Jaffé-Campanacci syndrome: an extremely rare cause of pathologic fracture of the femur

Introduction: Non-ossifying fibromas are common benign bone tumors of children and young adults. They are usually single, asymptomatic and regress spontaneously in adulthood. Some rare cases of pathologic fractures have been described. Jaffé-Campanacci syndrome is the association of multiple non-ossifying fibromas, "café-au-lait" spots and some degree of type 1 neurofibromatosis. While the relationship between the two entities remains unclear, there seems to be some genetic similarities (partial or complete deletion of the gene NF1). Case Report: A 17 yo female patient with a neurofibromatosis type 1 was referred to our tertiary centre with a pathologic fracture of the distal femur through a non-ossifying fibroma. She had a slight mental retardation and "café-au-lait" spots. Imaging revealed multiple typical non-ossifying fibromas of both distal femurs and proximal tibias. There was no impending fracture of the controlateral side, and no other findings on thoraco-abdominal CT scanner. The fracture was treated by minimal invasive plate osteosynthesis. Histological analysis of tissue samples taken during the intervention confirmed the histologic diagnosis of non-ossifying fibroma. The fracture healed eventless and the patient returned to work after 3 months. At 12 months follow-up, the patient remained pain-free. Imaging revealed remodelling of the lesions. Conclusion: Jaffé-Campanacci syndrome is an extremely rare cause of pathologic femur fracture. These fractures can be treated like any other, and good outcome is expected. There is still no consensus in regards to definition of the disease and its relationship with type 1 neurofibromatosis.

Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Kartagener syndrome: an uncommon cause of neonatal respiratory distress?

We report a newborn with respiratory distress and situs inversus totalis. The diagnosis of primary ciliary dyskinesia was confirmed by both ultrastructural and functional investigations. The immotile cilia syndrome was suspected because of respiratory distress, situs inversus, abnormal nasal discharge and hyperinflated chest X-ray. We suggest that ultrastructural and functional investigations of the respiratory mucosa should be done in any newborn with respiratory distress without explanation for the respiratory problems. Establishment of the correct diagnosis at an early stage may allow to improve the prognosis provided prophylactic physiotherapy, vaccinations, and aggressive antibiotic treatment of intercurrent respiratory infections are instituted. CONCLUSION Despite its rarity, primary ciliary dyskinesia should be considered in unexplained cases of neonatal distress.

Peripapillary neovascular membrane: A rare cause of acute vision loss in pediatric idiopathic intracranial hypertension.

We report a 14-year-old boy who presented with vision loss secondary to peripapillary neovascular membrane (PPNVM) as the initial and only symptom of papilledema secondary to idiopathic intracranial hypertension. After one lumbar puncture, visual acuity progressively recovered during the course of 1 week and further improved with the administration of oral acetazolamide. One year after the onset of vision loss, the patient's visual acuity had recovered to baseline measurements. The previously active PPNVM had involuted into a residual peripapillary fibrotic scar. To our knowledge, this is the first report of PPNVM complicating idiopathic intracranial hypertension in a child.

Natural genetic variation of root system architecture from Arabidopsis to Brachypodium: towards adaptive value.

Root system architecture is a trait that displays considerable plasticity because of its sensitivity to environmental stimuli. Nevertheless, to a significant degree it is genetically constrained as suggested by surveys of its natural genetic variation. A few regulators of root system architecture have been isolated as quantitative trait loci through the natural variation approach in the dicotyledon model, Arabidopsis. This provides proof of principle that allelic variation for root system architecture traits exists, is genetically tractable, and might be exploited for crop breeding. Beyond Arabidopsis, Brachypodium could serve as both a credible and experimentally accessible model for root system architecture variation in monocotyledons, as suggested by first glimpses of the different root morphologies of Brachypodium accessions. Whether a direct knowledge transfer gained from molecular model system studies will work in practice remains unclear however, because of a lack of comprehensive understanding of root system physiology in the native context. For instance, apart from a few notable exceptions, the adaptive value of genetic variation in root system modulators is unknown. Future studies should thus aim at comprehensive characterization of the role of genetic players in root system architecture variation by taking into account the native environmental conditions, in particular soil characteristics.

