No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Identical twins with lumbosacral lipomyelomeningocele
Abstract
Lipomyelomeningocele, a congenital spine defect, is presented as skin-covered lipomatous tissue that attaches to the cord in different ways according to its subtypes. Unlike other types of neural tube defects, the exact cause of this birth defect has not been confirmed yet, but it is proposed to be a multifactorial disease with involvement of both genetic and environmental factors. The authors describe identical twins with lipomyelomeningocele of the same subtype and location without any familial history of similar abnormality. Therefore, the same genetic and/or environmental risk factors could have played a part in their condition.
PurposeLipoma of the filum terminale (FL) is an abnormality in which fat is deposited in the filum terminale. This lipoma is often detected by skin abnormalities in the lumbosacral area such as a sacrococcygeal dimple. Some cases may develop tethered cord and become symptomatic. However, the genetic basis of FL is still unclear.Methods
This study aimed to determine whether there was a family history of FL or other forms of spina bifida among 54 families of 56 patients with FL and to examine whether there is a familial predisposition in FL. In addition, sex, age at diagnosis, presence of symptoms, presence of sacrococcygeal dimple, and the level of conus medullaris between familial and spontaneous cases were evaluated.ResultsOf the 54 families of FL patients, there were 48 siblings. Among the 48 siblings, 2 had “occult” FL. The frequency of FL among siblings was estimated to be 4.2% (2/48), which was significantly higher than the sum of previously reported cases of spontaneous FL (0.91%; p = 0.017). However, there was no significant difference in sex, age at diagnosis, presence of symptoms, presence of sacrococcygeal dimple, diameter of filum terminale, or level of conus medullaris between familial and spontaneous cases.Conclusion
To our knowledge, this is the first report on familial FL and examination of the frequency of FL among siblings. The high probability of FL among siblings of FL patients suggests that genetic factors may play a role in FL development.
Cervical lipomyelomeningocele is a very rare form of spina bifida occulta, which can cause some complications following tethered cord syndrome. We report a 10-year-old female with a history of progressive upper-extremity weakness, a very small soft-tissue mass at the posterior aspect of her neck, and evidence of lipomyelomeningocele in her radiological study. The patient underwent laminectomy of C6 and C7 together with resection of lipomatous tissue attaching to the cord from superficial tissue and cord untethering, which resulted in progressive improvement of her weakness.
Lipomyelomeningocele is a type of neural tube defect characterized by lipomatous tissue causing a defect in the vertebrae, infiltrating the dura, and tethering the spinal cord. Despite significant neurologic consequences, the underlying etiology remains poorly understood. We present a father and son with remarkably similar presentations of lipomyelomeningocele. Genetic testing did not reveal an underlying cause but whole exome sequencing identified variants in the ARHGAP29 and RADIL genes in the proband and his affected father. Genetic analyses of asymptomatic family members revealed several carriers of the ARHGAP29 or RADIL variants, but only the proband and his father carried both variants, suggesting a possible shared genetic mechanism. Rare cases of siblings affected with lipomyelomeningocele have suggested the possibility of autosomal recessive or germline mosaicism. We present the first documented cases of transgenerational lipomyelomeningocele with important implications for family counseling about the recurrence of lipomyelomeningocele.
Introduction Since the multi-site closure theory was first proposed in 1991 as explanation for the preferential localizations of neural tube defects, the closure of the neural tube has been debated. Although the multi-site closure theory is much cited in clinical literature, single-site closure is most apparent in literature concerning embryology. Inspired by Victor Hamburgers (1900-2001) statement that "our real teacher has been and still is the embryo, who is, incidentally, the only teacher who is always right", we decided to critically review both theories of neural tube closure. Materials and Methods To verify the theories of closure, we studied serial histological sections of 10 mouse embryos between 8.5 and 9.5 days of gestation and 18 human embryos of the Carnegie collection between Carnegie stage 9 (19-21 days) and 13 (28-32 days). Neural tube closure was histologically defined by the neuroepithelial remodeling of the two adjoining neural fold tips in the midline. Results We did not observe multiple fusion sites in neither mouse nor human embryos. A meta-analysis of case reports on neural tube defects showed that defects can occur at any level of the neural axis. Conclusions Our data indicate that the human neural tube fuses at a single site and, therefore, we propose to reinstate the single-site closure theory for neural tube closure. We showed that neural tube defects are not restricted to a specific location, thereby refuting the reasoning underlying the multi-site closure theory. This article is protected by copyright. All rights reserved.
Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition. We thus conclude that the need to study spina bifida in all its forms, both aperta and occulta, is more indicative of the spina bifida in surviving humans and that the measure of deterioration arising from caudal neural tube defects, more commonly known as spina bifida, must be determined by the level of the lesion both in mouse and in man.
Inevitable deterioration due to mechanical tethering is perceived as the natural history for complex congenital spinal lipomas of the conus medullaris region, even if asymptomatic at presentation. The conventional wisdom that prophylactic surgical untethering improves outcome has been challenged recently [1, 2]. This study examines the natural history of asymptomatic un-operated children with lumbosacral lipomas (LSL) and investigates whether predictive factors herald deterioration.
Over the past decade, children presenting with complex LSL to a single clinician at Great Ormond Street Hospital (GOSH), London, UK have undergone a thorough assessment focusing on neurological and urological evaluation and MRI of the lumbosacral spine. For children deemed to be asymptomatic, conservative management has been adopted with close periodic surveillance of neurological and urological function, thus avoiding untethering surgery unless symptomatic deterioration occurs. A retrospective review identified this cohort of children asymptomatic of their LSL and their progress closely recorded.
This study suggests that the natural history of this subgroup of dysraphic patients may be more benign than hitherto considered. Conservative management with adoption of a novel surveillance policy and timely intervention only in the presence of symptomatic deterioration resulted in 71 % of this series remaining clinically asymptomatic at mean follow up period of 5.9 years (range, 1.0-19.3 years). At 10 years, the cumulative risk of deterioration determined by the Kaplan-Meier method was 40 %. Children aged <2 years, female, with presence of a transitional type of LSL and associated syrinx were independently associated with a higher risk of deterioration.
Neural-tube defects (NTD) are common congenital malformations that can lead to severe disability or even death. Periconceptional supplementation with the B-vitamin folic acid has been demonstrated to prevent 50-70% of NTD cases. Since the identification of the first genetic risk factor of NTD, the C677T single-nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene, and the observation that elevated plasma homocysteine levels are associated with NTD, research has focused on genetic variation in genes encoding for enzymes of folate metabolism and the closely-related homocysteine metabolism. In the present review relevant SNP in genes that code for enzymes involved in folate transport and uptake, the folate cycles and homocysteine metabolism are summarised and the importance of these SNP discussed in relation to NTD risk.
Lipomas of the spinal cord are among the most fascinating lesions encountered by the pediatric neurosurgeon. An understanding of spinal lipomas may, however, be difficult because the terminology used to describe the accumulations of spinal fat is confusing, inconsistently applied, and at times contradictory. An anatomical characterization of lipomas may assist in understanding these lesions. Lipomas of the spinal cord are very rare and cause symptoms related to mass effect and secondary compressive myelopathy. Lipomas of the conus medullaris (or lipomyelomeningocele) are the most common form of fatty masses in the spine and can be divided into dorsal, caudal, and transitional forms. These lesions are a manifestation of occult spinal dysraphism and a common cause of the tethered cord syndrome (TCS). The natural history of untreated lipomyelomeningocele, although incompletely understood, appears to be progressive neurological deterioration with loss of bladder control. Timely, careful surgical intervention may prevent significant neurological deterioration and progressive disability in the majority of children harboring these lesions. In surgical intervention the surgeon seeks to disrupt the connection between the fibrofatty mass and underlying cord as well as to reestablish normal anatomical planes. Several intraoperative video segments illustrating lipomyelomeningocele resection are included in this paper. Lipomas of the terminal filum (fatty filum) are truly occult and are also associated with TCS. Surgical treatment of filum lipomas carries significantly lower risk than that for lipomas of the conus medullaris. Again, the goal of surgery is to disrupt the connection between the abnormal fibrofatty tissue and the underlying spinal cord.
Background:
In general, it seems that both genetic and environmental factors play important roles in the induction of neural tube defects. Lipomyelomeningocele (LipoMMC) is a rather common type of closed neural tube defect, but only limited studies have investigated the potential risk factors of this anomaly. Therefore, the purpose of this case-control study was to investigate the risk factors involved in LipoMMC formation.
