Association between rare variants in specific functional pathways and human neural tube defects multiple subphenotypes.

BACKGROUND: Neural tube defects (NTDs) are failure of neural tube closure, which includes multiple central nervous system phenotypes. More than 300 mouse mutant strains exhibits NTDs phenotypes and give us some clues to establish association between biological functions and subphenotypes. However, the knowledge about association in human remains still very poor. METHODS: High throughput targeted genome DNA sequencing were performed on 280 neural tube closure-related genes in 355 NTDs cases and 225 ethnicity matched controls, RESULTS: We explored that potential damaging rare variants in genes functioning in chromatin modification, apoptosis, retinoid metabolism and lipid metabolism are associated with human NTDs. Importantly, our data indicate that except for planar cell polarity pathway, craniorachischisis is also genetically related with chromatin modification and retinoid metabolism. Furthermore, single phenotype in cranial or spinal regions displays significant association with specific biological function, such as anencephaly is associated with potentially damaging rare variants in genes functioning in chromatin modification, encephalocele is associated with apoptosis, retinoid metabolism and one carbon metabolism, spina bifida aperta and spina bifida cystica are associated with apoptosis; lumbar sacral spina bifida aperta and spina bifida occulta are associated with lipid metabolism. By contrast, complex phenotypes in both cranial and spinal regions display association with various biological functions given the different phenotypes. CONCLUSIONS: Our study links genetic variant to subphenotypes of human NTDs and provides a preliminary but direct clue to investigate pathogenic mechanism for human NTDs.

Unjoined primary and secondary neural tubes: junctional neural tube defect, a new form of spinal dysraphism caused by disturbance of junctional neurulation.

INTRODUCTION: Primary and secondary neurulation are the two known processes that form the central neuraxis of vertebrates. Human phenotypes of neural tube defects (NTDs) mostly fall into two corresponding categories consistent with the two types of developmental sequence: primary NTD features an open skin defect, an exposed, unclosed neural plate (hence an open neural tube defect, or ONTD), and an unformed or poorly formed secondary neural tube, and secondary NTD with no skin abnormality (hence a closed NTD) and a malformed conus caudal to a well-developed primary neural tube. METHODS AND RESULTS: We encountered three cases of a previously unrecorded form of spinal dysraphism in which the primary and secondary neural tubes are individually formed but are physically separated far apart and functionally disconnected from each other. One patient was operated on, in whom both the lumbosacral spinal cord from primary neurulation and the conus from secondary neurulation are each anatomically complete and endowed with functioning segmental motor roots tested by intraoperative triggered electromyography and direct spinal cord stimulation. The remarkable feature is that the two neural tubes are unjoined except by a functionally inert, probably non-neural band. CONCLUSION: The developmental error of this peculiar malformation probably occurs during the critical transition between the end of primary and the beginning of secondary neurulation, in a stage aptly called junctional neurulation. We describe the current knowledge concerning junctional neurulation and speculate on the embryogenesis of this new class of spinal dysraphism, which we call junctional neural tube defect.

A practical clinical classification of spinal neural tube defects.

Current commonly used terminology to describe neural tube defects (NTD) is inconsistent, overlapping, contradictory and, at times, inaccurate making it difficult to convey the nature of the malformation and what needs to be done to optimally treat patients with these congenital abnormalities.NTD can be broadly divided into those that are open with exposed neural tissue and leaking cerebrospinal fluid (CSF) and those that are closed with no exposed neural tissue nor loss of CSF. It appears that the loss of CSF during development is the underlying factor that leads to the entire central nervous system involvement with an open NTD and lack thereof with a closed NTD, wherein only the spinal cord is malformed. There are, however, rare transitional cases that bridge the gap between the two forms.Agreeing on a nomenclature that is used in a standard fashion would be of help in addressing this group of congenital anomalies that have a great deal of variability and, at times, can be quite complex.

The outcome and course of pregnancies complicated with fetal neural tube defects.

PURPOSE: The objectives of this study were as follows: to present the course and outcome of pregnancies complicated with neural tube defects, determine the association between prenatal ultrasound diagnoses, and definitive diagnoses after autopsy. MATERIAL AND METHODS: The survey was designed as a retrospective study and included 24 pregnant women who were attending a regular ultrasound examinations at the Department of Gynecology and Obstetrics, Clinical Center of Serbia, or patients who were referred from other institutions in Serbia. RESULTS: Neural tube defects are divided into five subgroups: spina bifida, meningocele, myelomeningocele, acranius, and anencephaly. The most frequent in the present study was spina bifida with 67%. All pregnancies complicated with neural tube defects were terminated. CONCLUSION: Their clinical severity and uncertain cause make them priorities for further research, whether to better target primary preventive measures, to improve in-utero surgery for prenatal repair, or to identify the causative genes to provide an objective basis for individual genetic counselling.