Localization in sucrose gradients of the pyrophosphate-dependent proton transport of maize root membranes.

A maize (Zea mays L. cv LG 11) root homogenate was prepared and centrifuged to sediment the mitochondria. The pellet (6 KP) and the supernatant (6 KS) were collected and fractionated on linear sucrose density gradients. Marker enzymes were used to study the distribution of the different cell membranes in the gradients. The distribution of the ATP- and pyrophosphate-dependent proton pumping activities was similar after 3 hours of centrifugation of the 6 KS or the 6 KP fraction. The pumps were clearly separated from the mitochondrial marker cytochrome c oxidase and the plasmalemma marker UDP-glucose-sterolglucosyl-transferase. The pyrophosphate-dependent proton pump might be associated with the tonoplast, as the ATP-dependent pump, despite the lack of a specific marker for this membrane. However, under all the conditions tested, the two pumps overlapped the Golgi markers latent UDPase and glucan synthase I and the ER marker NADH-cytochrome c reductase. It is therefore not possible to exclude the presence of proton pumping activities on the Golgi or the ER of maize root cells. The two pumps (but especially the pyrophosphate-dependent one) were more active (or more abundant) in the tip than in the basal part of maize roots, indicating that these activities might be important in growth processes.

Target Molecular Size and Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis Analysis of the ATP-and Pyrophosphate-Dependent Proton Pumps from Maize Root Tonoplast.

Tonoplast-enriched membranes were prepared from maize (Zea mays L. cv LG 11) primary roots, using sucrose nonlinear gradients. The functional molecular size of the tonoplast ATP-and PPi-dependent proton pumps were analyzed by radiation inactivation. Glucose-6-phosphate dehydrogenase (G6PDH) was added as an internal standard. Frozen samples (-196 degrees C) of the membranes were irradiated with (60)Co for different periods of time. After thawing the samples, the activities of G6PDH, ATPase, and PPase were tested. By applying target theory, the functional sizes of the ATPase and PPase in situ were found to be around 540 and 160 kilodaltons, respectively. The two activities were solubilized and separated by gel filtration chromatography. The different polypeptides copurifying with the two pumps were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two bands (around 59 and 65 kilodaltons) were associated with the ATPase activity, whereas a double band (around 40 kilodaltons) was recovered with the PPase activity.

Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia.

Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.

Differential proteoglycan expression in two spinal cord regions after dorsal root injury.

Dorsal root injury leads to reactive gliosis in the spinal cord dorsal root entry zone and dorsal column, two regions that undergo Wallerian degeneration, but have distinct growth-inhibitory properties. This disparity could in part be due to differences in the number of degenerating sensory fibers, differences in glial cell activation, and/or to differential expression of growth-inhibitory molecules such as chondroitin sulfate proteoglycans. Laser capture microdissection of these two spinal cord white matter regions, followed by quantitative analysis of mRNA expression by real-time PCR, revealed that glial marker transcripts were differentially expressed post-injury and that the chondroitin sulfate proteoglycans Brevican and Versican V1 and V2 were preferentially up-regulated in the dorsal root entry zone, but not the dorsal column. These results indicate that reactive gliosis differs between these two regions and that Brevican and Versican are potential key molecules participating in the highly inhibitory properties of the dorsal root entry zone.

Direct and indirect root defences of milkweed (Asclepias syriaca): trophic cascades, trade-offs and novel methods for studying subterranean herbivory

