Laureline Berteloot

Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children

Marie-Louise Frémond, MD, Mathieu Paul Rodero, PhD, Nadia Jeremiah, PhD, Alexandre Belot, MD, PhD, Eric Jeziorski, MD, Darragh Duffy, PhD, Didier Bessis, MD, Guilhem Cros, MD, Gillian I. Rice, PhD, Bruno Charbit, MSc, Anne Hulin, PharmD, PhD, Nihel Khoudour, MD, Consuelo Modesto Caballero, MD, Christine Bodemer, MD, PhD, Monique Fabre, MD, Laureline Berteloot, MD, Muriel Le Bourgeois, MD, Philippe Reix, MD, Thierry Walzer, PhD, Despina Moshous, MD, PhD, Stéphane Blanche, MD, PhD, Alain Fischer, MD, PhD, Brigitte Bader-Meunier, MD, Fréderic Rieux-Laucat, PhD, Yanick Joseph Crow, MD, PhD, Bénédicte Neven, MD, PhD

Feasibility and efficacy of chronic transfusion for stroke prevention in children with sickle cell disease

Objectives:  In children with sickle cell disease (SCD), chronic transfusion to maintain haemoglobin S (HbS) below 30% markedly decreases both the risk of a first stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow velocities and the risk of recurrent stroke. Maintaining HbS below 30% may be difficult, especially in countries where blood donors and recipients belong to different ethnic groups and where the availability of closely matched blood products is limited. We assessed the feasibility and efficacy of chronic transfusion with an HbS target of 30% in children with SCD living in the Paris area.

Posterior fossa imaging in 158 children with ataxia

OBJECTIFS To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia. PATIENTS AND METHODS Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n=27), cerebellar hypoplasia (n=15), hemispheric cerebellar dysgenesis (n=6), unilateral hemispheric atrophy (n=5), global cerebellar atrophy (n=84), signal abnormalities (n=11) and normal MRI (n=10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders. RESULTS In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric cerebellar dysgenesis and normal MRI groups, no biological diagnosis was found for any of the patients. In the group of unilateral hemispheric atrophy, we hypothesized a clastic prenatal injury. CONCLUSION The proposed MR cerebellar algorithm was useful to guide genetic/malformative or biochemical investigations, allowing an etiological diagnosis in 55 children.

Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?

BackgroundPulmonary alveolar proteinosis (PAP) is very rare in children. Only a few small series have been published, with little information about long-term progression. The objective of our study was to describe the clinical, radiological and pathological features, and the long-term course of PAP in a cohort of 34 children from La Réunion Island.MethodsData were retrospectively collected from medical files. Radiological and pathological elements were reviewed by two pediatric radiologists and three pathologists, respectively.ResultsThirteen cases were familial and 32/34 (94%) cases were family connected. Disease onset occurred in the first six months of life in 82% of the patients. Thoracic computed tomography scans showed the typical “crazy-paving” pattern in 94% of cases. Respiratory disease was associated with a liver disorder, with the detection of liver enlargement at diagnosis in 56% of cases. The course of the disease was characterized by frequent progression to chronic respiratory insufficiency, accompanied by the appearance of cholesterol granulomas and pulmonary fibrosis. Overall prognosis was poor, with a mortality of 59% and an overall five-year survival rate from birth of 64%. Whole-lung lavages were performed in 21 patients, with no significant effect on survival. Liver disease progressed to cirrhosis in 18% of children, with no severe complication.ConclusionsPAP in children from la Réunion Island is characterized by an early onset, associated liver involvement, poor prognosis and frequent progression to lung fibrosis, despite whole-lung lavages treatment. The geographic clustering of patients and the detection of many familial links between most of the cases strongly suggest a genetic etiology, with an autosomal recessive mode of inheritance.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.A PI3KCA inhibitor reverses symptoms in a mouse model of PROS/CLOVES syndrome, which results from gain-of-function mutations in PI3KCA, and produces improvements in patients with PROS/CLOVES syndrome.

Extralobar pulmonary sequestration with combined gastric and intradiaphragmatic locations

Extralobar pulmonary sequestration is a congenital lung malformation characterized by a non‐functional lung segment with systemic feeding vessel. Over 90% of sequestrations are found in the thorax with less than 10% located in the abdomen. We present an unusual case of intra abdominal pulmonary sequestration, located suprarenally, adherent to both the stomach and the diaphragm. The malformation was surgically excised via laparoscopy in the second year of life, when no evidence of regression was found on follow up imaging. On the occasion of this description, the spectrum of bronchopulmonary foregut malformation is discussed. Pediatr Pulmonol. 2014; 49:512–514.

