Guideline No. 410: prevention, screening, diagnosis, and pregnancy Management for fetal neural tube defects

This revised guideline is intended to provide an update on the genetic aspects, prevention, screening, diagnosis, and management of fetal neural tube defects. Target population: Women who are pregnant or may become pregnant. Neural tube defect screening should be offered to all pregnant women. For prevention: a folate-rich diet, and folic acid and vitamin B12 supplementation, with dosage depending on risk level. For screening: second-trimester anatomical sonography; first-trimester sonographic screening; maternal serum alpha fetoprotein; prenatal magnetic resonance imaging. For genetic testing: diagnostic amniocentesis with chromosomal microarray and amniotic fluid alpha fetoprotein and acetylcholinesterase; fetal exome sequencing. For pregnancy management: prenatal surgical repair; postnatal surgical repair; pregnancy termination with autopsy. For subsequent pregnancies: prevention and screening options and counselling. The research on and implementation of fetal surgery for prenatally diagnosed myelomeningocele has added a significant treatment option to the previous options (postnatal repair or pregnancy termination), but this new option carries an increased risk of maternal morbidity. Significant improvements in health and quality of life, both for the mother and the infant, have been shown to result from the prevention, screening, diagnosis, and treatment of fetal neural tube defects. The benefits for patient autonomy and decision-making are provided in the guideline. Harms include an unexpected fetal diagnosis and the subsequent management decisions. Harm can also result if the patient declines routine sonographic scans or if counselling and access to care for neural tube defects are delayed. Cost analysis (personal, family, health care) is not within the scope of this clinical practice guideline. A directed and focused literature review was conducted using the search terms spina bifida, neural tube defect, myelomeningocele, prenatal diagnosis, fetal surgery, neural tube defect prevention, neural tube defect screening, neural tube defect diagnosis, and neural tube defect management in order to update and revise this guideline. A peer review process was used for content validation and clarity, with appropriate ethical considerations. The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). Maternity care professionals who provide any part of pre-conception, antenatal, delivery, and neonatal care. This guideline is also appropriate for patient education.

IGF2BP1 controls cell death and drug resistance in rhabdomyosarcomas by regulating translation of cIAP1.

Rhabdomyosarcoma (RMS), a neoplasm characterised by undifferentiated myoblasts, is the most common soft tissue tumour of childhood. Although aggressive treatment of RMS could provide long-term benefit, resistance to current therapies is an ongoing problem. We report here that insulin-like growth factor 2-binding protein 1 (IGF2BP1), an oncofetal protein, is expressed in RMS patient-derived cell lines and in primary tumours where it drives translation of the cellular inhibitor of apoptosis 1 (cIAP1), a key regulator of the nuclear factor-κB signalling pathway and of caspase-8-mediated cell death. We demonstrate that reducing the levels of cIAP1 in RMS, either by IGF2BP1 knockdown or by IAP antagonists, sensitises these cells to tumour necrosis factor-α-mediated cell death. Finally, we show that targeting cIAP1 by IAP antagonists delays RMS tumour growth and improve survival in mice. Our results identify IGF2BP1 as a critical translational regulator of cIAP1-mediated apoptotic resistance in RMS and advocate for the combined use of IAP antagonists and tumour necrosis factor-α as a therapeutic approach for this type of cancer.

Prenatal ultrasound and MRI findings of temporal and occipital lobe dysplasia in a twin with achondroplasia.

Thanatophoric dysplasia, hypochondroplasia and achondroplasia are all caused by FGFR3 (fibroblast growth factor receptor 3) mutations. Neuropathological findings of temporal lobe dysplasia are found in thanatophoric dysplasia, and temporal and occipital lobe abnormalities have been described recently in brain imaging studies of children with hypochondroplasia. We describe twins discordant for achondroplasia, in one of whom the prenatal diagnosis was based on ultrasound and fetal MRI documentation of temporal and occipital lobe abnormalities characteristic of hypochondroplasia, in addition to the finding of short long bones. Despite the intracranial findings suggestive of hypochondroplasia, achondroplasia was confirmed following postnatal clinical and genetic testing. These intracranial abnormalities have not been previously described in a fetus with achondroplasia.

