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Anorectal malformation (ARM) is the most common symptom in VACTERL syndrome (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies). The association of ARM and spinal dysraphisms (DYS) is well documented. We aim to better evaluate children with VACTERL association and ARM, considering the presence or not of DYS. Between 2000 and 2015, 279 children with VACTERL associations were identified in Necker Children's Hospital, Paris. We identified 61 VACTERL children (22%) with ARM. A total of 52 VACTERL children with ARM were included. DYS were identified in 36/52 of cases (69.2%). A total of 33 (63.5%) VACTERL children presented with sphincterial dysfunction. We constated that 28/33 (84.8%) of them had DYS + (p 0.0001). More children in ARM (DYS +) subgroup are presenting with initial urinary sphincter dysfunction (58 vs 19%, p 0.009) than ARM (DYS -). We identified 29 lipoma filum in our series, which were not statistically associated with urinary disorders (p = 0.143).Conclusion: We propose to refine the definition of VACTERL association, by adding S as Spinal defect to include it as an integral part of this syndrome, resulting in a novel acronym V.A.C.TE.R.L.S.What is Known:• The VACTERL association: congenital anomalies of the bony vertebral column (V), anorectal malformation (A), congenital cardiopathy (C), tracheo-esophageal defects (TE), renal and urinary tract anomalies (R), and limb malformations (L).• VACTERL children needs a complete appraisal, as early as possible, to adopt the most appropriate therapeutic management.What is New:• Include spine dysraphism (DYS) as a part of this syndrome, resulting in a novel acronym V.A.C.TE.R.L.S.• The significant correlation between VACTERL/DYS and urinary dysfunction requires to investigate the spine cord prenatally.

International audience; Secondary neurulation is a morphological process described since the second half of the 19th century; it accounts for the formation of the caudal spinal cord in mammals including humans. A similar process takes place in birds. This form of neurulation is caused by the growth of the tail bud region, the most caudal axial region of the embryo. Experimental work in different animal species leads to questioning dogmas widely disseminated in the medical literature. Thus, it is clearly established that the tail bud is not a mass of undifferentiated pluripotent cells but is made up of a juxtaposition of territories whose fate is different. The lumens of the two tubes generated by the two modes of neurulation are continuous. There seem to be multiple cavities in the human embryo, but discrepancies exist according to the authors. Finally, the tissues that generate the secondary neural tube are initially located in the most superficial layer of the embryo. These cells must undergo internalization to generate the secondary neurectoderm. A defect in internalization could lead to an open neural tube defect that contradicts the dogma that a secondary neurulation defect is closed by definition.

Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms. The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway. We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids., This work was supported by funding to SSM from the Fondation pour la Recherche Médicale (Equipe FRM EQU201903007943) and from the Fondation ARC (PJA 20171206591).

Meninges have long been considered as a protective and supportive tissue for the central nervous system. Nevertheless, new developmental roles are now attributed to them. The meninges that surround the cerebellum come from the cephalic mesoderm. They are essential for the cerebellum to develop normally. They induce and maintain the basal lamina and glia limitans. In the absence of these structures, the external granular cells of the cerebellum migrate aberrantly and penetrate the subarachnoid space. The molecules involved in the recognition between the cerebellar primordium and the basal lamina belong to two groups in humans: dystroglycan and laminin on the one hand, and GPR56 and collagen III on the other. Finally, molecules secreted by the meninges and acting on the cerebellum begin to be demonstrated; such is the case of SDF1 secreted under the action of FOXC1.

Introduction La maladie d’Alexander debutant a l’âge adulte a un phenotype clinico-radiologique different de la forme infantile. Nous rapportons ici deux observations. Observation Premier cas : Femme de 45 ans presentant depuis un an une ataxie, une dysarthrie, une tetraparesie pyramidale, une dysautonomie avec incontinence urinaire et fecale. Des troubles du comportement ont precede ces signes justifiant une mise sous curatelle. Deces a 47 ans. Sa mere, decedee a 62 ans, presentait des troubles similaires. Second cas : Homme de 49 ans consultant pour une tetraparesie pyramidale asymetrique a predominance gauche avec grabatisation rapide, suivie d’une incontinence urinaire et fecale. Des troubles de l’humeur et un syndrome frontal etaient decrits. Son pere etait decede a 65 ans dans les suites d’une paraplegie spastique evoluant sur 15 ans. Dans les deux cas, l’IRM cerebrale etait caracteristique : – atrophie prononcee de la moelle allongee et de la moelle cervicale avec un aspect de tetard du tronc cerebral en coupe sagittale T1 ; – hypersignal mesencephalique peripherique FLAIR sous pial evocateur ; – hypersignaux T2 de la substance blanche periventriculaires, mesencephaliques, des noyaux denteles, de la moelle allongee et de la moelle cervicale. Une mutation du gene codant la proteine GFAP a ete retrouvee dans ces deux cas. Discussion L’aspect clinique de la maladie d’Alexander a debut adulte est parfois deroutant. Neanmoins, les images d’IRM cerebrale, en particulier en fosse posterieure, sont assez stereotypees et tres evocatrices et doivent conduire a la recherche d’une mutation du gene GFAP surtout en cas d’antecedents familiaux suggerant une affection autosomique dominante. Conclusion La maladie d’Alexander debutant chez l’adulte est de diagnostic clinique difficile mais les anomalies cerebrales IRM sont tres evocatrices et doivent faire rechercher une mutation du gene GFAP.

