Feasibility and Added Value of Fetal DTI Tractography in the Evaluation of an Isolated Short Corpus Callosum: Preliminary Results.

BACKGROUND AND PURPOSE: Prognosis of isolated short corpus callosum is challenging. Our aim was to assess whether fetal DTI tractography can distinguish callosal dysplasia from variants of normal callosal development in fetuses with an isolated short corpus callosum. MATERIALS AND METHODS: This was a retrospective study of 37 cases referred for fetal DTI at 30.4 weeks (range, 25-34 weeks) because of an isolated short corpus callosum less than the 5th percentile by sonography at 26 weeks (range, 22-31 weeks). Tractography quality, the presence of Probst bundles, dysmorphic frontal horns, callosal length (internal cranial occipitofrontal dimension/length of the corpus callosum ratio), and callosal thickness were assessed. Cytogenetic data and neurodevelopmental follow-up were systematically reviewed. RESULTS: Thirty-three of 37 fetal DTIs distinguished the 2 groups: those with Probst bundles (Probst bundles+) in 13/33 cases (40%) and without Probst bundles (Probst bundles-) in 20/33 cases (60%). Internal cranial occipitofrontal dimension/length of the corpus callosum was significantly higher in Probst bundles+ than in Probst bundles-, with a threshold value determined at 3.75 for a sensitivity of 92% (95% CI, 77%-100%) and specificity of 85% (95% CI, 63%-100%). Callosal lipomas (4/4) were all in the Probst bundles- group. More genetic anomalies were found in the Probst bundles+ than in Probst bundles- group (23% versus 10%, P = .08). CONCLUSIONS: Fetal DTI, combined with anatomic, cytogenetic, and clinical characteristics could suggest the possibility of classifying an isolated short corpus callosum as callosal dysplasia and a variant of normal callosal development.

Prevalence of COL4A1 and COL4A2 mutations in severe fetal multifocal hemorrhagic and/or ischemic cerebral lesions.

OBJECTIVE: To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury. METHODS: This was a single-center retrospective analysis of all cases of fetal cerebral anomalies suggestive of COL4A1 or COL4A2 gene mutation over the period 2009-2018. Inclusion criteria were: (1) severe and/or multifocal hemorrhagic cerebral lesions; (2) multifocal ischemic-hemorrhagic cerebral lesions. These anomalies could be of different ages and associated with schizencephaly or porencephaly. Between fetuses with and those without a mutation, we compared gestational age at the time of diagnosis, parity and fetal gender. RESULTS: Among the 956 cases of cerebral anomaly diagnosed in our center during the 10-year study period, 18 fetuses were identified for inclusion. A pathogenic COL4A1 gene mutation was found in five of these cases, among which four were de-novo mutations. A variant of unknown significance was found in four fetuses: in the COL4A1 gene in one case and in the COL4A2 gene in three cases. No COL4A1 or COL4A2 mutation was found in the remaining nine fetuses. The median (interquartile range) gestational age at diagnosis was significantly lower in cases with a mutation (24 (22-26) weeks) than in cases without a mutation (32 (29.5-34.5) weeks) (P = 0.03). CONCLUSIONS: A phenotype suggestive of cerebral injury was found in 18 of the 956 (1.9%) cases in our population, in 28% of which there was an associated COL4A1 or COL4A2 mutation. COL4A1 and COL4A2 gene mutations should be sought systematically in cases of severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, with or without schizencephaly or porencephaly. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

[Preliminary results from the French study on prenatal repair for fetal myelomeningoceles (the PRIUM study)]. / Résultats préliminaires de l'étude PRIUM : programme de réparation in utero des myéloméningocèles.

OBJECTIVES: To present the preliminary results of the PRIUM study, a French pilot study of prenatal repair for myelomeningoceles (MMC). MATERIAL AND METHODS: The fetal surgery for MMC is offered in cases of patients that did not opt for termination of pregnancy. RESULTS: Thirty-six patients were referred in an 18-month period. Eight patients were not eligible for prenatal repair. Another type of dysraphism was made in 6 cases (one spina-lipoma, 5 cases of limited dorsal myeloschisis). Twenty-two patients were eligible to fetal surgery. A prenatal repair was performed in three cases (14%). Four patients opted for a conventional postnatal treatment. Fifteen patients opted for termination of the pregnancy. CONCLUSION: The establishment of a prenatal repair of MMC protocol in France was justified. The experience of the first 18months of this study however suggests that only a limited number of couples will choose this procedure after specialized counseling in a reference center.