Overlapping DNA methylation profile between placentas with trisomy 16 and early-onset preeclampsia.

INTRODUCTION: Maternal preeclampsia is associated with altered placental development in the first trimester of pregnancy. Confined placental trisomy 16 mosaicism (CPM16) is a genetic abnormality of the placenta that is highly predisposing to preeclampsia. We previously demonstrated widespread alterations in DNA methylation in 3rd trimester placentae associated with chromosomally normal early-onset preeclampsia (EOPET) and questioned whether similar changes would be associated with CPM16, making this condition a potential model for studying EOPET-associated changes early in pregnancy. METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, 3rd trimester CPM16 placental samples (N = 10) were compared to gestational age matched controls, and to 1st trimester trisomy 16 placentae (N = 5). RESULTS: DNA methylation differences associated with CPM16 were identified at 2254 CpGs using stringent criteria (FDR < 0.01, Δß > 0.15). A subset of these differences (11%; p < 0.0001) overlapped those observed in chromosomally normal EOPET using similarly stringent criteria (FDR < 0.01; Δß > 0.125). Importantly, the majority of EOPET-associated CpGs were significantly altered (p < 0.05) in CPM16 with a similar Δß distribution. This was true for CPM16 with (N = 5) and without (N = 5) EOPET, although EOPET cases showed a tendency towards larger changes. Of the shared CPM16/EOPET associated changes, three CpGs near two genes (ARGHEF37 and JUNB) were also altered in 1st trimester trisomy 16 placentae. DISCUSSION: Despite the limited sample size, widespread DNA methylation changes are observed in Trisomy 16 that overlap those seen previously in chromosomally normal EOPET. Hence, Trisomy 16 may provide a model to study the progression of placental changes that occurs in EOPET across different gestational ages.

[Haemophagocytic syndrome in pregnancy: a case report]. / Syndrome d'activation macrophagique et grossesse: à propos d'un cas.

Haemophagocytic syndrome (HPS) results from an inappropriate stimulation of macrophages in bone marrow and lymphoid organs, leading to haemophagocytosis and hypercytokinemia. HPS may be primitive, essentially in pediatric population, or secondary to malignancy, infection or autoimmune disease. This disease is rare and prognosis is poor. A small number of cases during pregnancy have been described in literature. We report one HPS case in a pregnant patient at 21 week's gestation with systemic lupus erythematosus. We discuss diagnostic difficulties, obstetrical complications and therapeutic options.

[Anaesthetic management for caesarean delivery and acute myocardial infarction by spontaneous coronary dissection]. / Anesthésie pour césarienne à la phase aiguë d'un infarctus du myocarde par dissection coronaire.

Myocardial infarction is rare during pregnancy and is associated with a high maternal and foetal mortality rate. We report the case of a 32-year-old woman at 38 weeks gestation who developed a myocardial infarction with spontaneous coronary dissection treated with coronary angioplasty and who needed an emergency caesarean section. We discuss the anaesthetic management of urgent caesarean section in this context.

Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy.

Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.

General design of the International Fusion Materials Irradiation Facility deuteron injector: source and beam line.

In the framework of the International Fusion Materials Irradiation Facility-Engineering Validation and Engineering Design Activities (IFMIF-EVEDA) project, CEA/IRFU is in charge of the design and realization of the 140 mA cw deuteron Injector. The electron cyclotron resonance ion source operates at 2.45 GHz and a 4 electrode extraction system has been chosen. A 2 solenoid beam line, together with a high space charge compensation have been optimized for a proper beam injection in the 175 MHz radio frequency quadrupole. The injector will be tested with proton and deuteron beam production either in pulsed mode or in cw mode on the CEA-Saclay site before to be shipped to Japan. Special attention was paid to neutron emission due to (d,D) reaction. In this paper, the general IFMIF Injector design is reported, pointing out beam dynamics, radioprotection, diagnostics, and mechanical aspects.

Outcome of prenatally diagnosed isolated clubfoot.