International audience; OBJECTIVE:C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers.METHODS:Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age.RESULTS:At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline.INTERPRETATION:Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.

Background Learning surgical anatomy of the petrous pyramid can be a challenge, especially in the beginning of the training process. Providing an easier, holistic approach can be of help to everyone with interest in learning and teaching skull base anatomy. We present the complex organization of petrous pyramid anatomy using a new compartmental approach that is simple to understand and remember. Methods The surfaces of the petrous pyramid of two temporal bones were examined; and the contents of the petrous pyramid of 8 temporal bones were exposed through progressive drilling of the superior surface. Results The petrous pyramid is made up of a bony container, and its contents were grouped into 4 compartments (mucosal, cutaneous, neural, and vascular). Two reference lines were identified (mucosal and external-internal auditory canal lines) intersecting at the level of the middle ear. The localization of contents relative to these reference lines was then described, and 2 methods of segmentation (the X method and the V method) were then proposed. This description was then used to describe middle ear relationships, facial nerve anatomy, and air cell distribution. Conclusions This new compartmental approach allows a comprehensive understanding of the distribution of petrous pyramid contents. Dividing it into anatomic compartments, and then navigating this mental map along specific reference points, lines, spaces, and segments, could create a useful tool to teach or learn its complex tridimensional anatomy.

Trying to understand the mechanisms involved in human development is both a complex and fascinating problem. It is also the absolute prerequisite for an analysis of human malformations. Self-evidently, the genesis of malformation syndromes cannot be understood without a knowledge of the normal steps of development. This contradicts the classical works of human embryology, which were devoted to the analysis of malformation syndromes in the attempt to decipher the normal steps of human development — a method that may be called “reverse embryology”. Nowadays, this old method is of no value and it has been necessary to develop new paradigms to discover the normal pathways of development.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. Methods Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. Results In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. Conclusions Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation., Highlights • (SMA) type 3 and 4 is a lower motor neuron syndrome. Nevertheless, wider involvement of the nervous system might be possible. • 25 adults type 3 and 4 SMA patients were studied using brain and cervical spinal cord neuroimaging techniques. • Grey matter atrophy was observed in the spinal cord. No white matter degeneration was present at brain and spinal level. • Increased grey matter density was detected in cerebral motor regions and explained as compensatory mechanism.

International audience; The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities.

International audience; Agenesis of the corpus callosum (AgCC) is a frequent brain disorder found in over 80 human congenital syndromes including ciliopathies. Here, we report a severe AgCC in Ftm/Rpgrip1l knockout mouse, which provides a valuable model for Meckel–Grüber syndrome. Rpgrip1l encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in several cell types in mouse including neuroepithelial cells in the developing forebrain. We show that AgCC in Rpgrip1l−/– mouse is associated with a disturbed location of guidepost cells in the dorsomedial telencephalon. This mislocalization results from early patterning defects and abnormal cortico-septal boundary (CSB) formation in the medial telencephalon. We demonstrate that all these defects primarily result from altered GLI3 processing. Indeed, AgCC, together with patterning defects and mispositioning of guidepost cells, is rescued by overexpressing in Rpgrip1l−/− embryos, the short repressor form of the GLI3 transcription factor (GLI3R), provided by the Gli3Δ699 allele. Furthermore, Gli3Δ699 also rescues AgCC in Rfx3−/− embryos deficient for the ciliogenic RFX3 transcription factor that regulates the expression of several ciliary genes. These data demonstrate that GLI3 processing is a major outcome of primary cilia function in dorsal telencephalon morphogenesis. Rescuing CC formation in two independent ciliary mutants by GLI3Δ699 highlights the crucial role of primary cilia in maintaining the proper level of GLI3R required for morphogenesis of the CC.