[A difficult transition from childhood to adult healthcare: the case of epilepsy]. / Le difficile passage à l'âge adulte en matière de soins : l'exemple de l'épilepsie.

OBJECTIVE: The purpose of this study was to analyze modalities of the transition from pediatric to adult epilepsy care and patients' acquisition of autonomy. METHOD: This study was conducted using semidirected interviews composed of three major parts: the patient's criteria of transition toward adult healthcare (factors taken into account, anticipation, the patient's opinion, etc.), conditions (teamwork with the neurologists, transmission of the medical record, continuity of health care, etc.), and the role played by social workers and psychologists. We interviewed 10 doctors belonging to six major Parisian hospital units involved in the monitoring of children and adolescents with epilepsy and working in Pediatric Neurology Departments of the Île-de-France region. RESULTS: For most of the doctors, reaching 18 years of age was the major argument taken into account to consider transition to adult care. According to the doctors interviewed, parents are generally worried when their child has to find another doctor (7/10). According to eight out of 10 doctors, the neurologist is selected to take over. The doctors recognize the importance of psychologists and social workers even if they are not always included. The process by which the patient gains autonomy depends a great deal on the role played by the pediatricians and parents, although some parents are very protective. This behavior weakens the patient's capacity for autonomy and it varies according to the degree of his or her physical and/or neurological disabilities. Furthermore, developing autonomy requires interdisciplinary work that is not yet fully in place. CONCLUSION: The lack of structures well-adapted to the uniqueness of each patient and the lack of coordination between the various institutions do not favor the acquisition of autonomy. A network that could efficiently respond to the needs of epileptic patients as well as medical care tailored to adolescents would be the answer to this dilemma.

Prenatal unilateral cerebellar hypoplasia in a series of 26 cases: significance and implications for prenatal diagnosis.

OBJECTIVE: To define imaging patterns of unilateral cerebellar hypoplasia (UCH), discuss possible pathophysiological mechanisms and underline the etiology and prognosis associated with these lesions. METHODS: In this retrospective study we reviewed the charts of 26 fetuses diagnosed between 2003 and 2011 with UCH, defined by asymmetrical cerebellar hemispheres with or without decreased transverse cerebellar diameter. The review included analysis of the anatomy of the cerebellar hemispheres, including foliation, borders and parenchymal echogenicity, and of the severity of the hypoplasia. Data from clinical and biological work-up and follow-up were obtained. RESULTS: Our series could be divided into two groups according to whether imaging features changed progressively or remained constant during follow-up. In Group 1 (n = 8), the progression of imaging features, echogenic cerebellar changes and/or hyposignal in T2*-weighted MR images were highly suggestive of ischemic/hemorrhagic insult. In Group 2 (n = 18), imaging features remained constant during follow-up; UCH was associated with abnormal foliation in three proven cases of clastic lesions, a cystic lesion was noted in three cases of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac abnormalities/aortic coarctation, eye abnormalities) syndrome and, in the remaining cases, UCH remained unchanged, with no imaging pattern typical of hemorrhage. In 24 cases the infant was liveborn and follow-up was continued in 23, for a mean period of 3 years. Among these, neurological complications were identified in seven (in one of seven (at a mean of 46 months) in Group 1 and in six of 16 (at a mean of 35 months) in Group 2). The surface loss of cerebellar hemisphere was > 50% in 19/24 fetuses and the vermis was clearly normal in appearance in 19/24. Predisposing factors for fetal vascular insult were identified in eight cases: these included maternal alcohol addiction, diabetes mellitus, congenital cytomegalovirus infection and pathological placenta with thrombotic vasculopathy and infarctions. CONCLUSION: UCH is defined as a focal lesion of the cerebellum that may be secondary to hemorrhage and/or ischemic insult, suggesting a clastic origin, particularly when imaging follow-up reveals changes over time. UCH may also be a clue for the prenatal diagnosis of PHACE syndrome. The amount of surface loss of cerebellar hemisphere does not correlate with poor prognosis. UCH with normal vermis is often associated with normal outcome.