Neural tube defects in the Republic of Ireland in 2009-11.

BACKGROUND: Neural tube defects (NTDs) are associated with deficient maternal folic acid peri-conceptionally. In Ireland, there is no mandatory folic acid food fortification, partly due to declining NTD rates in recent years. The aim of this study was to ascertain the incident rate of NTD during the period 2009-11 and describe epidemiologically NTD in Ireland. METHODS: Cases were ascertained through multiple sources, including three regional congenital anomaly registers, all maternity hospitals nationally and paediatric hospitals providing care for children with spina bifida in the Republic of Ireland during the period 2009-11. RESULTS: From 225 998 total births, 236 NTDs were identified, giving an incidence of 1.04/1 000 births, increasing from 0.92/1 000 in 2009 to 1.17/1 000 in 2011. Of all cases, 45% (n = 106) had anencephaly, 49% (n = 115) had spina bifida and 6% (n = 15) had an encephalocoele; 78% (n = 184) were liveborn or stillborn and 22% (n = 52) were terminations abroad. Peri-conceptional folic acid supplement intake was 13.7% among the 52.5% (n = 124) of cases whose folic acid supplement intake was known. CONCLUSION: The incidence of NTDs in the Republic of Ireland appears to be increasing. Renewed public health interventions, including mandatory folic acid food fortification, must be considered to reduce the incidence of NTD.

[A painful occipital mass revealing a posterior encephalocele]. / Une tuméfaction occipitale douloureuse révélant une encéphalocèle postérieure.

Encephalocele is a congenital malformation caused by a neural tube defect during embryonic development. We report a case of posterior encephalocele in a 7-month-old infant with a painful occipital mass known since birth. Pathological examination of the mass showed different mature tissues derived from the brain and its coverings (e.g., neuroglia, ependymal canals and clusters of meningothelial cells). A diagnosis of encephalocele was made. The different forms of neural tube defect will be briefly discussed, especially the "aborted" forms (e.g., non-specific midline mass lesion or angioma) that the pathologist may encounter in his/her daily practice.

Classification, clinical features, and genetics of neural tube defects.

Neural tube defects (NTDs) constitute a major health burden (0.5-2/1000 pregnancies worldwide), and remain a preventable cause of still birth, neonatal, and infant death, or significant lifelong handicaps. The malformations result from failure of the neural folds to fuse in the midline, and form the neural tube between the third and the fourth week of embryonic development. This review article discusses their classification, clinical features, and genetics. Most NTDs are sporadic and both genetic, and non-genetic environmental factors are involved in its etiology. Consanguinity was suggested to contribute to the high incidence of NTDs in several countries, including Saudi Arabia. Syndromes, often associated with chromosomal anomalies, account for <10% of all NTDs; but a higher proportion (20%) has been documented in Saudi Arabia. Genetic predisposition constitutes the major underlying risk factor, with a strong implication of genes that regulate folate one-carbon metabolism and planar cell polarity.

Sacrococcygeal dimple: new classification and relationship with spinal lesions.

PURPOSE: This study aims to ascertain which specific types of sacrococcygeal dimples are associated with underlying spinal cord malformations. METHODS: From 2008 to 2011, we prospectively examined children less than 2 years old with sacrococcygeal dimples. Each patient underwent clinical assessment of dimples and magnetic resonance imaging. We devised the following new classification of dimples according to their location: type 1, dimples located within the gluteal crease, including coccygeal pits; type 2, dimples located at the upper edge of the gluteal crease with associated curving or deformity of that crease; and type 3, dimples located well above the gluteal crease. RESULTS: We evaluated 142 patients with sacrococcygeal dimples. Although we identified spinal malformations such as spinal lipomas, filum cysts, and thickened fila terminalia in only 17 % of infants with type 1 dimples, we observed them in 45 % with type 2 and 55 % with type 3. Thus, in terms of the rate of spinal malformations, there are significant differences between types 1 and 2 and between types 1 and 3. CONCLUSIONS: We propose a new classification of sacrococcygeal dimples. Although type 2 dimples have previously been classified as simple dimples that require no further investigation, we have identified that they are strongly associated with spinal deformities, comparable to atypical type 3 dimples. Thus, both types 2 and 3 dimples warrant radiological investigation.

