# Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosomiasis
### Craniosynostosis: A Heterogeneous Condition  
Craniosynostosis (CS) is a congenital defect resulting from the premature fusion of one (simple or single-suture CS) or more (complex or multi-suture CS) skull sutures. This results in the abnormal growth of the skull, which is constrained perpendicularly to the fused suture and enhanced in a plane parallel to it, owing to the rapid brain growth underneath during the first years of postnatal life [3]. From a clinical point of view, the CS manifestations are heterogeneous, as it can be a feature in several distinct syndromes or it can occur as an isolated finding in nonsyn-dromic phenotypes [4; 5]. Syndromic CS groups a wide variety of different syndromes with multisystem involvement, including CS in their phenotype. Table 1 lists all known syndromes featuring CS in their phenotype; the reported data include reference to the OMIM (Online Mendelian Inheritance in Man; www.omim.org (accessed on 2 July 2020)) ID, whenever available, or to the literature originally describing the genotype/phenotype. Nonsyndromic forms are usually single-suture CS, classified based on the involved suture site; these are listed in Table 2, with reference to the papers that have characterized the genetic etiology and/or the OMIM ID, whenever available. The etiology of CS is also extremely heterogeneous. A genetic cause, being either a chromosomal structural aberration or a gene mutation, can be found in roughly 75-80% of syndromic forms [6]. An increasing number of disease-associated genes have been discovered during recent years and account for the allelic heterogeneity of CS (Table 1). Nonsyndromic CS (NCS) forms account for nearly three quarters of all craniosynostoses, being even more heterogeneous and unclear in their etiology [5; 7]. Some NCS, at least those involving the sagittal suture, are believed to represent multifactorial disorders owing to the interplay between a significant genetic background and environmental risk factors [8]. Different genes have been recently associated with NCS, suggesting possible genotype/phenotype correlations between the mutated genes and the patterns of suture closure [5; 7; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19]. On this regard, it is worth noting that the presence of gene mutations may affect the neurodevelopmental prognosis in both syndromic and nonsyndromic CS patients [18; 20]. The suture mesenchyme represents a unique skeletonic stem cell niche in the developing skull, serving as a transient reservoir of mesenchymal stromal cells (MSC) and osteoporosis (see Figure 1) [21; 22]. Regardless of the initial trigger underlying CS etiology, it is believed that in these disorders the calvariant suture stem cell niche undergoes an accelerated exhaustion, which ultimately drives the premature ossification of the suture mesenchyme [20; 23]. Therefore, strategies to maintain and/or replenish the stem cell reservoir, either through direct cell transplantation, or through paracrine stimulation of endogenous cells, would be highly desirable. CS heterogeneity can sometimes hamper an early and accurate diagnosis, which is mandatory to prompt a timely intervention. CS is treated by surgery for cranial vault remodeling (as detailed in the following paragraph), to relieve the constraint that may  
Figure 1: Skull sutures and craniosynostosis. The figure shows a structural and pathophysiological overview of craniosynostosis. (**a**) skull bones in the newborn skull, shown in frontal (**left**) and superior (**right**) views, are kept together by sutures (shown in pink); note that the frontal bone originates as two distinct bony pieces kept together by the ectopic suture, which ossifies during early postnatal life. Fontanelles (i.e., palpable soft spots in the newborn skull) are found at crossroads between intersecting sutures and cause the skull to be elastic as needed to adapt dynamically to the rapid brain growth underneath.