bone effects of phosphate correction and vitamin D levels, the direct role of burosumab on bone cells has never been studied. The objective of this project is to study the osteoblastic biology of patients with RH compared to control patients, and to evaluate the direct impact of the treatments used in this pathology on human osteoblasts.

Syndromic craniosynostoses (SCS) are rare genetic disorders defined by premature cranial suture fusion, resulting in abnormal craniofacial development and constrained brain growth. These conditions, including Muenke, Saethre-Chotzen, Crouzon, Apert, Pfeiffer and craniofrontonasal syndromes, are typically caused by gain- or loss-of-function variants in key regulators of suture biology such as FGFR1/2/3, TWIST1 and TCF12. Current management is exclusively surgical, relying on early cranial vault remodelling and subsequent reconstructive procedures, which carry substantial risks (e.g. blood loss, infection, re-synostosis) and do not address the underlying molecular etiology. Recent advances in RNA-based therapeutics have demonstrated the potential of mutation-specific approaches to normalize aberrant osteogenic differentiation in patient-derived cells. However, clinical translation remains limited by inefficient delivery and lack of sustained therapeutic activity. The NAUTILUS project aims to overcome these barriers by developing a non-invasive, ultra-personalized therapeutic platform based on mutation-specific antisense oligonucleotides (ASOs) delivered via a nano-engineered system. The project will design and validate patient-tailored ASOs targeting the molecular drivers of SCS, with the goal of either silencing pathogenic gain-of-function alleles or restoring physiological expression in loss-of-function contexts. Functional efficacy will be assessed in patient-derived cellular models by evaluating transcript modulation and rescue of protein function. In parallel, NAUTILUS will optimize a nano-ink delivery platform combining PLGA-PEG-bis-sulfone nanoparticles with a GelMA-based hydrogel scaffold, enabling localized, controlled, and sustained ASO release within the cranial suture niche. Preclinical validation in relevant mouse models will assess the capacity of this platform to delay or prevent pathological suture ossification, ultimately reducing the need for repeated surgical interventions. By directly targeting the genetic basis of disease, NAUTILUS proposes a transformative approach to SCS management. This strategy has the potential to decrease treatment invasiveness, improve clinical outcomes, and enhance quality of life, establishing a precision medicine paradigm for rare craniofacial disorders.

Hemodynamic evaluation during pediatric anesthesia is essential to care management. Intraoperative cardiovascular instability is frequent in major surgeries, and appropriate monitoring is necessary to ensure safe anesthetic conduction and promptly detect changes in blood pressure, cardiac output, blood volume, and organ perfusion. In this context, advanced hemodynamic monitoring, continuous measuring, and estimating various parameters can allow a more specific hemodynamic profile and help identify the causal mechanisms of its variability. Moreover, the reference ranges of hemodynamic values in different pediatric ages and how to best monitor hemodynamic status in pediatrics are still debated. Surgical treatment of craniosynostosis is usually performed at an early age, between 3 and 8 months of age. The operation is burdened by a high risk of hemodynamic instability related mainly, but not only, to potential substantial hemorrhagic losses. This study aims to characterize the hemodynamic events occurring during corrective craniosynostosis surgery, recorded simultaneously with standard monitoring and Pressure Recording Analytic Method (PRAM), and to analyze the paired measurements.

Craniostenosis is a congenital disorder caused by early fusion of the cranial sutures between the skull bones, resulting in orbito-naso-frontal deformities. The damage is primarily aesthetic, but intracranial hypertension may also be observed. The treatment of craniostenosis involves surgery, to restore harmonious growth between the skull bones and the brain, and proper development of the latter. There are various surgical techniques for correction, based on remodeling of the upper forehead and the orbito-naso-frontal band (BONF). However, BONF reshaping is difficult to tailor to each individual child. In most cases, the surgeon performs the reshaping "freehand", without a template. The result is therefore subject to the surgeon's experience and judgment. A surgical instrument (template) has been developed to guide the surgeon in the ideal reshaping of the BONF in patients with anterior craniostenosis (anterior plagiocephaly and trigonocephaly), according to each child's specific morphology. The aim of EPBONF research is to evaluate the benefits of using this template on the symmetry and angle of the BONF.