Material and method:
Various risk factors were evaluated in 35 children between 1 month and 10 years of age with LipoMMC in a hospital-based case-control study. The 2 control arms consisted of 35 children with myelomeningocele (MMC group) and 35 children with congenital anomalies other than central nervous system problems (control group). All groups were matched for age and visited the same hospital. A structured questionnaire was used for the collection of all data, including the mothers' weight and height during pregnancy, education, reproductive history, previous abortions, and socioeconomic status, as well as the parents' consanguinity and family history of the same anomalies.
Results:
Univariate analysis of the children with LipoMMC compared to the control group showed that the use of periconceptional folic acid supplementation was significantly lower in the MMC and LipoMMC groups compared to the control group. In addition, comparison of the MMC and control groups revealed statistically significant differences regarding the use of folic acid and maternal obesity. In multivariate analysis, use of folic acid in the periconceptional period and during the first trimester was an independent risk factor for LipoMMC and MMC. Furthermore, maternal obesity was a significantly positive risk factor for MMC.
Conclusion:
The probable risk factors for LipoMMC were investigated in this case-control study. Consumption of folic acid in the periconceptional period and during the first trimester is an independent protective factor against LipoMMC. It seems that larger studies are needed to examine other possible risk factors.
Many studies have accessed the association between methionine synthase (MTR) A2756G polymorphism and neural tube defect (NTD). However, the conclusions are inconsistent. Our study aimed to clarify the nature of the genetic risks contributed by this polymorphism for NTD using meta-analysis. We searched electronic literature from the PubMed, EMBASE, and Medline databases, from which 11 articles were selected according to the inclusion criteria. The meta-analysis was conducted in 3 groups, namely, NTD patients, mothers with NTD offspring and fathers with NTD offspring. Pooled odds ratios (ORs) and 95% confidence intervals were used to evaluate the strength of the association and the result was corrected by multiple testing. To sum up, no associations between the MTR A2756G polymorphism and NTD risk were found among the 3 groups in all genetic models. However, as their sample size is not large enough, this result needs further research.
Lipomyelomeningocele represents a rare but complex neurological disorder that may present with neurological deterioration secondary to an inherent tethered spinal cord. Radiological testing is beneficial in determining the morphology of the malformation. Specialized testing such as urodynamic studies and neurophysiological testing may be beneficial in assessing for neurological dysfunction secondary to the lipomyelomeningocele. Early surgical intervention may be beneficial in preventing further neurological decline.
Neural tube defects (NTDs), including anencephaly and spina bifida, have a complex etiology. Defects in the planar cell polarity (PCP) signaling pathway have been strongly associated with NTDs in animal models and human cohorts. In this genetic study, we examined the core PCP gene CELSR1 in NTDs and caudal agenesis cases to determine whether mutations at this gene predispose to these defects.
We sequenced the coding region and the exon-intron junctions of CELSR1 in a cohort of 473 patients affected with various forms of open and closed NTDs (412) or caudal agenesis (61). Novel and rare variants (<1%) were genotyped in a cohort of 639 ethnically-matched individuals. The effect of novel missense mutations absent in controls and in public databases on protein function was predicted in silico.
We identified in our cohort one nonsense mutation in exon 1 of CELSR1 that truncates the majority of the protein in one patient with NTD and one in-frame 12 bp deletion that removes a putative PKC phosphorylation "SSR" motif in one caudal agenesis patient. We also detected a total of 13 novel missense variants in 12 patients (11 NTDs and 1 caudal agenesis) that were predicted to be pathogenic in silico.
We detected novel CELSR1 mutations predicted to be pathogenic in 2.9% of our NTD cohort and 3.3% of our caudal agenesis cohort. Our findings implicate CELSR1 as a risk factor for NTDs or caudal agenesis and provide additional evidence for a pathogenic role of PCP signaling in these malformations.
Craniorachischisis (CRN) is a severe neural tube defect (NTD) resulting from failure to initiate closure, leaving the hindbrain and spinal neural tube entirely open. Clues to the genetic basis of this condition come from several mouse models, which harbor mutations in core members of the planar cell polarity (PCP) signaling pathway. Previous studies of humans with CRN failed to identify mutations in the core PCP genes, VANGL1 and VANGL2. Here, we analyzed other key PCP genes: CELSR1, PRICKLE1, PTK7, and SCRIB, with the finding of eight potentially causative mutations in both CELSR1 and SCRIB. Functional effects of these unique or rare human variants were evaluated using known protein-protein interactions as well as subcellular protein localization. While protein interactions were not affected, variants from five of the 36 patients exhibited a profound alteration in subcellular protein localization, with diminution or abolition of trafficking to the plasma membrane. Comparable effects were seen in the crash and spin cycle mouse Celsr1 mutants, and the line-90 mouse Scrib mutant. We conclude that missense variants in CELSR1 and SCRIB may represent a cause of CRN in humans, as in mice, with defective PCP protein trafficking to the plasma membrane a likely pathogenic mechanism.
