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I. M. J. Mathijssen - Craniosynostosis: Clinical and fundamental aspects

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SUMMARY

Because of the insufficiency of the traditional classification system for craniosynostosis syndromes (chapter I.1) an attempt was made to develop a new classification based on, amongst others, morphologic analysis of the calvaria and, later on, the genetic background of craniosynostosis. The morphologic studies of normal human fetuses describe the macroscopic development of the frontal and parietal bones with the coronal, metopic and sagittal sutures arising in between (chapters II.1 and II.2). The tubers mark the locus at which the frontal and parietal bones started to ossify, i.e. the frontal and parietal bone centers. Growth of the bones spreads in a concentric manner from the bone centers on, which can be seen as a radiating pattern of the bones. Each suture is found to develop at a highly consistent period during the fetal period of embryogenesis, in a characteristic pattern. At 16 weeks of gestation the first onset of the coronal suture can be seen, situated exactly in line with the frontal and parietal bone centers. It is at this locus that the frontal and parietal bones get in close contact first. Coronal suture development spreads from here on in both cranial and caudal direction. The metopic suture is formed from 15 weeks of gestation on and the sagittal suture development starts at 18 weeks.

Observations done on dry fetal skulls and patients’ skulls during surgery, or on their CT scans revealed typical displacement of the frontal and/or parietal bone centers for affected coronal, metopic or sagittal sutures. The associated bone centers were located just next to the synostotic suture and the radiating pattern of the bones was disrupted. The altered positions of the bone centers point out the developmental stage at which the synostosis was initiated. The distance between the two bone centers correlates into the developmental stage at which the bone centers are physiologically positioned from one another and further growth between the bone centers was arrested due to synostosis of the suture. For the coronal suture this period was determined at about 16 weeks of gestation, the time at which the first onset of the suture arises. These results can be translated to the appropriate timing for prenatal screening for craniosynostosis through ultrasound. Although the findings of these morphological studies did result in clinically relevant findings, no new classification for craniosynostosis came from it.

The genetic background of craniosynostosis appeared to be a better foundation for such a classification. This requires the mapping of phenotypic variations associated with each specific mutation. In a pilot study we analyzed this relation for all our patients with craniosynostosis for whom the mutation was known. For most mutations the number was too limited to allow meaningfull analysis. We reported the clinical findings in a patient with the Ser351Cys mutation in FGFR2 in view of the very severe phenotype (chapter IV.1). This phenotype is very similar to that of other individually described patients, indicating a strong relationship between genotype and phenotype for the Ser351Cys mutation. Furthermore, the FGFR3 mutation Pro250Arg was highlighted because of its high incidence and the detection of additional findings in its phenotype within our population (chapter IV.2). At the present, a clinically fulfilling classification based on genetics can still not be be developed. This is caused by a. the fact that in only half of the patients with a craniosynostosis syndrome a genetic mutation is traced, b. the number of patients for each individual mutation is very low, and c. the inconsistent interactions between genotype and phenotype for most mutations.

The discovery of genes involved in craniosynostosis gave a new impulse to the research on its pathogenesis. Their expression and function during normal suture development are largely unknown, making it even more difficult to understand the mechanism through which they induce craniosynostosis. For this reason, the first experimental study concerned normal development of the coronal suture in mice (chapter III.1). This study focused on the occurrence of programmed cell death, i.e., apoptosis, since this process is known to be essential during embryogenesis and is involved in the pathogenesis of numerous congenital malformations. Apoptosis during coronal suture development was shown to take place from a specific stage on, 16 days post conception, and at a restricted site, the osteogenic fronts of the frontal and parietal bones where these bones are in close vicinity. To study the biological processes resulting in premature suture ossification, a mouse model was developed in which the craniosynostosis associated fibroblast growth factor receptor (FGFR) 2 gene mutation was mimicked (chapter III.2). Exposing the coronal suture of a mouse embryo to an ectopic dose of fibroblast growth factor (FGF) 2 or 4 through ex utero surgery achieved this. Results showed that bone precursor cells within the suture underwent bone differentiation and apoptosis prematurely with enhanced mineralization of the osteoid. An attempt is made to translate the results of these studies to the human situation. It appears that the mutated receptor forces the expressing cells within the developing suture to undergo bone differentiation prematurely, at the expense of proliferation. As a result, ossification is enhanced while growth within the suture is restricted. Circumstantial evidence on the involvement of apoptosis in bone differentiation and mineralization is given by the associated increase of apoptotic cells within the treated murine suture. Thus, the genetic mutations in craniosynostosis cause a shift in the balance between proliferation and differentiation – including apoptosis - in the suture towards the latter. Given the similar morphological aspects of the calvaria in isolated and syndromic craniosynostosis, a comparable disturbance in developmental biology of the suture might underlie these congenital malformations.

This study has dealt with aspects of classification, morphology, genetics, and pathogenesis of craniosynostosis. Although relevant findings resulted of both clinical as well as fundamental character, numerous unsolved features remain for which recommendations are given for future research (chapter V).
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