, et al.. Early MRI in neonatal hypoxic-ischaemic encephalopathy treated with hypothermia: Prognostic role at 2-year follow-up.European Journal of Radiology, Elsevier, 2016, 85 (8), pp.1366-1374. 10.1016/j.ejrad.2016 CONFLICTS OF INTERESTThe authors have no conflict of interest to declare. Conflict of InterestEarly MRI in neonatal hypoxic-ischaemic encephalopathy treated with hypothermia: prognostic role at 2-year follow-up

The primary objective of this study was to evaluate changes in cerebral blood flow (CBF) using arterial spin labeling MRI between day 4 of life (DOL4) and day 11 of life (DOL11) in neonates with hypoxic-ischemic encephalopathy (HIE) treated with hypothermia. The secondary objectives were to compare CBF values between the different regions of interest (ROIs) and between infants with ischemic lesions on MRI and infants with normal MRI findings. We prospectively included all consecutive neonates with HIE admitted to the neonatal intensive care unit of our institution who were eligible for therapeutic hypothermia. Each neonate systematically underwent two MRI examinations as close as possible to day 4 (early MRI) and day 11 (late MRI) of life. A custom processing pipeline of morphological and perfusion imaging data adapted to neonates was developed to perform automated ROI analysis. Twenty-eight neonates were included in the study between April 2015 and December 2017. There were 16 boys and 12 girls. Statistical analysis was finally performed on 37 MRIs, 17 early MRIs and 20 late MRIs. Eleven neonates had both early and late MRIs of good quality available. Eight out of 17 neonates (47%) had an abnormal on late MRI as performed and 7/20 neonates (35%) had an abnormal late MRI. CBF values in the basal ganglia and thalami (BGT) and temporal lobes were significantly higher on DOL4 than on DOL11. There were no significant differences between DOL4 and DOL11 for the other ROIs. CBF values were significantly higher in the BGT vs. the cortical GM, on both DOL4 and DOL11. On DOL4, the CBF was significantly higher in the cortical GM, the BGT, and the frontal and parietal lobes in subjects with an abnormal MRI compared to those with a normal MRI. On DOL11, CBF values in each ROI were not significantly different between the normal MRI group and the abnormal MRI group, except for the temporal lobes. This article proposes an innovative processing pipeline for morphological and ASL data suited to neonates that enable automated segmentation to obtain CBF values over ROIs. We evaluate CBF on two successive scans within the first 15 days of life in the same subjects. ASL imaging in asphyxiated neonates seems more relevant when used relatively early, in the first days of life. The correlation of intra-subject changes in cerebral perfusion between early and late MRI with neurodevelopmental outcome warrants investigation in a larger cohort, to determine whether the CBF pattern change can provide prognostic information beyond that provided by visible structural abnormalities on conventional MRI.

Early MRI may provide valuable information about brain injury to help parents and neonatologists in intensive-care decisions at the end of hypothermia treatment.

Monogenic early-onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in WNT11 (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor LGR5, was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but WNT3A recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2–LGR5 complex via the non-canonical Wnt pathway.

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Background. Osteonecrosis (ON) is a long-known complication of acute leukemia (AL) management affecting 1 to 10% of young patients, leading to long-term morbidity. Widespread access to Magnetic Resonance Imagery (MRI) over the past ten years has allowed earlier detection and more accurate assessment. This study investigated clinical and radiological features of ON, among the large French cohort L.E.A (Leucémie Enfant Adolescent) Procedure. Patients with ON were retrospectively enrolled and risk factors for the onset, the multifocal involvement and severe damage were analyzed. Quality of life (QoL) was also evaluated. A sub-study described radiological features. Results. 129/4973 patients developed ON (2.5%) and were preferentially aged over 10 years at time of AL diagnosis (OR 22.46, p <10-6). Females were preferentially affected (OR 1.8, p=0.002) like patients treated for relapse (OR 1.81, p=0.041). Patients presenting ON suffered more frequently from other sequelae (p<10-6). Most of the necrosis were involving weight-bearing joints and multiple joints in 69% of cases. MRI of 39 patients with ON were double blinded reviewed. Overall, 14/39 suffered from severe impairment, preferentially on hips. QoL of adolescents and adults was poor and permanently affected once ON occurred. Conclusions. Age of over 10 years at diagnosis of AL, relapse and female sex were at risk of developing ON involving preferentially multiple joints. One third was severe and lasting poor QoL impacting several domains was found. Future studies should include prospective data on management and biological genetic features to build a targeted screening program to detect and manage ON earlier.