Kibar Z, Salem S, Bosoi CM, Pauwels E, De Marco P, Merello E, Bassuk AG, Capra V, Gros P. Contribution of VANGL2 mutations to isolated neural tube defects.
Vangl2 was identified as the gene defective in the Looptail (Lp) mouse model for neural tube defects (NTDs). This gene forms part of the planar cell polarity (PCP) pathway, also called the non-canonical Frizzled/Dishevelled pathway, which mediates the morphogenetic process of convergent extension essential for proper gastrulation and neural tube formation in vertebrates. Genetic defects in PCP signaling have strongly been associated with NTDs in mouse models. To assess the role of VANGL2 in the complex etiology of NTDs in humans, we resequenced this gene in a large multi-ethnic cohort of 673 familial and sporadic NTD patients, including 453 open spina bifida and 202 closed spinal NTD cases. Six novel rare missense mutations were identified in seven patients, five of which were affected with closed spinal NTDs. This suggests that VANGL2 mutations may predispose to NTDs in approximately 2.5% of closed spinal NTDs (5 in 202), at a frequency that is significantly different from that of 0.4% (2 in 453) detected in open spina bifida patients (p = 0.027). Our findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations.
Maternal diabetes during pregnancy is a well-known teratogen that increases the risk for birth defects, such as neural tube defects (NTDs). We have previously shown that maternal diabetes profoundly affects gene expression in the developing embryo, in particular a suite of known NTD genes. In rodent experimental systems, NTDs present as phenotypes of incomplete penetrance in diabetic pregnancies. This property is difficult to reconcile with observations of consistently altered gene expression in exposed embryos. We here show that maternal diabetes increases the overall variability of gene expression levels in embryos.
Altered gene expression and increased variability of gene expression together may constitute the molecular correlates for incomplete phenotype penetrance.
Based on this model, we suggest that maternal diabetes reduces the precision of gene regulation in exposed individuals. Loss of precision in embryonic gene regulation may include changes to the epigenome via deregulated expression of chromatin-modifying factors. Unraveling the mechanisms underlying such epigenetic modifications in diabetic pregnancies will help to understand how teratogenic insults compromise embryonic development and possibly provide avenues for therapeutic intervention.
Maternal first cousins of an individual with a neural tube defect (NTD) are at increased risk for an NTD. It is not known if they are also at risk for other serious birth defects.
We carried out an interview study of uncles and aunts and first cousins in Irish NTD families covering their pregnancy histories and the health of family members.
Maternal first cousins were more likely than paternal first cousins to have a birth defect (9.4% vs. 5.5%, p = 0.02; adjusted odds ratio: 1.72, 95% confidence interval: 1.04, 2.84).
This study shows that two generations of distant relatives (uncles/aunts and first cousins) in NTD families have similar maternal excesses of NTDs and birth defects overall. Inheritance mechanisms favouring matrilineal transmission, currently unknown, may contribute to birth defect occurrence in these families.
Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.
We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.
Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).
Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.
This report describes and illustrates the early prenatal diagnosis of a familial recurrence of congenital lipomyelomeningocele. Diagnosis was made from longitudinal and transverse ultrasound views of the fetal spine at 17 weeks' gestation showing a fourth echogenic area in the lumbosacral dorsal midline. Early diagnosis and resection of this often harmless-appearing, rare teratomatous tumor of the spinal cord is necessary to prevent irreversible neurologic damage during childhood. Familial recurrence has not previously been documented. This case emphasizes that reproductive counseling after the birth of an infant with a rare malformation must always include the possibility of recurrence. The antenatal sonographic and neonatal appearance is presented.