Diastematomyelia: a 35-year experience.

STUDY DESIGN: Retrospective case series study. OBJECTIVE: This article describes our experience of the management of diastematomyelia. SUMMARY OF BACKGROUND DATA: Diastematomyelia is a rare entity, which presents distinct clinical characteristics and requires different managements compared with other more common occult spinal dysraphism. METHODS: A total of 156 patients with diastematomyelia were reviewed. All the patients underwent neurological and radiological examinations. Surgical excision of the lesion was performed for most patients and intradural exploration of the lumbar region was done to release tethering of conus in some patients. One patient died and autopsy was performed. Follow-up was carried out for all the patients, including surgical and nonsurgical approaches. RESULTS: There were 123 cases of type I diastematomyelia and 33 cases of type II diastematomyelia. The lumbar and thoracolumbar region was the most common site for diastematomyelia, and most spinal cords were split among 6 segments. The postoperative course was complicated by cerebrospinal fluid leakage in 2 patients, temporary neurological deterioration in 4 patients, and epidural hematoma in 1 patient. All cases did not have aggravation of symptoms during the follow-up of 2 to 20 years (mean of 4.5 yr). For the 123 patients with type I diastematomyelia, clinical symptoms were improved in 96 after surgical intervention and no worsening or occurrence of new clinical signs were observed during the follow-up. Those who did not receive surgery showed stabilization of neurological manifestation. Of the 33 type II cases, 9 surgical patients remained neurologically stable during the postoperative years without significant improvement in function, and 24 nonsurgical patients neither improved nor worsened in their neural deficit. CONCLUSION: Surgical treatment is the necessary management for type I diastematomyelia causing progressive neurological deterioration or with tethered filum, whereas conservative treatment is recommended to asymptomatic type I diastematomyelia and all type II diastematomyelia. LEVEL OF EVIDENCE: 5.

Safety and efficacy of 1-stage surgical treatment of congenital spinal deformity associated with split spinal cord malformation.

STUDY DESIGN: Retrospective clinical study. OBJECTIVE: The aim of this study was to evaluate retrospectively the safety and efficacy of 1-stage surgical treatment of 45 consecutive patients, who had progressive congenital spinal deformity associated with split spinal cord malformation (SSCM). SUMMARY OF BACKGROUND DATA: For correction of progressive congenital spinal deformity with SSCM, it has been reported that all SSCM should be operated on before any orthopedic intervention, and then surgery for correction and stabilization of the spinal deformity should be performed 3 to 6 months later. Recently, different viewpoints have been approved, and the common treatment of these 2 associated conditions needs to be re-evaluated. METHODS: Patients had 1-stage surgery. After exposure of the determined levels and placement of instruments, bony spur was resected in the patients of type 1; in patients of type 2, we did nothing to the SSCM. In the corrective stage of surgery, posterior fusion surgery was performed in 38 patients; nonfusion surgery was performed in 7 patients. RESULTS: Thirty-six female patients and 9 male patients formed the basis of the study. The mean age was 14 years, and the mean follow-up period was 31 months. Type 1 SSCM was in 15 patients, and type 2 SSCM was in 30 patients. Seven patients had progressive neurological deteriorations preoperatively. The mean major curves were corrected from an average of 73.7° to 33.5°, with a correction rate of 54.5%. The overall complication was transient, including 2 patients of neurological compromise and 1 patient of cerebrospinal fluid leakage. The average loss of correction at final follow-up was 2.5° for major curves. CONCLUSION: The 1-stage surgical treatment of congenital spinal deformity associated with SSCM provides a satisfactory option to improve the spinal deformity without significant complications effectively. Neurosurgical interventions are recommended to patients with type 1 SSCM before spinal deformity surgery; however, patients with type 2 SSCM can be treated safely without a need of neurosurgical intervention.

[Intracerebral neurenteric cysts in newborn infants]. / Quistes neuroentericos intracerebrales en neonatos.

