1. Fetal MR Imaging of Craniosynostosis Impact on Diagnosis, Prognosis and Pathophysiology José Eduardo Alves 1, Xin Mu 1, Duan Xu 1, Audrey Foster-Barber 2, Orit Glenn 1 1- Department of Radiology and Biomedical Imaging – University of California San Francisco 2- Department of Child Neurology – UCSF Benioff Children’s Hospital eP-181

2. Disclosure  The authors have nothing to disclosure

3. Purpose  Craniosynostosis is a condition characterized by the premature fusion of one or more of the cranial sutures  In 10%-20% of cases, it presents in a syndromic form 1, associated with other skeletal and different organs abnormalities  Apert syndrome is one of the most severe forms of craniosynostosis, accounting for 40-50% of the syndromic variants 2,3  In recent years, genes associated with these syndromes have been identified, like fibroblast growth factor receptors (FGFR1, 2 and 3), RECQL4, TWIST and MSX2 genes

4. Purpose  Brain abnormalities are frequently associated with syndromic craniosynostosis, but their nature is still poorly understood  Although prenatal ultrasound can detect premature closure of sutures and the abnormal cranial shape, fetal MR imaging is more accurate in the detection and description of associated brain abnormalities, and thus has higher prognostic value 4  The purpose of this study was to provide a detailed description of both craniofacial and intracranial MRI findings in fetuses with proven syndromic craniosynostosis

5. Materials and Methods  A search was conducted for all cases of suspected craniosynostosis in the database of fetal MR imaging performed at UCSF between November 1996 and July 2015  Cases with a proven diagnosis of craniosynostosis through fetal genetic testing, autopsy or postnatal evaluation, were included for further evaluation  MR images were retrospectively reviewed by 2 neuroradiologists, who assessed calvarial, skull base, facial and brain morphology

6. Materials and Methods  Fetal MR protocol: ParameterValue Magnetic field 1.5T Fetal or maternal sedation No Receiver coil Torso or cardiac phased array Sequences Triplanar ssFSE T2 WI all fetuses (3 acquired with Real-Time Imaging 5 ), axial fast gradient T1-WI, axial and coronal gradient echo-planar T2 and axial diffusion-weighted images Slice thickness (mm) 3 (no skip) Field of view (cm) 24-32

7. Results  Four fetuses with syndromic craniosynostosis:  3 cases of Apert syndrome  1 fetus with Pfeiffer syndrome type 2  Median maternal age at conception: 37 years (range 30-42)  Gestational age at fetal MRI: 20-35 weeks

8. Results  All fetuses demonstrated abnormal calvarial configuration Brachycephaly and frontal bossing in a fetus with Apert syndrome Abnormal thickening along the coronal suture (black arrows) in a fetus with Apert syndrome, indicating it is prematurely fusing “Cloverleaf” configuration of the skull in the fetus with Pfeiffer syndrome.

9. Results  Facial structures and/or skull base dysmorphism were common to all fetuses Hypertelorism Cleft palate (white arrow) Dysplastic right vestibular apparatus (black arrow)

10. Results  All Apert’s cases had an abnormal distribution of CSF in the middle cranial fossa Decreased CSF lateral to the temporal, parietal and occipital lobes (black and white arrows) and CSF accumulation anterior to the temporal poles (white arrowheads)

11. Results  Temporal lobe overexpansion in the 3 fetuses with Apert syndrome Abnormal bulging of the lateral surface of the temporal lobes beyond the contour of the adjacent frontoparietal lobes. One fetus showed agenesis of the corpus callosum (black arrow) and 2 had abnormal hippocampal morphology (white dashed arrow)

12. Results  All Apert’s cases had abnormal sulcation in the inferomedial temporooccipital lobes Bilateral atypical deep infoldings in the inferomedial regions of temporal lobes (black arrows), extending posteriorly as far as the calcarine sulci in 2 cases and past the calcarine sulci in 1 case

13. Results  Abnormal temporal sulcation persisted postnatally Abnormal temporal lobe sulcation (black arrow) and hippocampal morphology (white arrow) identified in the fetal MR (top row) persisted postnatally (bottom row). This fetus had also extensive bilateral frontal and perisylvian polymicrogyria

14. Conclusion  Our findings support the high prevalence and great diversity of brain, facial and skull base abnormalities in fetuses with syndromic craniosynostosis  Fetal MRI enables a detailed and early characterization of these conditions and has great value both as a diagnostic and a prognostic tool  All Apert’s cases had an abnormal distribution of CSF in the middle cranial fossa and this feature may be used as an indirect sign of craniosynostosis

15. Conclusion  Temporal lobes overexpansion and temporooccipital abnormal sulcation are consistent findings in fetuses with Apert syndrome and can be detected as early as 20 weeks gestational age  Although the pathological mechanisms of brain malformations in Apert syndrome and other syndromic craniosynostosis are not completely understood yet, our findings support their primary nature rather than secondary to a dysmorphic skull

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17. Fetal MR Imaging of Craniosynostosis Impact on Diagnostic, Prognostic and Pathophysiology José Eduardo Alves 1, Xin Mu 1, Duan Xu 1, Audrey Foster-Barber 2, Orit Glenn 1 1- Department of Radiology and Biomedical Imaging – University of California San Francisco 2- Department of Child Neurology – UCSF Benioff Children’s Hospital eP-181