Radiological investigation of the lumbo-sacral spine was undertaken to determine the incidence of spina bifida occulta in parents of children affected with spina bifida cystica. The incidence of spina bifida occulta was 14.3% among 188 mothers and 26.8% among 179 fathers: an over-all incidence of 20.4% among 367 parents. The incidence of spina bifida occulta in a control group of 200 adults living in the same district was 5%. Although this difference is highly significant, no help can be derived for the genetic advice of individual couples, because spina bifida occulta was not commoner among parents with more than one affected child, and because in the majority of families neither parent had spina bifida occulta.
Each year spina bifida and anencephaly, the two most common forms of neural-tube defects, occur in 1 in 1000 pregnancies in the United States1 and an estimated 300,000 or more newborns worldwide.2 Although these severe conditions have been recognized since antiquity, never before has progress been so fast and substantive, particularly in the area of prevention. The results of randomized trials indicate that at least half the cases of neural-tube defects could be prevented if women consumed sufficient amounts of the B vitamin folic acid before conception and during early pregnancy.3,4 Elsewhere in this issue of the Journal, Berry . . .
Despite the strong association between twinning and neural-tube defects (NTD), concordance of twins with NTDs is very rare. A case of concordant NTDs in dizygotic twins is reported in view of its extreme rarity.
Lipomyelomeningocele is a form of spina bifida occulta with a distinct pathogenesis that differentiates it from open neural tube defects. Familial forms are rare and the condition may be polygenic. We report on 2 affected siblings with similar lesions and raise the possibility of an autosomal recessive pattern of inheritance with implications for genetic counselling.
Neural tube defects (NTDs) are a group of widely varying congenital malformations resulting from incomplete or improper fusion of the neural tube during embryonic development. NTDs are traditionally classified by the presence or absence of a layer of skin covering the spinal defect. Although a genetic component has been well established in the etiology of open NTDs, studies examining the genetics of closed NTDs such as lipomyelomeningocele are rare. We and others have previously observed families in which multiple members were affected with a broad spectrum of NTDs, suggesting the possibility of a common genetic etiology.
We calculated the sibling recurrence risk in 52 pedigrees in which the proband was diagnosed with lipomyelomeningocele (LMM), defining recurrence broadly to include both closed and open neural tube defects.
Although no recurrences of LMM were observed among younger siblings, one younger sibling had myelomeningocele, yielding an estimate of recurrence risk of 0.04 (95% CI 0.01-0.20). When all siblings of the proband were included, two additional affected siblings were identified, one with anencephaly and another with fatty filum, yielding an estimate of recurrence risk of 0.043 (95% CI 0.01-0.12).
Although the sample size is small, these data are not inconsistent with recurrence risks for myelomeningocele, ranging from 2% to 5% in siblings. These data suggest the underlying genetic basis for closed defects may be the same or closely related to that for myelomeningocele in some families, although a larger sample will be necessary before these data are appropriate for use in a clinical setting. Further characterizations, including whether risk for recurrence of NTDs or LMM in families in which the proband is affected with LMM are altered by folate supplementation, may shed light on the underlying genetics.
Recent studies reported no reduction in the frequency of lipomeningomyelocele (LMMC) in Hawaii and Nova Scotia after the implementation of a folic acid food fortification policy in 1998, while a marked reduction in the prevalence of other NTDs was observed. This study was performed to assess the prevalence of LMMC in Canada in relation to the timing of food fortification.
The study population included livebirths, stillbirths, and terminations of pregnancies because of fetal anomaly to women residing in seven Canadian provinces, from 1993 to 2002. In each province, the ascertainment of NTD cases relied on multiple sources, and in addition all medical charts were reviewed. The study period was divided into pre-, partial, and full fortification periods, based on results of red cell folate tests published in the literature.
A total of 86 LMMC cases were recorded among approximately 1.9 million live births. The average birth prevalence rate was 0.05/1,000, ranging from a minimum of 0.01/1,000 in 2002 to a maximum of 0.08/1,000 in 1999. There was statistical heterogeneity between years (p = .01), but no pattern compatible with a decrease following fortification. Comparing the full fortification period with the prefortification period, there was a slight but not statistically significant decrease in LMMC birth prevalence.
LMMC seems to be pathogenically distinct from myelomeningocele and more studies are needed to understand the embryologic mechanisms leading to this condition, and the environmental and genetic factors involved in its etiology.
Children's Hospital Medical Center
- Farideh Nejat
Farideh Nejat, Children's Hospital Medical Center, Tehran
University of Medical Sciences, Gharib St., Tehran 14155-7854,
Iran. email: nejat@sina.tums.ac.ir.