Pathophysiology and consequences of Craniosynostosis: Novel approaches in genetic, neuroimaging and aesthetic studies

Research output: Types of ThesisDoctoral ThesisInternal

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Chapter 1 describes the background and rationale for the studies presented in this thesis. Craniosynostosis is a rare congenital anomaly defined by premature fusion of one or more cranial sutures leading to a deformed skull shape. Craniosynostosis can have a wide range of adverse effects throughout the course of life. Our understanding of the development of the cranial vault and premature suture fusion has improved over the last decades, but many factors involved in the pathophysiology of craniosynostosis remain unknown. Therefore, the general aim of this thesis was to gain further insight into the pathophysiology and long-term consequences of craniosynostosis, for which we focused on three main objectives: 1) To investigate the genetic diagnostics yield in craniosynostosis; 2) to obtain further insight into the pathophysiology of metopic synostosis and associated disorders; 3) to establish methods for uniform assessments of phenotypical severity and aesthetic outcome for metopic and sagittal synostosis across Europe to facilitate cross-center comparison of treatment outcome in the future. The studies presented in this thesis were conducted in (subsets of) a large clinical cohort of patients with craniosynostosis in the Erasmus Medical Center, Rotterdam, the Netherlands and in a collaboration with European reference network (ERN) CRANIO.

Chapter 2 describes studies on the genetic background of craniosynostosis. In Chapter 2.1, we describe the genetic diagnostic yield in a large 11-year birth cohort of craniosynostosis patients. We found pathogenic variants in 35% of patients who underwent genetic diagnostics. Diagnostic yield was significantly higher in syndromic craniosynostosis (62%) than in non-syndromic craniosynostosis (6%). We conclude that microarray and the Whole Exome Sequencing (WES) craniosynostosis panel are key to identifying pathogenic variants in craniosynostosis patients. Given the advances in genetic diagnostics, we recommend to consider extensive genetic diagnostics if no diagnosis is obtained through microarray and/or WES craniosynostosis panel. In Chapter 2.2, we present a case report and review of the literature on the co-occurrence of craniosynostosis and congenital diaphragmatic hernia. Through clinical whole exome sequencing, we identified a BCL11B missense variant in a patient with a congenital diaphragmatic hernia as well as sagittal suture craniosynostosis. After targeted sequencing of BCL11B in patients with craniosynostosis, we identified three additional BCL11B missense variants in patients with craniosynostosis. We conclude that both craniosynostosis as well as congenital diaphragmatic hernia may be associated with BCL11B pathogenic variants, although further studies are needed to establish if BCL11B variants are causative pathogenic variants for both conditions.

Chapter 3 describes studies focused on radiological imaging in patients with metopic synostosis to gain insight into the pathophysiology of metopic synostosis and associated disorders. In Chapter 3.1, we present our study on white matter microstructure of major frontal lobe white matter tracts in young, unoperated metopic synostosis patients. Using automated diffusion tension imaging analyses, we found no significant differences in white matter microstructure in metopic synostosis patients compared to healthy controls. In Chapter 3.2, we found that preoperatively, total white matter volume was significantly smaller in young metopic synostosis patients compared to healthy controls. We observed an accelerated catch-up growth pattern of white matter volume. This pattern appears to be similar to white matter growth patterns described in autism. We observed no significant differences in total intracranial volume, total brain volume, total cerebrospinal fluid volume and total grey matter volume volumes in metopic synostosis patients compared to controls. In Chapter 3.3 we found that metopic synostosis patients have more shallow, wider, higher orbits with decreased interorbital distance compared to sagittal synostosis patients. We also found smaller globe height in metopic synostosis patients, although other eye dimensions (width and axial length) were similar to those in sagittal synostosis patients.

In Chapter 4 studies conducted within ERN CRANIO are described. ERNs are networks of specialized health care providers, that aim to pool together disease-specific expertise and resource from across Europe to ensure equal high quality care to all patients in Europe. ERN CRANIO is the ERN for rare and complex craniofacial anomalies, including craniosynostosis, and ear, nose and throat disorders. In Chapter 4.1 we observed that ERN CRANIO’s coverage of craniosynostosis varies across European countries and should be optimized further. In Chapter 4.2 and Chapter 4.3, we developed 2D photo scores for assessing phenotypical severity and aesthetic outcome of metopic and sagittal synostosis, respectively, the two most common types of craniosynostosis. In both studies we observed substantial interrater agreement on overall assessment of phenotypical severity, but considerable interrater differences were present for specific phenotypical features, despite the fact that scoring was done by experienced expert surgeons that were also involved in defining the photo scores.

Finally, Chapter 5 provides a general discussion in which the main findings from the work in this thesis are described in context of previous literature. We discuss methodological considerations, clinical implications, and suggestions for future research. To conclude, the studies in this thesis further underline the importance of genetic diagnostics in patients with craniosynostosis. Our observations in patients with metopic synostosis, suggest an intrinsic brain anomaly may be a key pathophysiological mechanism contributing to the neurodevelopmental disorders associated with metopic synostosis. The photo scores for uniform assessment of phenotypical severity of metopic and sagittal synostosis, developed in this thesis, may provide a useful clinical tool to uniformly score and compare aesthetic outcome in metopic and sagittal synostosis patients after treatment in multicenter settings.
Original languageEnglish
Awarding Institution
  • Erasmus University Rotterdam
  • Mathijssen, Irene, Supervisor
  • van Veelen-Vincent, Marie L.C., Co-supervisor
  • Vrooman, Henri, Co-supervisor
Award date31 Oct 2023
Place of PublicationRotterdam
Publication statusPublished - 31 Oct 2023


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