Associations Among Mucosal and Transmural Healing and Fecal Level of Calprotectin in Children With Crohn’s Disease

Background & Aims: Bowel healing is an important goal of therapy for patients with Crohns disease (CD). Although there have been many studies of mucosal healing, transmural healing (ie, in the bowel wall) has not been investigated in children. We analyzed data from the ImageKids study to determine associations among mucosal, transmural healing and levels of calprotectin and C‐reactive protein in children with CD. Methods: We collected data from a multi‐center study designed to develop 2 magnetic resonance enterography (MRE)‐based measures for children with CD (6–18 years old). In our analysis of 151 children (mean age, 14.2 ± 2.4 years), all patients underwent MRE and a complete ileocolonoscopic evaluation; fecal levels of calprotectin and blood levels of C‐reactive protein were measured. Mucosal healing was defined as simple endoscopic severity index in CD score below 3, transmural healing as an MRE visual analogue score below 20 mm, and deep healing as a combination of transmural and mucosal healing. Results: We identified mucosal healing with transmural inflammation in 9 children (6%), transmural healing with mucosal inflammation in 38 children (25%), deep healing in 21 children (14%), and mucosal and transmural inflammation in 83 children (55%). The median level of calprotectin was lowest in children with deep healing (mean level, 10 &mgr;g/g; interquartile range, 10–190 &mgr;g/g), followed by children with either transmural or mucosal inflammation, and highest in children with mucosal and transmural inflammation (810 &mgr;g/g; interquartile range, 539–1737 &mgr;g/g) (P < .001). Fecal level of calprotectin identified children with deep healing with an area under the receiver operating characteristic curve value of 0.93 (95% CI, 0.89–0.98); level of C‐reactive protein identified children with deep healing with an area under the receiver operating characteristic curve value of 0.81 (95% CI, 0.71–0.9). A calprotectin cutoff value of 100 &mgr;g/g identified children with deep healing with 71% sensitivity and 92% specificity; a cutoff value of 300 &mgr;g/g identified children with mucosal healing with 80% sensitivity and 81% specificity. Conclusions: In a prospective study of children with CD, we found that one‐third have healing in only the mucosa or the bowel wall (not both). Levels of fecal calprotectin below 300 &mgr;g/identify children with mucosal healing, but a lower cutoff value (below 100 &mgr;g/g) is needed to identify children with deep healing. Clinicaltrials.gov no: NCT01881490.

A new method based on template registration and deformable models for pelvic bones semi-automatic segmentation in pediatric MRI

In this paper we address the problem of bone segmentation in MRI images of children, in the region of the pelvis. To cope with the complex structure of the bones in this region and their changing topology during growth, we propose a method relying on 3D bone templates. These models are built from 3D CT images. For a given MRI volume, the closest template is chosen and registered on the MRI data. This leads to an initial segmentation which is then refined using a deformable model approach, where the regularization parameters depend on the local curvature, and the landmarks used during the registration are fixed anchors during the deformation. This approach was successfully applied to 15 MRI volumes of children between 1 and 18 years old, with an average accuracy in terms of medium distance of MD = 1.17 ± 0.29mm and Dice Index of DC = 0.81 ± 0.04.

Bronchopulmonary sequestrations in a paediatric centre: ongoing practices and debated management

OBJECTIVES Bronchopulmonary sequestration (BPS) is the second most common congenital lung malformation, with an estimated incidence ranging from 0.15% to 1.8%. Surgical treatment is elective in patients with symptoms, but the management of asymptomatic patients remains controversial. METHODS We retrospectively reviewed the medical records of 99 patients treated for BPS in our institution from January 2000 to December 2015. BPS was diagnosed prenatally in 86 (87%) cases. Management throughout this 16-year period was based on 3 interventions: resection by open surgery, resection by thoracoscopy and embolization. RESULTS Among the 86 patients with a prenatal diagnosis of BPS, 14% had symptoms at birth and 10% had delayed symptoms at a median delay of 8 months (4.5-42 months). For the other 13 patients, symptoms occurred at a median age of 34 months (range 3-96 months). Embolization of the feeding vessel was performed in 46 patients with 6 secondary surgical resections (13%). A total of 59 patients were operated on: 23 cases by open surgery and 36 cases by thoracoscopy. The mean hospitalization stay was significantly longer for open surgery: 4.8 ± 1.3 days vs 4.1 ±1.5 days, respectively (P = 0.03). Differences in hospitalization stay were also found between asymptomatic and symptomatic patients: 3.5 ± 1.2 vs 5.1 ±1.6 days, respectively (P = 0.002). Two of the operated patients died. CONCLUSIONS When surgery is chosen, thoracoscopy appears to be a valuable procedure. A better understanding of the natural history of BPS is still needed to define the optimal management and the respective roles of surgery, embolization or non-interventional follow-up.

Segmentation of Pelvic Vessels in Pediatric MRI Using a Patch-Based Deep Learning Approach

In this paper, we propose a patch-based deep learning approach to segment pelvic vessels in 3D MRI images of pediatric patients. For a given T2 weighted MRI volume, a set of 2D axial patches are extracted using a limited number of user-selected landmarks. In order to take into account the volumetric information, successive 2D axial patches are combined together, producing a set of pseudo RGB color images. These RGB images are then used as input for a convolutional neural network (CNN), pre-trained on the ImageNet dataset, which results into both segmentation and vessel labeling as veins or arteries. The proposed method is evaluated on 35 MRI volumes of pediatric patients, obtaining an average segmentation accuracy in terms of Average Symmetric Surface Distance of \(ASSD = 0.89 \pm 0.07\) mm and Dice Index of \(DC = 0.79 \pm 0.02\).