Sphingosine 1-phosphate (S1P) is a bioactive lipid that acts via G protein-coupled receptors. The S1P receptor S1P1, encoded by S1pr1, is expressed in developing heart but its roles there remain largely unexplored. Analysis of S1pr1 LacZ knockin embryos revealed β-galactosidase staining in cardiomyocytes in the septum and in the trabecular layer of hearts collected at 12.5 days post coitus (dpc) and weak staining in the inner aspect of the compact layer at 15.5 dpc and later. Nkx2-5-Cre− and Mlc2a-Cre−mediated conditional knockout of S1pr1 led to ventricular noncompaction and ventricular septal defects at 18.5 dpc and to perinatal lethality in the majority of mutants. Further analysis of Mlc2a-Cre conditional mutants revealed no gross phenotype at 12.5 dpc but absence of the normal increase in the number of cardiomyocytes and the thickness of the compact layer at 13.5 dpc and after. Consistent with relative lack of a compact layer, in situ hybridization at 13.5 dpc revealed expression of trabecular markers extending almost to the epicardium in mutants. Mutant hearts also showed decreased myofibril organization in the compact but not trabecular myocardium at 12.5 dpc. These results suggest that S1P signaling via S1P1 in cardiomyocytes plays a previously unknown and necessary role in heart development in mice.

Background: Pfeiffer syndrome is a rare syndromic craniosynostosis disorder, with a wide range of clinical manifestations. This study aims to investigate the structural abnormalities of cranial fossa and skull base development in Pfeiffer patients, to provide an anatomic basis for surgical interventions. Method: Thirty preoperative CT scans of Pfeiffer syndrome patients were compared to 35 normal controls. Subgroup comparisons, related to differing suture synostosis, were performed. Results: Overall, the volume of anterior and middle cranial fossae in Pfeiffer patients were increased by 31% (P < 0.001) and 19% (P = 0.004), versus controls. Volume of the posterior fossa in Pfeiffer patients was reduced by 14% (P = 0.026). When only associated with bicoronal synostosis, Pfeiffer syndrome patients developed enlarged anterior (68%, P = 0.001) and middle (40%, P = 0.031) fossae. However, sagittal synostosis cases only developed an enlarged anterior fossa (47%, P < 0.001). The patients with solely bilateral squamosal synostosis, developed simultaneous reduced anterior, middle and posterior cranial fossae volume (all P ≤ 0.002). The overall skull base angulation, measured on both intracranial and subcranial surfaces, grew normally. Conclusion: Enlarged anterior cranial fossae in Pfeiffer syndrome children is evident, except for the squamosal synostosis cases which developed reduced volume in all fossae. Volume of the middle cranial fossa is influenced by associated cranial vault suture synostosis, specifically, sagittal synostosis cases develop normal middle fossa volume, while the bicoronal cases develop increased middle fossa volume. Posterior cranial fossa development is restricted by shortened posterior cranial base length. Surgical intervention in Pfeiffer syndrome patients optimally should be indexed to different suture synostosis.

Background: The association of isolated craniosynostosis and the influence of syndromic forms confound the understanding of craniofacial morphologic development. This study attempts to clarify the individual influences of isolated bicoronal synostosis, Apert syndrome, and Crouzon syndromes on skull base morphology. Methods:: One hundred seventeen computed tomographic scans were included (nonsyndromic bicoronal synostosis, n = 36; Apert syndrome with bicoronal synostosis, n = 25; Crouzon syndrome with bicoronal synostosis, n = 11; controls, n = 45). Cephalometric measurements were analyzed using Materialise software. Results: Nonsyndromic bicoronal synostosis patients developed a shortened cranial base length, with a significantly shortened distance between nasion and sella (p = 0.005). The cranial base angles of nonsyndromic bicoronal synostosis in both the cranial side (N-S-BA) and facial side (N-SO-BA) increased significantly, by 17.04 degrees (p < 0.001) and 11.75 degrees (p < 0.001), respectively. However, both the N-S-BA and N-SO-BA angles of Apert syndrome and Crouzon syndrome were narrowed more than that of nonsyndromic bicoronal synostosis [by 12.11 degrees (p < 0.001) and 12.44 degrees (p < 0.001), respectively, in Apert syndrome; and by 11.66 degrees (p = 0.007) and 13.71 degrees (p = 0.007), respectively, in Crouzon syndrome]. However, there is no statistically significant difference of these two angles between Apert syndrome and Crouzon syndrome, when they were only associated with bicoronal synostosis. Contrary to the relatively normal subcranial space of nonsyndromic bicoronal synostosis, both Apert and Crouzon syndromes developed a reduced subcranial space. Conclusions: Isolated bicoronal synostosis resulted in a flattened cranial base, whereas Apert syndrome and Crouzon syndrome developed a normal cranial base angle when only associated with bicoronal synostosis. The syndromic skulls had additional significantly reduced subcranial space.