In higher vertebrates, the primordium of the nervous system, the neural tube, is shaped along the rostrocaudal axis through two consecutive, radically different processes referred to as primary and secondary neurulation. Failures in neurulation lead to severe anomalies of the nervous system, called neural tube defects (NTDs), which are among the most common congenital malformations in humans. Mechanisms causing NTDs in humans remain ill-defined. Of particular interest, the thoracolumbar region, which encompasses many NTD cases in the spine, corresponds to the junction between primary and secondary neurulations. Elucidating which developmental processes operate during neurulation in this region is therefore pivotal to unraveling the etiology of NTDs. Here, using the chick embryo as a model, we show that, at the junction, the neural tube is elaborated by a unique developmental program involving concerted movements of elevation and folding combined with local cell ingression and accretion. This process ensures the topological continuity between the primary and secondary neural tubes while supplying all neural progenitors of both the junctional and secondary neural tubes. Because it is distinct from the other neurulation events, we term this phenomenon junctional neurulation. Moreover, the planar-cell-polarity member,Prickle-1, is recruited specifically during junctional neurulation and its misexpression within a limited time period suffices to cause anomalies that phenocopy lower spine NTDs in human. Our study thus provides a molecular and cellular basis for understanding the causality of NTD prevalence in humans and ascribes toPrickle-1a critical role in lower spinal cord formation.

Primary cilia are essential for CNS development. In the mouse, they play a critical role in patterning the spinal cord and telencephalon via the regulation of Hedgehog/Gli signaling. However, despite the frequent disruption of this signaling pathway in human forebrain malformations, the role of primary cilia in forebrain morphogenesis has been little investigated outside the telencephalon. Here we studied development of the diencephalon, hypothalamus and eyes in mutant mice in which the Ftm/Rpgrip1l ciliopathy gene is disrupted. At the end of gestation, Ftm−/− fetuses displayed anophthalmia, a reduction of the ventral hypothalamus and a disorganization of diencephalic nuclei and axonal tracts. In Ftm−/− embryos, we found that the ventral forebrain structures and the rostral thalamus were missing. Optic vesicles formed but lacked the optic cups. In Ftm−/− embryos, Sonic hedgehog (Shh) expression was virtually lost in the ventral forebrain but maintained in the zona limitans intrathalamica (ZLI), the mid-diencephalic organizer. Gli activity was severely downregulated but not lost in the ventral forebrain and in regions adjacent to the Shh-expressing ZLI. Reintroduction of the repressor form of Gli3 into the Ftm−/− background restored optic cup formation. Our data thus uncover a complex role of cilia in development of the diencephalon, hypothalamus and eyes via the region-specific control of the ratio of activator and repressor forms of the Gli transcription factors. They call for a closer examination of forebrain defects in severe ciliopathies and for a search for ciliopathy genes as modifiers in other human conditions with forebrain defects. SIGNIFICANCE STATEMENT The Hedgehog (Hh) signaling pathway is essential for proper forebrain development as illustrated by a human condition called holoprosencephaly. The Hh pathway relies on primary cilia, cellular organelles that receive and transduce extracellular signals and whose dysfunctions lead to rare inherited diseases called ciliopathies. To date, the role of cilia in the forebrain has been poorly studied outside the telencephalon. In this paper we study the role of the Ftm/Rpgrip1l ciliopathy gene in mouse forebrain development. We uncover complex functions of primary cilia in forebrain morphogenesis through region-specific modulation of the Hh pathway. Our data call for further examination of forebrain defects in ciliopathies and for a search for ciliopathy genes as modifiers in human conditions affecting forebrain development.

As bus rapid transit (BRT) continues to grow in popularity in the United States, a better understanding of the mode's impacts on land uses and property values continues to be needed. This research sought to quantify the impacts of access to BRT stations on the sale prices of surrounding condominiums located along Washington Street in Boston, Massachusetts, where Phase 1 of the Silver Line BRT began operating in 2002. The hypothesis that the BRT stations had an impact on market value similar to light rail transit projects (considering the level and permanence of the investment) was tested with a hedonic regression methodology for estimating the impact of access to BRT stations on sale prices of condominium units. A key result was that, for condominium sales in 2007 or 2009, the BRT premium was approximately 7.6%. For condominium sales in 2000 and 2001, before the opening of the Silver Line, no sales premium existed for proximity to the corridor. These results suggest that access to high-quality transit service, not necessarily the mode itself, induces this premium. Although this study is specific to the Boston Silver Line Washington Street corridor, further research into the impacts of BRT is encouraged as a means to provide policy makers and the transit industry with the best information possible for making optimal transit investment decisions in their communities.

International audience; no abstract

The skeleton of the head and neck represents a very complex set of bones whose development is both complicated and precise. It is by now impossible to write a precise and thorough chapter to account for the tremendous amount of new data gained by experimental embryology. So, I will focus my presentation on: (1) some elements of descriptive embryology that are mandatory to give the readers landmarks for human development; (2) the origin of the cells that are fated to form these structures and their subsequent development; (3) tissue interactions that could account for the malformative associations that can be observed in humans; and (4) genetic controls of these processes.