INTRODUCTION: Intracranial neurenteric cysts are very infrequent congenital lesions. Within the nervous system, they are most commonly located in the rachis. Another frequent site is the craniocervical junction. Few cases of supratentorial location have been reported. A differential diagnosis is required to distinguish them from other cysts. They are not often diagnosed in the paediatric age. The clinical features they give rise to are due to the mass effect or episodes of chemical meningitis. Magnetic resonance imaging is the best diagnostic method although on many occasions they cannot be distinguished from arachnoid cysts. Treatment consists in surgery with complete resection of the membranes in order to prevent recurrences. CASE REPORTS: We report two cases of infants who, in the last weeks of gestation, presented supratentorial intracerebral cystic lesions that resembled arachnoid cysts. A neonatal magnetic resonance scan confirmed the existence of such supratentorial cysts with septae inside them. After presenting an increase in the cranial perimeter, surgical treatment was undertaken with a neuronavigation-guided craniotomy and debridement of the cysts. The cysts contain mucus and have thick membranes. Pathological study results are consistent with a neurenteric cyst. One of the patients presented complete resolution after the intervention with good cerebral expansion. In the second case, there was persistence of an adjoining arachnoid cyst, in which placement of a cyst-peritoneal shunt was necessary with full resolution. CONCLUSIONS: Most intracranial cysts are arachnoid cysts, but there are other cystic lesions that must be treated by surgical means so that they can be completely excised and sent for pathological analyses.

Cutaneous vascular anomalies associated with neural tube defects: nomenclature and pathology revisited.

BACKGROUND: Lumbosacral cutaneous vascular anomalies associated with neural tube defects are frequently described in the literature as "hemangiomas." The classification system for pediatric vascular anomalies developed by the International Society for the Study of Vascular Anomalies provides a framework to accurately diagnose these lesions. OBJECTIVE: To apply this classification to vascular cutaneous anomalies overlying myelodysplasias. METHODS: A retrospective analysis of patients with neural tube defects and lumbosacral cutaneous vascular lesions was performed. All eligible patients had detailed histopathologic analysis of skin and spinal cord/placode lesions. Clinical and radiologic features were analyzed. Conventional histology and GLUT-1 immunostaining were performed to differentiate infantile capillary hemangiomas from capillary vascular malformations. RESULTS: Ten cases with cutaneous lesions associated with neural tube defects were reviewed. Five lesions were diagnosed as infantile capillary hemangiomas based upon histology and positive GLUT-1 endothelial reactivity. These lesions had a strong association with dermal sinus tracts. No reoperations were required for residual intraspinal vascular lesions, and overlying cutaneous vascular anomalies involuted with time. The remaining 5 lesions were diagnosed as capillary malformations. These occurred with both open and closed neural tube defects, did not involute, and demonstrated enlargement and darkening due to vascular congestion. CONCLUSION: The International Society for the Study of Vascular Anomalies scheme should be used to describe the cutaneous vascular lesions associated with neural tube defects: infantile capillary hemangiomas and capillary malformations. We advocate that these lesions be described as "vascular anomalies" or "stains" pending accurate diagnosis by clinical, histological, and immunohistochemical evaluations.

Unusual patterns of neural tube defects in a high risk region of northern China.

OBJECTIVE: To study the prevalence of different types of neural tube defects (NTDs) in Luliang Prefecture, Shanxi province, where the prevalence of NTDs is unusually high and the correlation between NTDs prevalence and patterns. METHODS: A surveillance population-based birth defects was performed in Luliang Prefecture, Shanxi province. RESULTS: The results of our study showed that the prevalence of NTDs was 2-fold higher in Luliang Prefecture than in other areas of Shanxi province. Unusual patterns of NTDs were found, however, multiple NTDs were relatively common in Luliang Prefecture, accounting for over 13% of all NTDs cases in China. CONCLUSION: The prevalence of NTDs is associated with its patterns.

Pattern of neural tube defects at Tikur Anbessa Hospital, Addis Ababa, Ethiopia.

BACKGROUND: Neural Tube Defect (NTD) is the most common of the central nervous system malformations. Although there is scarcity of information in Ethiopia, the burden of disease is high in low socioeconomic countries. OBJECTIVE: To assess the pattern and frequency of Neural Tube defects (NTDs). METHODS: Charts of a total of 115 children with neural tube defect (NTD) were reviewed retrospectively from JANUARY, 2001 to June 2005 in Ethio Swedish Children's Hospital. RESULTS: The most common defect seen was myelomeningocele (64.4%); followed by meningocele (18.3%) and encephalocele (13.0%). Associated anomalies like clubfoot undescended testis, different types of hernias, hydroceles etc. were noted in 28.7% of the patients. CONCLUSION: This study showed that the frequency distribution of the different neural tube defects in Tikur Anbessa hospital is not different from previous findings mentioned in the literature. However, overall frequency of neural tube defects could not be calculated from this study since the total live births in the study area during the study period were unknown. Hence, further prospective study is needed to substantiate these facts.