OBJECTIVES: To analyze the aneuploidy risk and treatment outcome of prenatally diagnosed isolated clubfoot, to determine the false-positive rate (FPR) of ultrasound diagnosis and to calculate the risk of diagnostic revision to complex clubfoot. METHODS: By chart review, 65 patients were retrospectively ascertained to have unilateral or bilateral clubfeet diagnosed prenatally. We calculated the rates of false positives, aneuploidy and diagnostic revision to complex clubfoot, and used an ad hoc scoring system to determine orthopedic outcome. Published rates of aneuploidy were pooled and evaluated. RESULTS: Prenatally diagnosed isolated clubfoot FPR (defined as 1 - positive predictive value) was 10.5% (95% CI, 5.8-18%) (calculated per foot). After a minimum of 1-year postnatal follow-up, 13% (95% CI, 6-26%) of patients had revised diagnoses of complex clubfoot. No patients had aneuploidy identified by cytogenetic analysis or clinical assessment. Of the 34 patients with 2-year postnatal follow-up, 76.5% were treated with serial casting with or without Botox. All children with isolated clubfoot were walking and had an average outcome score of 'very good' to 'excellent'. CONCLUSIONS: When counseling women regarding prenatally diagnosed isolated clubfoot, it is important to tell them that approximately 10% of individuals will have a normal foot or positional foot deformity requiring minimal treatment. Conversely, 10-13% of prenatally diagnosed cases of isolated clubfoot will have complex clubfoot postnatally, based on the finding of additional structural or neurodevelopmental abnormalities. Although this study did not identify an increased risk of fetal aneuploidy associated with isolated clubfoot, a review of the literature indicates a risk of 1.7-3.6% with predominance of sex chromosome aneuploidy.

[Comparative evaluation of quality of life in patients with schizophrenia treated with conventional versus atypical neuroleptics: results of a transversal study]. / Evaluation comparative de la qualité de vie de patients schizophrènes traités par neuroleptiques classiques et neuroleptiques atypiques: résultats d'une étude transversale.

AIM: The World Health Organization has defined quality of life as "the perception of an individual, his/her place in life, in the context of the culture and the system of values in which he/she lives and in relation to his/her objectives, expectations, standards and concerns". The quality of life of the schizophrenic patients has been largely studied for the evaluation of their medical, social and therapeutic needs. The impact of neuroleptics, in particular atypical neuroleptics, on the subjective quality of life of these patients remains to be specified. The aim of this study was to compare the subjective quality of life of schizophrenic patients treated with classical neuroleptics (CN) or atypical neuroleptics (AN). METHODS: One hundred patients meeting DSM IV criteria for the diagnosis of schizophrenia (American Psychiatric Association, 1994) were included in the study. Sixty-four schizophrenic patients were treated with CN and thirty-six with AN. The symptomatology of the patients was assessed using the Positive And Negative Syndrome Scale, (PANSS, Kay et al., 1987) and the Schedule for the Deficit Syndrome (SDS, Kirkpatrick et al., 1989). The extra-pyramidal symptoms were assessed using the Extrapyramidal Symptom Rating Scale (Chouinard et al., 1980). The Subjective quality of life was studied using the Lehman Quality of Life Interview (QOLI, Lehman, 1988) translated and validated in France. RESULTS: The patients treated by CN did not differ from the patients treated by AN in terms of severity of the positive and negative symptoms. The patients treated with AN presented significantly less extrapyramidal side effects than the patients treated with CN. No significant difference in terms of quality of life was found between both groups of patients. CONCLUSION: The kind of neuroleptic (CN vs AC) does not seem to influence the quality of subjective life of schizophrenic patients.

V37I connexin 26 allele in patients with sensorineural hearing loss: evidence of its pathogenicity.

Sensorineural hearing loss (SNHL) is the most common inherited sensory disorder, reported in 1-3 of every 1,000 births. It has been estimated that 50% of all cases of prelingual SNHL are genetically determined. There is tremendous genetic heterogeneity, with multiple dominant and recessive loci. Mutations of the gap junction beta-2 gene (GJB2) emerge as a leading cause of autosomal recessive non-syndromic SNHL. Over 90 sequence alterations have been reported, the pathogenicity of some of them being unknown or unclear. The status of the V37I allele of connexin 26 (GJB2 amino acid product) with regards to its association with SNHL has been controversial. This study examines the pathogenicity of V37I by comparing the frequency of this allele in 40 patients with SNHL of Chinese and Caucasian descent with the frequency of the allele in 100 anonymized, ethnically matched controls. The V37I allele was identified in 43.75 and 11.5% of the patient and control alleles of Chinese ethnicity, respectively, but was not found in either Caucasian cohort. We also compiled the audiograms of 15 individuals with SNHL homozygous for the V37I allele, and showed that these individuals present with a mild to moderate SNHL. These results indicate that (1) the V37I allele is common in individuals of Chinese descent but rarely present in individuals of Caucasian decent; and (2) the V37I allele is pathogenic, but produces milder hearing loss compared to nonsense mutations of connexin 26 such as the 35delG mutation.