Normal EEG in childhood: from neonates to adolescents.

The important EEG changes that occur throughout childhood are a major challenge for the neurophysiologist. These reflect brain maturation, which is especially fast during the first year of life. This article describes normal EEG features and variants, characteristic patterns of development, as well as some patterns that are unusual for age, from the neonatal period to adolescence. We also describe how to adapt techniques and prepare patients in order to get interpretable records of appropriate duration, in neonates, infants, and young children.

[Diagnostic investigations for an unexplained developmental disability]. / Stratégie d'exploration d'une déficience intellectuelle inexpliquée.

Developmental disability/mental retardation is a major public health problem and a common cause of consultation in pediatrics, neuropediatrics, and genetics. Etiologies of mental retardation are highly heterogeneous. Diagnostic strategies have been explored in a small number of consensus publications, essentially from English-speaking countries. In these publications, the utility of the conventional karyotype, fragile X screening, metabolic workup, and brain imaging were discussed. Recently, investigations in mental disabilities have been dramatically modified by molecular cytogenetics and the emergence of new metabolic pathologies. Based on the published experiments, the Reference centers for rare disease network "mental deficiencies with rare causes" elaborated an updated protocol for the investigation of nonsyndromal mental disability that takes into account recent innovations in genetics and genomics. Whenever local facilities make it possible, we recommend array CGH investigation as the first step or, when CGH is not available, a combination of classic karyotype with systematic screening of telomeric and interstitial rearrangements by MLPA, fragile X screening in both sexes, and a reorientation of metabolic screening toward certain diseases that have recently been described: congenital disorders of glycosylation (CDG), thyroid hormone carrier deficiency, and creatine metabolism deficiency. We recommend MRI imaging only if head size is abnormal, if neurological examination is abnormal, or regression occurs if walking is not achieved by 2 years, or if development is severely delayed.

Pediatric outcome of children with the prenatal diagnosis of isolated septal agenesis.

BACKGROUND: Isolated Septal Agenesis (SA) is a rare disease with clinical outcomes (especially neurological outcomes) that are unknown. The purpose of this study was to evaluate the clinical outcome of these children. METHODS: We conducted a retrospective multicenter study of 17 children with an isolated SA or SA combined with a moderate ventricular dilatation (VD) that was diagnosed antenatally and confirmed by a magnetic resonance imaging (MRI) performed in the antenatal period. RESULTS: Of the 17 children, 14 had normal neurological examinations, 2 had language development delay and visuo-spatial dyspraxia, and 3 of the 17 children had behavioral problems. Eight children had neuropsychological evaluations, and the results were normal in six cases. There were 3 cases of septo-optic dysplasia (SOD) diagnosed postnatally, which highlighted the difficulties in assessing the optic tract and hypothalamic-pituitary region in antenatal imaging. Language delay and behavioral disorders were the main abnormalities at follow-up. CONCLUSION: The discovery of an isolated SA reveals the difficulties of prenatal diagnosis to correlate the neurological and functional prognosis to morphological findings. The prognosis seemed to be good. It appears necessary to improve the diagnostic performance of fetal brain imaging and to follow-up these children prospectively to assess their long-term cognitive-behavioral outcomes.

Prenatal diagnosis of 18q-syndrome: a case of fetal mosaicism with a normal karyotype in chorionic villi.

We report a case of fetoplacental discrepancy with normal karyotype on chorionic villi and deletion of the long arm of chromosome 18 on amniotic fluid. Cytogenetic tests were repeated because of a short corpus callosum on ultrasound examination. This 18q-syndrome has been reported to be associated with poor neurodevelopmental outcome.

[Impact of prenatal corpus callosum agenesis diagnosis on pregnancy outcome. Evaluation of 155 cases between 2000 and 2006]. / Impact du dépistage anténatal des agénésies du corps calleux sur le devenir des grossesses. Etude de 155 dossiers de 2000 à 2006.