Congenital spinal lipomatous malformations: part I--Classification.

BACKGROUND: Congenital spinal lipomatous malformations constitute a diverse group of lesions. There is considerable confusion in the literature regarding their terminology and a proper classification is long overdue. The first part of this two part report sets out a proposed classification scheme. METHODS: On the basis of this author's experience with 80 patients with a congenital spinal lipomatous malformation treated over a 10 year period, a new classification is proposed. The proposed classification divides congenital spinal lipomatous malformations into two broad groups: 1. Lipomas without dural defect and, 2. Lipomas with dural defect. Within each group, there are several subtypes. These two broad groups differ from one another in their embryology, clinical presentation, operative findings, complications and prognosis FINDINGS: Group I consists of Lipomas without dural defect. Included in this group are: Filum lipoma, caudal lipoma without dural defect, and intramedullary lipoma. Group II consists of lipomas with dural defect. Included in this group are: dorsal lipoma, caudal lipoma with dural defect, transitional lipoma, lipomyelocele, and lipomyelomeningocele. The definitions of the various subtypes and radiological and operative findings of all these lesions are described. CONCLUSIONS: Congenital spinal lipomatous malformations constitute a wide spectrum of lesions ranging from relatively simple lipomas of the filum terminale to complex malformations. These lesions differ from one another in their embryology, clinical presentation, operative strategies, complications and prognosis. Failure to differentiate between the different forms of congenital spinal lipomatous malformations may lead to inaccurate assumptions regarding prognosis and inappropriate management. The proposed classification seeks to address these issues.

Spinal sonography in newborns and infants - part II: spinal dysraphism and tethered cord.

UNLABELLED: Patients with cutaneous markers in the lumbo-sacral region as well as infants with bladder and bowel dysfunction, orthopedic anomalies and progressive neurological dysfunction are at risk for spinal dysraphism and tethered cord. Three types of spinal dysraphism can be distinguished: Type I - open spinal dysraphisms with a non-skin covered back mass; type II - closed spinal dysraphisms with a skin covered back mass; type III - occult spinal dysraphisms without a back mass. All spinal dysraphisms can be associated with a tethered cord, characterized by a low position of the conus medullaris below L3. Type I dysraphisms are meningomyeloceles and myeloceles, which are associated with CHIARI-II malformations characterized by the low position of the cerebellar vermis within the foramen magnum. Type II dysraphisms are lipomyeloceles, lipomyelomeningoceles, posterior meningoceles and myelocystoceles. Lipomeningoceles and lipomyelomeningoceles are characterized by a subcutaneous echogenic mass which communicates with the spinal canal and may cause tethered cord. Posterior meningoceles are, dorsal cystic space occupying lesions without internal neural tissue. Myelocystoceles are characterized by a cystic dorsal mass which communicates with a dilated central canal characteristic of syringo-hydromyelia. Type III dysraphisms without a back mass are frequently associated with cutaneous markers in the lumbo-sacral region. Sonographically dermal sinus tracts, diastematomyelia, tight filum and lipoma of the filum terminale and the caudal regression syndrome have to be distinguished. Dermal sinuses are characterized by an echogenic tract from the skin to the spinal canal, often associated with a spinal dermoid. Diastematomyelia is characterized by a complete or partial duplication of the spinal cord which can only be shown on axial images. Tight filum terminale or lipoma of the filum terminale is characterized by a thick echogenic filum with a diameter of more than 2 mm, and a conus below L3. CONCLUSION: All different forms of spinal dysraphisms and tethered cord can be diagnosed sonographically in the neonatal period as long as the spinal arches are not completely ossified.

Closed neural tube defects: neurologic, orthopedic, and gait outcomes.

PURPOSE: The purpose of our study was to obtain a clear understanding of the various diagnoses within the closed neural tube defect (NTD) groups included in the large database of clients in our Spina Bifida Clinic and a clear picture of the outcomes for the various NTD groups. METHODS: One hundred and four clients with closed NTD were categorized using a classification system devised by Tortori-Donati et al. Various clinical markers were investigated, including ambulation and the need for orthoses and wheelchairs. RESULTS: Most clients are ambulatory, requiring an orthoses, but not a wheelchair, despite the high incidence of ankle/foot abnormalities. CONCLUSIONS: This classification system has enhanced our knowledge of this group of clients, provided a greater understanding of the varied outcomes of these children and clinical management required.