[The role of spiral computerized tomography in the diagnosis of pulmonary embolism]. / Place actuelle de l'angioscanner spiralé dans l'embolie pulmonaire.

The diagnostic strategy of pulmonary embolism has changed in the last few years with the use of the pulmonary spiral angio-scan. It has become the investigation of first intention for the positive diagnosis of pulmonary embolism. Its limitations are known, essentially the difficulties in visualisation of distal pulmonary embolism. However, the introduction of new 64-slice scanners has considerably improved the resolution. The indications of the spiral angioscanner have recently increased with the study of pulmonary artery vascularisation and the calculation of Qanadli's obstruction index, the study of the peripheral venous system and the evaluation of right ventricular dysfunction by the calculation of the ratio of surfaces (or diameters) of RV/LV.

Raman spectroscopy of free-standing individual semiconducting single-wall carbon nanotubes.

The radial breathing modes and tangential modes have been systematically measured on a large number of individual semiconducting single-wall carbon nanotubes (thin bundles) suspended between plots (free-standing single-wall carbon nanotubes). The strong intensity of the Raman spectra ensures the precision of the experimentally determined line shapes and frequencies of these modes. The diameter dependence of the frequencies of the tangential modes was measured. This dependence is discussed in relation with recent calculations. The present data confirm/contradict some previous interpretations.

Illustration of genetic syndromes in the nursery.

Reading to children and storytelling has documented developmental benefits. Traditional Nursery Rhymes (Mother Goose tales in North America) encapsulate 'snapshots' of the people described and chronicle their customs, superstitions, and amusements. Art has long been employed to document the impact of human imperfections and diseases. We investigated whether illustrations accompanying nursery rhymes, suggest that any characters illustrated may have had or been based on recognized morphological abnormalities, and if this literature documents a role for grandmothers as storytellers. Archival materials were reviewed at the Victoria and Albert museum and Mary Evans picture library, and via the web. As early as 1695, Perrault included a frontispiece of a mature woman as storyteller in his book of fairytales. Similar scenes by various artists (Boilly, Cruikshank, Guy, Highmore, Maclise, Richter, and Smith) are found consistently from 1744 to 1908. Many illustrators (Aldin, Caldecott, Cruikshank, Doré, Dulac, Gale, Greenaway, Rackham, Tarrant, and Wood) portray infants, children, and adults who are dwarfed, giant, or whimsically grotesque. Many images certainly suggest genetic syndromes, and in some characters consistency of specific features is evident between artists. Our research confirms the wealth of children's nursery rhyme illustrations suggesting pathology; that an authoritative compilation of the morphologies depicted is lacking; and that historically, grandmothers have a central role as storytellers.

Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH.

Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35-49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50-70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5-10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome-wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a approximately 15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004; Lapierre et al., 2004; Schoumans et al., 2004; Vermeesch et al., 2005] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3-13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3-13.1, Xp22.3 is provided.

Introduction of picture archiving and communication system at The Townsville Hospital.

The performance of a medical imaging department (MID) can be judged by the timing and availability of an image and its report to the treating physician, as this can impact on the patient's treatment, as well as the length and cost of a patient's hospitalization. The use of digital imaging has dramatically improved report turnaround time. In October 2001, The Townsville Hospital (TTH) was opened as a 460 bed greenfield site and as part of the installation a picture archiving and communication system, including web distribution of images and reports to wards and clinics, was included. This retrospective analysis of the MID at TTH is the first data on departmental productivity and individual workload and how these have changed since the hospital's opening 2 years ago, with some ideas for further improvement.