The purpose of this study was to investigate the changes between 2000 and 2006 in pregnancy outcome when a diagnosis of either isolated or associated fetal corpus callosum agenesis (CCA) was made, given that beginning in 2003, the information provided to couples facing this problem related a good prognosis in nearly 80 % of cases of isolated CCA and a poor prognosis in 20 % of cases. We retrospectively analyzed all pregnancies with a fetal diagnosis of CCA between 2000 and 2006 (n=155) and compared two periods: the first group from 2000 to June 2003, the second from July 2003 to 2006. For each group, we analyzed the type of CCA during pregnancy - either isolated or associated - and the outcome of pregnancy. We compared the rate of pregnancy termination before and after 2003 and analyzed the accuracy of the prenatal CCA diagnosis. Of the 155 patients studied, 62 terminated the pregnancy. The overall rate of termination decreased from 31/70 to 31/85. When CCA was said to be isolated prenatally, the rate of pregnancy termination fell from 13/35 to 9/44 (-17 %) (p<0.05). Nine diagnoses of CCA were corrected after birth or by postmortem examination. Improvement of prenatal diagnosis requires better quality of prenatal screening, with a more systematic study of dysmorphic features, a study of correlations between the type of CCA and the neurological prognosis, and more genetic studies.

[New treatments of epilepsy in infancy]. / Epilepsie de l'enfant : nouveaux médicaments.

Epilepsy is a repetition of seizures. It is frequent child pathology: 40% of all epileptic people have less than 15 years of age. Seizures appear on a developing brain. Treatment must avoid frequent and long lasting seizures but at the same time must spare cognitive development. New antiepileptic drugs seem to have more specialized indications, less side effects and thus represent a very interesting tool for neuropediatrician. Monotherapy has to be preferred as often as possible to assure good cognitive function.

[Changes in the methods of practitioners of fetal medicine after the Perruche judgement and the law passed on the 4th of March 2002]. / Modifications des pratiques des acteurs de la médecine foetale après l'arrêt Perruche et la loi du 4 mars 2002.

OBJECTIVES: The aim of this study was to evaluate the effect of the "Perruche case" and that of law issued on the 4th of March 2002 in order to moderate the effect of the case on the daily practice of prenatal diagnosis and fetal medicine. MATERIALS AND METHODS: We sent questionnaires to the 186 sonologists of two French regions. Changes in their daily practice, as well as communication with the parents to-be, teaching, and stake in a discussion about the future of their specialty were evaluated. RESULTS: We received 54 answers (29%). Diagnosis and prognosis of fetal anomalies have become more difficult to expose than before for 40% of them. Written information as well as medical reports or explanation about ability and limits of ultrasound have been improved, in content for 64% and in use for 42%. For 45% of practitioners, it has become particularly important to carefully chose words used with patients. Some clinicians stopped or limited second (60%) and third (45%) trimester scans. They expressed their need to learn about legal regulations (50%) or improve communication skills (44%). About 60% felt the Perruche case and the subsequent law help to improve reflection about the future of fetal medicine and prenatal scans. CONCLUSION: While the law was poorly perceived by many physicians, it has enabled a careful reorganization and formalization of fetal medicine and particularly prenatal scans. Further debate is needed on the objectives of fetal sonography. Practitioners themselves should initiate this discussion.

[Brain MRI: ante and postnatal correlations]. / IRM cérébrale: corrélations pré et post-natales.

Fetal brain MRI provides complementary information to ultrasonography exploration, the gold standard for antenatal evaluation. Certain specific correlations between the antenatal and postnatal findings merit discussion: cysts after increase in volume during the perinatal period; certain anomalies are at the limit of resolution (tuber of tuberous sclerosis, heterotopy); anatomic visibility of certain structures does not exclude function deficiency (optical chiasma in septo-optic dysplasia; ventricular dilatation is a frequent sign but can occur in very different entities.

[Partial corpus callosum agenesis]. / Agénésie partielle du corps calleux de l'enfant.

