169 General Discussion (6-18 years). However, if we consider the significant difference as a real finding, several reasons can by hypothesized. Perhaps, microstructural properties are affected by CBF. In unoperated syndromic craniosynostosis patients, Doerga et al showed that these patients with sCS < 1 year old have lower CBF than control subjects.1 In their study, CBF of these patients normalizes with age and surgical treatment, but with a delay in the usual physiological peak in childhood. Whether this normalization is related to progressing age and maturation or to skull enlargement/ shunt treatment could not be identified. We can try to tie the results of both studies: CBF normalizes in time and diffusivity properties increase. This gives the suggestion that a lower CBF in patients with sCS < 1 years old may influence white matter properties at a later stage. According to this philosophy, a lower CBF in the first years of life provides a lower supply of oxygen, what subsequently leads to an increase in diffusivity properties in the following years. The normalization of CBF in time would be then the new balance with appropriate CBF for a decreased myelin quality. In this case, it would be interesting to investigate if these sCS children have more collateral arteries, a mechanism to accommodate for chronic lack of oxygen. Information on the effects of CBF on the long term is lacking. Literature reports contradicting findings on the relation of CBF and microstructural properties. Aslan et al. and Ouyang et al. observed a paradoxically inverse correlation: higher CBF tended to have a lower FA or AD, where higher CBF tended to have a higher RD.21, 22 On the contrary, histological studies show highly perfused white matter underlying a highly perfused cortex.23 This scenario would predict greater white matter integrity with higher CBF. Contradicting findings remain to be reconciled. In conclusion, to understand more about the relation between white matter and CBF in sCS patients, it will be important to assess both values from a corresponding MRI and per patient in the course of time. Besides age and CBF, also gene mutations may influence microstructural properties over time. Mutations in genes encoding the fibroblast growth factor receptors (FGFR) – which are expressed during early embryonic development– are known to be involved in the pattern of abnormal skull development and also known to affect the development of brain tissue in sCS.24-28 It is known that mutations in FGFR-1 or FGFR-2 are associated with decreased myelin thickness29, 30 and that FGFR genes have a major influence on myelination of WM tracts by involving the development of oligodendrocytes.29, 31, 32 TWIST 1 (Saethre-Chotzen syndrome), a basic helix-loop-helix (bHLH) domaincontaining transcription factor, plays an important role in cortical and mesodermal development.33, 34 Wilson et all shows cortical surface area is significantly different for FGFR patients in comparison to controls. 35 Taking all of the above together, gene mutations may play a role in microstructural architecture.16, 18, 36, 37 38, 39 Finally, it would be of interest to assess which other extrinsic factors other than FOHR, for example OSA and abnormal skull growth, play a role in microstructural properties. 10
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