Congenital spinal lipomas are closed spinal dysraphisms belonging to the neural tube defects (NTDs) group. They include a broad spectrum of lesions ranging from simple lipomas of the filum terminale to complex malformations. On histological evaluation, various tissue components of ectodermal, mesodermal or endodermal origin are found within the lipomas, with prevalence for nerves and striated muscle and, more rarely, cartilage and bone. Overall, rib malformations have been occasionally observed in patients with NTDs and in NTD mouse models. However, an ectopic rib arising within the spinal lipoma and articulating with the iliac crest has not been reported in either animal models or in humans.We describe four patients affected by lipomyeloschisis or lipomyelomeningocele, with an unusual fibrocartilaginous protuberance arising within the lipoma and connecting to one iliac crest, strongly resembling an ectopic rib. Histological evaluation confirmed the presence of cartilaginous tissue.We expand the clinical spectrum of fibrocartilaginous anomalies associated with spinal lipoma, suggesting the presence of an ectopic rib as a new possible phenotype in NTDs. A careful analysis by neuroradiologists and pathologists should be performed in spinal lipomas to assess the presence of an ectopic rib or other uncommon developmental anomalies. Furthermore, molecular studies are required to detect the genetic cause of this unusual phenotype. Birth Defects Research (Part A) 106:530-535, 2016. © 2016 Wiley Periodicals, Inc.

The development of bus rapid transit (BRT) systems is relatively recent in the United States; however, several systems are operating and many more are being planned. More comprehensive understanding is needed of the relationship between land use and BRT, particularly in comparison with other fixed-guideway modes. This paper describes an effort to quantify the impacts of BRT stations on the values of surrounding single-family homes. The hypothesis is that BRT stations have an impact on property value that is commensurate with rail transit projects, considering the level and permanence of services and facilities. To test that hypothesis, a hedonic regression model was used to estimate the impact of distance to a BRT station on the fair market value of single-family homes. Because many BRT systems operating in the United States may be too new to find evidence of capitalization into property values, data from East Busway, in Pittsburgh, Pennsylvania, one of the oldest operating BRT systems in the country, was used. Decreasing marginal effects were found: moving from 101 to 100 ft from a station increases property value approximately $18.90; moving from 1,001 to 1,000 ft increases property value by approximately $2.71. The results shown in this paper are valid only for the data used in Pittsburgh's case. As more BRT systems continue to operate in the United States, this method should be applied to other cities and other types of properties to gain a better understanding of the general impacts of proximity to BRT.

Neural crest cells (NCCs) arising from trunk neural tube (NT) during primary and secondary neurulation give rise to melanocytes, glia and neurons, except for those in the caudal-most region during secondary neurulation (somites 47 to 53 in the chick embryo), from which no neurons are formed, either in vivo or in vitro. To elucidate this discrepancy, we have specifically analyzed caudal-most NCC ontogeny. In this region, NCCs emerge at E5/HH26, one day after full cavitation of the NT and differentiation of flanking somites. The absence of neurons does not seem to result from a defect in NCC specification as all the usual markers, with the exception of Msx1, are expressed in the dorsal caudal-most NT as early as E4/HH24. However, Bmp4-Wnt1 signaling, which triggers trunk NCC delamination, is impaired in this region due to persistence of noggin (Nog) expression. Concomitantly, a spectacular pattern of apoptosis occurs in the NT dorsal moiety. Rostral transplantation of either the caudal-most somites or caudal-most NT reveals that the observed features of caudal-most NCCs relate to properties intrinsic to these cells. Furthermore, by forced Nog expression in the trunk NT, we can reproduce most of these particular features. Conversely, increased Bmp4-Wnt1 signaling through Nog inhibition in the caudal-most NT at E4/HH24 induces proneurogenic markers in migratory NCCs, suggesting that noggin plays a role in the lack of neurogenic potential characterizing the caudal-most NCCs., CNRS, UPMC, FCT and AFM. L.O. is a recipient of a grant from FCT (SFRH/BD/11858/2003) and from ARC

In the prospective lumbo-sacral region of the chick embryo, neurulation is achieved by cavitation of the medullary cord, a process called secondary neurulation. Neural crest cells (NCC) are generated in this region and they give rise to the same types of derivatives as in more rostral parts of the trunk where neurulation occurs by dorsal fusion of the neural plate borders (primary neurulation). However, no molecular data were available concerning the different steps of their ontogeny. We thus performed a detailed expression study of molecular players likely to participate in the generation of secondary NCC in chick embryos between Hamburger and Hamilton stages 18-20 (HH18-20) at the level of somites 30 to 43. We found that specification of secondary NCC involves, as in primary neurulation, the activity of several transcription factors such as Pax3, Pax7, Snail2, FoxD3 and Sox9, which are all expressed in the dorsal secondary neural tube as soon as full cavitation is achieved. Moreover, once specification has occurred, emigration of NCC from the dorsal neuroepithelium starts facing early dissociating somites and involves a series of changes in cell shape and adhesion, as well as interactions with the extracellular matrix. Furthermore, Bmp4 and Wnt1 expression precedes the detection of migratory secondary NCC and is coincident with maturation of adjacent somites. Altogether, this first study of molecular aspects of secondary NCC ontogeny has revealed that the mechanisms of neural crest generation occurring along the trunk region of the chick embryo are generally conserved and independent of the type of neurulation involved., We are grateful to our colleagues for helpful discussions. We thank Dr Jean-Loup Duband for fibronectin and NC1 antibodies and Dr James Briscoe for Sox9 plasmid. This work has been supported by Centre National de la Recherche Scientifique (CNRS), University Paris 6 (UPMC), Fundacao para Ciencia e Tecnologia (FCT), Association Francaise contre les Myopathies (AFM). LO is a recipient of a grant from FCT (SFRH/BD/1185812003).