P>1. Entomopathogenic nematodes can function as indirect defence for plants that are attacked by root herbivores. By releasing volatile organic compounds (VOCs), plants signal the presence of host insects and thereby attract nematodes.2. Nonetheless, how roots deploy indirect defences, how indirect defences relate to direct defences, and the ecological consequences of root defence allocation for herbivores and plant biomass are essentially unknown.3. We investigate a natural below-ground tritrophic system, involving common milkweed, a specialist root-boring beetle and entomopathogenic nematodes, and asked whether there is a negative genetic correlation between direct defences (root cardenolides) and indirect defences (emission of volatiles in the roots and nematode attraction), and between constitutive and inducible defences.4. Volatiles of roots were analysed using two distinct sampling methods. First, we collected emissions from living Asclepias syriaca roots by dynamic headspace sampling. This method showed that attacked A. syriaca plants emit five times higher levels of volatiles than control plants. Secondly, we used a solid phase micro-extraction (SPME) method to sample the full pool of volatiles in roots for genetic correlations of volatile biosynthesis.5. Field experiments showed that entomopathogenic nematodes prevent the loss of biomass to root herbivory. Additionally, suppression of root herbivores was mediated directly by cardenolides and indirectly by the attraction of nematodes. Genetic families of plants with high cardenolides benefited less from nematodes compared to low-cardenolide families, suggesting that direct and indirect defences may be redundant. Although constitutive and induced root defences traded off within each strategy (for both direct and indirect defence, cardenolides and VOCs, respectively), we found no trade-off between the two strategies.6. Synthesis. Constitutive expression and inducibility of defences may trade off because of resource limitation or because they are redundant. Direct and indirect defences do not trade off, likely because they may not share a limiting resource and because independently they may promote defence across the patchiness of herbivore attack and nematode presence in the field. Indeed, some redundancy in strategies may be necessary to increase effective defence, but for each strategy, an economy of deployment reduces overall costs.

The transventricular-transseptal access to the aortic root : a new route for extrapleural trans-catheter aortic stent-valve implantation

Rapport de synthèseObjectif: le remplacement valvulaire aortique par voie transcathétère est, actuellement, une méthode fiable indiquée pour des patients à haut risque porteurs d'une sténose valvulaire aortique. La voie transfémorale est utilisable seulement en cas d'absence de maladie vasculaire et la voie transapicale est contrindiquée en cas de dysfonction pulmonaire chronique sévère. Une alternative pour ne pas passer a travers l'espace pleural serait par voie sous- xiphoïdienne et trans-septale à travers le ventricule droit.Méthode: une expérience animale a été amené au laboratoire de recherche du CHUV. Cinq cochons (poids : 52.3±10.9 kg) ont été endormi et, sous anesthésie générale, le ventricule droit a été préparé a travers un accès sous- xiphoïdien. Ensuite, sous guide fluoroscopique et avec l'utilisation d'une échocardiographie intracardiaque, un accès trans-septal a été crée entre le ventricule droit et le ventricule gauche en utilisant des dilatateur de diamètre croissant (de 8F à 26F). Par la suite, une valve stentée crée dans le laboratoire en utilisant un stent en nitinol et du péricarde a été chargé dans une cartouche et introduite dans le ventricule gauche à travers un introducteur trans-septal. Enfin, la valve a été amené dans la chambre de chasse du ventricule gauche et ensuite dans la racine aortique et puis déployé au bon endroit. Quand le système a été retiré, le septum ventriculaire a pu être réparé par mise en place d'un système d'occlusion septal Amplazer. Trente minutes après la procédure, les animaux ont été sacrifié et le coeur a été analysé pour étudier le positionnement da la valve stentée, l'efficacité de la fermeture du septum inter-ventriculaire et la fermeture de la paroi du ventricule droit.Résultat : les cinq cochon ont tous eu un parfait positionnement et pose de la prothèse en position aortique au premier essai (efficacité 100%). Les procédures ont duré, moyennement, 49±4 minutes et la progressive dilatation de l'accès trans-septale à donné lieu à une communication inter-ventriculaire mesurable après dilatation avec du 18F et plus. Toutes les valves stentées ont été déployées au bon endroit avec un bon résultat du fonctionnement des valves prothétiques et absence d'insuffisance para prothétique. Pendant les procédures, des battement prématurés ainsi que des épisodes isolées de tachycardie supra ventriculaire ont été détectés. Par contre, il n'y a pas eu de bloc atrio-ventriculaire. Les pertes sanguines pendant les procédures étaient de 280±10mL, et les systèmes d'occlusion Amplatzer étaient tous bien déployés sans shunts inter-ventriculaires résiduels.Conclusion: la technique d'introduction de valve stentées par voie extrapleural (trans-ventriculaire et trans-septale) est techniquement possible et elle jette les bases pour le remplacement valvulaire aortique trans-ventriculaire sous anesthésie locale.