Risk of mosaicism and uniparental disomy associated with the prenatal diagnosis of a non-homologous Robertsonian translocation carrier.

OBJECTIVE: To estimate the fetal risk of uniparental disomy (UPD) associated with the presence of a Robertsonian translocation (RT) in a parent or in the fetus, to determine whether it is clinically indicated to test these pregnancies for UPD. METHODS: Retrospective analysis of our Centre's experience in testing prenatal specimens for UPD in cases of known familial RTs or fortuitous RT finding. In addition, all reports dealing with prenatal UPD testing in similar populations obtained from PUBMED and the 1995-2001 American Society of Human Genetics Meeting's abstracts were assessed. RESULTS: No case of UPD 14 or 15 was found among the 51 tests performed at our Centre. Meta-analysis identified one case of UPD13 out of 687 UPD studies, conducted in 400 prenatal diagnoses. The 95% confidence interval of the risk of UPD in the population studied (1 in 738) is 0.02-0.76%. In one report, trisomy mosaicism for one of the chromosomes involved in the translocation was found in 3 cases out of 169 (95% confidence interval: 0.1-3 %). CONCLUSIONS: Fetuses carrying a Robertsonian translocation have a risk of UPD of 0.02-0.76% (95% CI). In this population, trisomy mosaicism is more frequent than UPD. This finding justifies the study of additional colonies in all cases of prenatally diagnosed RT.

Mutational and expression analysis of the chromosome 12p candidate tumor suppressor genes in pre-B acute lymphoblastic leukemia.

Allelic losses on chromosome 12p12-13 are associated with childhood acute lymphoblastic leukemia (ALL) and several solid neoplasias, suggesting the presence of a tumor suppressor locus. The recent construction of a transcription map of this locus has enabled the identification of eight genes, of which five were previously known: ETV6, BCL-G, LRP6, MKP-7, and CDKN1B. The three other candidate genes, LOH12CR1, LOH12CR2, and LOH12CR3, have no known functions. To evaluate whether one (or more) of the candidate genes is the actual target of the 12p12-13 deletions, we examined the genomics and the expression status of these genes in ALL patients. Although we found nine DNA variants in these genes, no inactivating mutations were found in the leukemia cells of patients with 12p hemizygous deletions. Expression analysis revealed that most 12p hemizygously deleted samples also carried a t(12;21) translocation, of which none expressed ETV6 from the nontranslocated allele. Furthermore, we observed one case of t(12;21) without deletion of ETV6, in which the expression of this gene was greatly reduced, indicating a different mechanism of inactivation. None of the other genes showed a significant decrease in expression, suggesting that ETV6 is indeed the target of deletions in ALL patients.

Canadian survey of clinical status at dialysis initiation 1998-1999: a multicenter prospective survey.

AIMS: The current growth in end-stage kidney disease populations has led to increased efforts to understand the impact of status at dialysis initiation on long-term outcomes. Our main objective was to improve the understanding of current Canadian nephrology practice between October 1998 and December 1999. METHODS: Fifteen nephrology centers in 7 provinces participated in a prospective data collection survey. The main outcome of interest was the clinical status at dialysis initiation determined by: residual kidney function, preparedness for chronic dialysis as measured by presence or absence of permanent peritoneal or hemodialysis access, hemoglobin and serum albumin. Uremic symptoms at dialysis initiation were also recorded, however, in some cases these symptom data were obtained retrospectively. RESULTS: Data on 251 patients during 1-month periods were collected. Patients commenced dialysis at mean calculated creatinine clearance levels of approximately 10 ml/min, with an average of 3 symptoms. 35% of patients starting dialysis had been known to nephrologists for less than 3 months. These patients are more likely to commence without permanent access and with lower hemoglobin and albumin levels. Even of those known to nephrologists, only 66% had permanent access in place. CONCLUSIONS: Patients commencing dialysis in Canada appear to be doing so in relative concordance with published guidelines with respect to timing of initiation. Despite an increased awareness of kidney disease, a substantial number of patients continues to commence dialysis without previous care by a nephrologist. Of those who are seen by nephrologists, clinical and laboratory parameters are suboptimal according to current guidelines. This survey serves as an important baseline for future comparisons after the implementation of educational strategies for referring physicians and nephrologists.