International audience; Subcutaneous tumors with extra limbs are very rare, and they are considered either as fetus in fetu or fetiform teratoma. We report here the case of a 6-day-old presenting a mass extending at the level of the occipital bone. This mass is developed in the extracranial region and contains two forelimbs including hands with digits. CT shows that the squamous part of the occipital bone is involved with several defects through which a part of the cerebellum herniates. The boy was operated on and the tumor was removed. The herniated region of the cerebellum has also been removed. After surgery, the boy develops normally. This type of tumor is extremely rare and is only the second case that has been reported at this exact location. This could be the so-called c,phalom,lie described by Isidore Geoffroy Saint-Hilaire in a duck in his famous Treatise of Teratology (1836). The cause of this malformation is still a matter for debate.

The posterior fossa is a favorite subject for our colleagues involved in pediatric neurosurgery. Indeed, most of the serious illnesses affecting children lie at this level. It is therefore important to present here an aspect (albeit simplified) illustrating the development of these structures.

International audience; Beckwith–Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron–exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS

Little is known about the ontogeny of naturally occurring CD4+CD25+ regulatory/suppressor T cells that play a major role in maintaining self-tolerance in mice and humans. In rodents, thymectomy on day 3 of life leads to multiple organ-specific autoimmune diseases that can be prevented by adoptive transfer of regulatory T cells, suggesting their neonatal development. We investigated regulatory T-cell ontogeny in 11 human fetuses. Together with the first mature T cells, thymic CD4+CD25+ cells were detected as early as 13 weeks of gestation. Thymic CD25+ cells appeared to be positively selected at the CD4+CD8+CD3hi differentiation stage, as assessed by CD1a and CD69 expression. The proportion of thymic CD4+CD25+ cells appeared quite stable with age, around 6% to 7%, similar to the proportion observed in infant thymi. Extrathymic CD4+CD25+ T cells could hardly be detected at 13 weeks of gestation but were present from week 14 onwards. As adult regulatory T cells, purified CD4+CD25+ fetal cells were anergic and suppressed T-cell proliferative responses; they expressed intracellular cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and Foxp3 mRNA. Altogether, our results indicate that the generation of regulatory/suppressor T cells is consubstantial to the generation of a functional and self-tolerant immune system. (Blood. 2005;105:4715-4721)

The caudal neural tube (CNT) of the avian embryo is devoid of both dorsal and ventral roots. We show that the lack of ventral roots in the CNT, from somite 48 caudalwards, is due to an absence of post-mitotic motoneurons (MNs). The absence of MNs is not due to a defective notochordal induction since Sonic Hedgehog (SHH) signaling is intact and the caudal notochord is able to induce ectopic MNs when grafted laterally to a host neural tube. The transcription factors involved in MN specification (Pax6, Nkx6.1, and Olig2) are all expressed in the CNT, despite the lower expression level of Pax6, but an overlap between Olig2 and the ventrally expressed transcription factor Nkx2.2 is observed in the CNT. Grafting a quail CNT into the cervical level of a chick host rescues MN generation, demonstrating both the CNT potential for MN generation and the key role of the caudal environment in the MN differentiation blockade. The transplantation of the CNT-flanking somites into the cervical level does not inhibit MN generation. Furthermore, implantation of a retinoic-acid-soaked bead laterally to the CNT does not rescue MN generation. Together, these data indicate that the rostral environment contains a signal different from both SHH and Retinoic Acid that acts on MN differentiation.

ZFHX1B encodes Smad-interacting protein 1, a transcriptional corepressor involved in the transforming growth factors beta (TGFbeta) signaling pathway. ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects. We compared the distribution of ZFHX1B transcripts during mouse and human embryogenesis as well as in adult mice and humans. This showed that this gene is strongly transcribed at an early stage in the developing peripheral and central nervous systems of both mice and humans, in all neuronal regions of the brains of 25-week human fetuses and adult mice, and at varying levels in numerous nonneural tissues. Northern blot analysis suggested that ZFHX1B undergoes tissue-specific alternative splicing in both species. These results strongly suggest that ZFHX1B determines the transcriptional levels of target genes in various tissues through the combinatorial interactions of its isoforms with different Smad proteins. Thus, as well as causing neural defects, ZFHX1B mutations may also cause other malformations.