PURPOSE: The diagnosis of corpus callosum agenesis (CCA) with prenatal MRI relies on indirect signs. However, they are known to be inconstant in case of incomplete CCA. The purpose of this study is to specify the frequency of indirect signs in partial CCA to approach the reliability of fetal MRI. MATERIALS AND METHODS: This retrospective study included 33 children with partial CCA. MRI were reviewed by two observers and a standardized radiological and clinical data collection was performed. Depending on the ratio CC length/anteroposterior brain diameter, two groups were statistically compared: subtotal partial CCA and mild partial CCA. RESULTS: 14% of patients had none indirect sign and 33% had only one sign. We found a significative difference of frequency for most of the indirect signs. 48% of patients had other cerebral anomalies. Clinical correlation showed no statistical difference between the two groups. CONCLUSION: This series shows that indirect signs are inconstant in partial CCA and related to the CC length. In contrast, mild and subtotal CCA have a similar neurological outcome. These data suggest that greatest care has to be taken in the interpretation of fetal MRI.

[Parent's information and prenatal diagnosis of cerebral malformation with an uncertain prognosis]. / Information des couples et diagnostic prénatal d'une malformation cérébrale à pronostic incertain: analyse des pratiques.

UNLABELLED: Fetal ultrasounds examinations allow identification of brain malformations; announce of diagnosis and information about prognosis may be difficult when malformation is rare and prognosis uncertain. OBJECTIVES: In this study we tried to analyze how fetal imaging for prenatal screening was organized and how couples were managed and supported. METHODS: We focused on the procedures used to inform couples: content, method of delivery and consequences. A referent physician in each large multidisciplinary center for prenatal diagnosis in Paris area was questioned by semi-directed interview. RESULTS: Our study showed that it is difficult to standardize the way in which information is supplied before and after fetal ultrasounds examination; uncertainty about prognosis led more often to abortion. CONCLUSION: Thus, couples should have clear and complete information provided by a multidisciplinary team including specialists particularly concerned by the malformation (neuropediatrician and/or neurosurgeon)--moreover when prognosis is uncertain, in order to support them, and to accompany their decision concerning pregnancy.

Agitation and changes of Bispectral Index and electroencephalographic-derived variables during sevoflurane induction in children: clonidine premedication reduces agitation compared with midazolam.

BACKGROUND: This double-blind randomized study was undertaken to assess agitation, Bispectral Index (BIS) and EEG changes during induction of anaesthesia with sevoflurane in children premedicated with midazolam or clonidine. METHODS: Children were allocated randomly to receive rectal midazolam 0.4 mg kg(-1) (n=20) or oral clonidine 4 microg kg(-1) (n=20) as premedication. Rapid induction of anaesthesia was achieved with inhalation of sevoflurane 8% in nitrous oxide 50%-oxygen 50%. After tracheal intubation, the children's lungs were mechanically ventilated and the inspired sevoflurane concentration was adjusted to achieve an end-tidal fraction of 2.5%. The EEG and BIS were recorded during induction until 10 min after tracheal intubation. The EEG was analysed using spectral analysis at five points: baseline, loss of eyelash reflex, 15 s before the nadir of the BIS (BIS(nadir)), when both pupils returned to the central position (immediately before intubation), and 10 min after intubation. RESULTS: Agitation was observed in 12 midazolam-treated and five clonidine-treated patients (P=0.05). At baseline, EEG rhythms were slower in the clonidine group. Induction of anaesthesia was associated with similar EEG changes in the two groups, with an increase in total spectral power and a shift towards low frequencies; these changes were maximal around the end of the second minute of induction (BIS(nadir)). When the pupils had returned to the central position, fast EEG rhythms increased and BIS was higher than BIS(nadir) (P<0.05). In both groups, agitation was associated with an increase in slow EEG rhythms at BIS(nadir). CONCLUSIONS: Compared with midazolam, clonidine premedication reduced agitation during sevoflurane induction. During induction with sevoflurane 8% (oxygen 50%-nitrous oxide 50%), the nadir of the BIS occurred at the end of the second minute of inhalation. Agitation was associated with a more pronounced slowing of the EEG rhythms at BIS(nadir) compared with inductions in which no agitation was observed. The BIS may not follow the depth of anaesthesia during sevoflurane induction in children.