Introduction Un patient, âge de 31 ans, issu d’une famille marocaine consanguine, nous a ete adresse pour troubles neurologiques jamais investigues evoluant depuis l’enfance, associes a un contexte de photosensibilite. Observation Le patient est ne a terme, avec developpement psychomoteur initial normal. A l’âge de 6 mois, est notee une photosensibilite avec eruption cutanee a l’ensoleillement responsable de phlyctenes et de cicatrices lentigineuses. Un trouble du langage avec begaiement apparait a l’âge de 6 ans, puis a 8 ans une deformation des pieds en varus equin. Sa scolarite est perturbee des le CE1, avec mise en secteur protege necessaire. Depuis 2012, une majoration des troubles de la marche et des troubles vesico-sphincteriens compromet l’autonomie. Il est adresse en neurologie, ou l’examen clinique retrouve un retard mental, une abolition diffuse des reflexes osteotendineux, un signe de Babinski bilateral et un syndrome cerebelleux. L’examen cutane montre des lentigines avec cicatrices hypopigmentees dans les zones photo-exposees. Le bilan etiologique retrouve une atrophie diffuse et une hyperostose crânienne a l’IRM cerebrale, l’EMG une polyneuropathie axonale (PRN) sensitivomotrice, un bilan biologique normal et le bilan genetique une mutation homozygote c.682C>T dans l’exon 6 du gene XPA codant une proteine tronquee p.Arg228 * (la plus frequente parmi les mutations de XPA en Afrique du Nord). Ces donnees confirment le diagnostic de Xeroderma pigmentosum (XP) de type A. Discussion Le XP est une genodermatose autosomique recessive rare liee a un defaut de reparation de l’ADN. L’atteinte principale est cutanee (photosensibilite et risque eleve de cancer). Cinq des 8 groupes comportent des symptomes neurologiques (deficit cognitif, microcephalie, epilepsie, syndrome cerebelleux, PRN, surdite). La mutation de XPA presentee ici donne une atteinte neurologique predominante et une atteinte cutanee secondaire avec rarete des cancers. Conclusion 30 % des patients XP ont une atteinte neurologique. Le diagnostic est genetique. La prise en charge multidisciplinaire avec depistage des cancers, protection anti-UV et traitement symptomatique ameliorent le pronostic cutane.

Neuroepithelial b2T cells were derived from the hindbrain and the spinal cord of mouse transgenic embryos, which expressed SV40 T antigen under the control of a Hoxb2 enhancer. Strikingly, b2T cell lines of either origin exhibit a very similar gene expression pattern, including markers of the hindbrain and the spinal cord, such as Hox genes, but not of more anterior cephalic regions. In addition, the broad expression pattern of b2T cells, probably linked to culture conditions, appeared to be appropriately modulated when the cells were reimplanted at different longitudinal levels into chick host embryos, suggesting that these cells are responsive to exogenous signalling mechanisms. Further support for these allegations was obtained by culturing b2T cells in defined medium and by assessing the expression of Krox20, an odd-numbered rhombomere marker, which appeared to be modulated by a complex interplay between FGF, retinoic acid (RA), and noggin. With respect to these as yet unique properties, b2T cells constitute an original alternative tool to in vivo models for the analysis of molecular pathways involved in the patterning of the neural tube.

Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with pressure palsies (HNPP) are two frequent hereditary motor and sensory neuropathies. CMT is characterized by slowly progressive weakness and atrophy, primarily in peroneal and distal leg muscles. The most frequent form, CMT1A, is due, in most cases, to the duplication of a 1.5 Mb region on chromosome 17p11.2 containing the peripheral myelin protein 22 gene (PMP22). The phenotype seems to result from dosage of the PMP22 gene. This hypothesis is reinforced by the existence of HNPP, which is clinically characterized by various recurrent truncular palsies or sensory loss precipitated by minor trauma, which is caused by deletion of the same 1.5 Mb region in 17p11.2. In clinical practice, the detection of the duplication or the deletion in 17p11.2, which permits a positive diagnosis, is still performed by time consuming methods (Southern blot or various combinations of molecular tools). We developed a method for the rapid detection of 17p11.2 rearrangements, using “direct FISH” and PRINS analyses, which does not require cell culture. In a prospective study of 92 patients with CMT and 38 with suspected HNPP, we compared this new technique to classical strategies like Southern blot. The results demonstrate the high sensitivity and specificity of the new FISH technique for the diagnosis of CMT1A and HNPP. Moreover, because of its simplicity and rapidity, this technique provides a useful alternative to the molecular approaches that have been used to diagnose segmental aneusomies, especially in the case of duplications that often go undetected. © 2003 Wiley-Liss, Inc.

Notomelia associated with neural tube defects are rare diseases. A baby was born in Niger with multiple congenital embryonic malformations on the posterior midline. The most rostral malformation was an accessory limb (polymelia) at the level of the lumbar vertebrae composed of two long bones, a foot and three toes. Accessory male genitalia were present at the base of this malformed accessory limb which had no apparent motor or sensory innervation. The second malformation was a sacral vestigial appendage with an adjacent dermal sinus opening onto the posterior midline and extending internally to the dura through a defect of the vertebral arches. From the published literature and this particular case, we conclude that notomelia is a rare clinical sequela of a neural tube defect (NTD) and is correctly classified as a dysraphic appendage. The recent occurrence of three similar cases in the same ethnic group from Niger, three from consanguineous parents, suggests that genetic factors are likely to contribute significantly to the genesis of this syndrome, consistent with a recent report that mutation of the bovine NHLRC2 gene resulting in a V311A substitution at a highly conserved locus in the NHLRC2 protein is, when homozygous, causally associated with several forms of polymelia including notomelia, with heteropagus conjoined twinning and with other NTD-related embryonic malformations. Detailed genome-wide studies of children with dysraphic appendages are indicated.

Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease.

The LYMMO bus rapid transit service, operated by LYNX Transit in Orlando, Florida, began in August 1997 as one of the first premium bus-based downtown circulators in the United States. The Center for Urban Transportation Research (CUTR) at the University of South Florida recently conducted an evaluation of the LYMMO to see how well it has performed for the last 15 years. The evaluation found that ridership quickly plateaued after 1997 and has fallen off since 2010. Nevertheless, the LYMMO still carries more annual passengers than several rail streetcars of comparable length and at a lower operational cost. Surveys of LYMMO riders and downtown employers revealed that a majority of respondents believe the LYMMO has reduced congestion in downtown Orlando, contributed to the economic development of downtown, and made downtown a more attractive place to live and work.

The avian spinal cord is characterized by an absence of motor nerves and sensory nerves and ganglia at its caudalmost part. Since peripheral sensory neurons derive from neural crest cells, three basic mechanisms could account for this feature: (i) the caudalmost neural tube does not generate any neural crest cells; (ii) neural crest cells originating from the caudal part of the neural tube cannot give rise to dorsal root ganglia or (iii) the caudal environment is not permissive for the formation of dorsal root ganglia. To solve this problem, we have first studied the pattern of expression of ventral (HNF3beta) and dorsal (slug) marker genes in the caudal region of the neural tube; in a second approach, we have recorded the emergence of neural crest cells using the HNK1 monoclonal antibody; and finally, we have analyzed the developmental potentials of neural crest cells arising from the caudalmost part of the neural tube in avian embryo in in vitro culture and by means of heterotopic transplantations in vivo. We show here that neural crest cells arising from the neural tube located at the level of somites 47-53 can differentiate both in vitro and in vivo into melanocytes and Schwann cells but not into neurons. Furthermore, the neural tube located caudally to the last pair of somites (i.e. the 53rd pair) does not give rise to neural crest cells in any of the situations tested. The specific anatomical aspect of the avian spinal cord can thus be accounted for by limited developmental potentials of neural crest cells arising from the most caudal part of the neural tube.

The genetic studies of syndromic craniosynostoses lead to the characterisation of genes that regulate the correct development of the bones of the skull. From these studies, it appears that FGF/FGFR signalling has a crucial role in this problem. Numerous mutations affecting the genes coding for FGFR1, 2 or 3 are responsible for these syndromes. It is interesting to note that some identical mutations produced various different phenotypes, suggesting that other genes modulate the phenotypic expressivity. The other involved genes in these syndromes code for such proteins as Msx2 or Twist that interact in the cellular pathways responsible for FGF action. From these genetic studies, it is now important to establish the role of these proteins during the development of the skull. Msx2 plays a repressive role in osteogenesis, whereas FGFRs act as promoting proteins. In the near future, it will be very important to improve our understanding of these phenomena in order to test specific treatments to prevent the development of such syndromes.

The clinical, radiologic, and pathologic data from a series of 234 patients hospitalized in the Pediatric Neurosurgical Department of the Necker–Enfants Malades Hospital, Paris, for congenital intraspinal lipomas and operated on from 1976 to 1995 were examined. Histological studies showed that these lesions may be simple lipomas, similar to those developing elsewhere in the body, or they may be more complex forms including in addition to the lipomatous component a variety of unusual ectopic tissues of ectodermal, mesodermal, and/or endodermal origin. These complex forms indica te the malformative nature of these tumors. When they contain elements that are truly foreign to the region, the possibility of teratoma with a tumoral potential should be considered. Data found in the literature and from Necker–Enfants Malades Hospital are discussed.

The spatial and temporal analysis of GATA-3 expression pattern in the human embryo revealed its expression in new anatomical sites. These include the endoderm of the primitive foregut, pharynx and allantois, the branchial arches and the mesenchymal cells surrounding the stomach and dorsal aorta. On the other hand, human (h) GATA-3 expression in the central nervous system, somites and embryonic kidney confirms the tissue specificity of this gene throughout vertebrate evolution.

X-SCLH/LIS syndrome is a neuronal migration disorder with disruption of the six-layered neocortex. It consists of subcortical laminar heterotopia (SCLH, band heterotopia, or double cortex) in females and lissencephaly (LIS) in males, leading to epilepsy and cognitive impairment. We report the characterization of a novel CNS gene encoding a 40 kDa predicted protein that we named Doublecortin and the identification of mutations in four unrelated X-SCLH/LIS cases. The predicted protein shares significant homology with the N-terminal segment of a protein containing a protein kinase domain at its C-terminal part. This novel gene is highly expressed during brain development, mainly in fetal neurons including precursors. The complete disorganization observed in lissencephaly and heterotopia thus seems to reflect a failure of early events associated with neuron dispersion.

Epilepsy with myoclonus is thought to be linked to the motor system. At birth, development of the central nervous system in humans is far from being achieved. Post-natal changes take place at different levels in this neuronal system. These modifications suggest that the motor cortex is a highly dynamic structure during post-natal development. They may account for the age-dependence of various epileptic syndromes. (1) The number of synapses increases during the early post-natal years and then decreases to reach the adult level around puberty. (2) Neurons differentiate and synthesize various neurotransmitters. (3) Dendrites grow actively and participate in the formation of local cortical circuits. (4) Electrophysiological properties of cortical neurons change during the first months of rodent development. This could reflect modifications of the ion channels present in the cell membrane. (5) The pyramidal tract myelinate and exuberant collaterals are selectively removed. These two processes are dependent on neuronal electrical activity. It has been demonstrated that selective collateral stabilization is promoted by glutamate release and stimulation of the N-methyl- d -aspartate (NMDA) receptor. So, seizures occurring during the neonatal period may interact with these normal developmental features. Furthermore, neuronal electrical activity and seizures stimulate the transcription of specific messenger RNAs coding for neurotrophic factors like nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF). The overproduction of neurotrophic factors leads to maldevelopment of the cortex.

Spina bifida with lipoma is a human malformation that most often affects the lumbosacral area. It is a complex morphological type. Its origin is controversial, and none of the previous hypotheses can be retained in view of the most recent advances in experimental embryogenesis. Contrary to earlier opinons, adipocytes cannot arise from meninges, vessels or glial cells and spina bifida cannot be explained by incarceration of mesodermal tissues during primary neurulation or developmental defect at the level of the tail bud. Spina bifida with lipoma, which actually involves all the derivatives of the so-called dorsal mesoderm, must therefore result from abnormal development of this mesoderm, which is induced by the dorsal neural tube. The location of the primary defect (dorsal mesoderm or neural tube) remains to be established.

The nervous system is divided into the central nervous system (CNS) composed of the brain, the brainstem, the cerebellum, and the spinal cord and the peripheral nervous system (PNS) made up of the different nerves arising from the CNS. The PNS is divided into the cranial nerves III to XII supplying the head and the spinal nerves that supply the upper and lower limbs. The general anatomy of the PNS is organized according to the arrangement of the fibers along the rostro-caudal axis. The control of the development of the PNS has been unravelled during the last 30 years. Motor nerves arise from the ventral neural tube. This ventralization is induced by morphogenetic molecules such as sonic hedgehog. In contrast, the sensory elements of the PNS arise from a specific population of cells originating from the roof of the neural tube, namely the neural crest. These cells give rise to the neurons of the dorsal root ganglia, the autonomic ganglia and the paraganglia including the adrenergic neurons of the adrenals. Furthermore, the supportive glial Schwann cells of the PNS originate from the neural crest cells. Growth factors as well as myelinating proteins are involved in the development of the PNS.

The nervous system is divided into the central nervous system (CNS) composed of the brain, the brainstem, the cerebellum, and the spinal cord and the peripheral nervous system (PNS) made up of the different nerves arising from the CNS. The PNS is divided into the cranial nerves III to XII supplying the head and the spinal nerves that supply the upper and lower limbs. The general anatomy of the PNS is organized according to the arrangement of the fibers along the rostro-caudal axis. The control of the development of the PNS has been unravelled during the last 30 years. Motor nerves arise from the ventral neural tube. This ventralization is induced by morphogenetic molecules such as sonic hedgehog. In contrast, the sensory elements of the PNS arise from a specific population of cells originating from the roof of the neural tube, namely the neural crest. These cells give rise to the neurons of the dorsal root ganglia, the autonomic ganglia and the paraganglia including the adrenergic neurons of the adrenals. Furthermore, the supportive glial Schwann cells of the PNS originate from the neural crest cells. Growth factors as well as myelinating proteins are involved in the development of the PNS.