[Show abstract][Hide abstract] ABSTRACT: Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly.
No preview · Article · Dec 2015 · European journal of medical genetics
[Show abstract][Hide abstract] ABSTRACT: Conradi-Hünermann-Happle (CDPX2) syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in males while affected females show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only 6 antenatal presentations.
To better characterize the phenotype in female fetuses, we included 9 antenatally-diagnosed cases of females with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism.
The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially since the majority of such cases involve de novo mutations. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2015 · Prenatal Diagnosis
[Show abstract][Hide abstract] ABSTRACT: The stillbirth rate, included in perinatal mortality rate: that is a perinatal indicator needed to monitor perinatal and public health policy. Since 2008, there is no longer reliable stillbirth data since the regulation changes in August 2008. However, this stillbirth indicator must be produced to the European Members States. This article provides an update of the evolution of registration terms for recording stillbirths, measuring stillbirth rate and circumstances of stillbirth’s occurrence. Insee was responsible for the production of stillbirth indicator until 2008. From 2009, the PMSI became an information system according to WHO criteria. However, these legal changes cause difficulties in the calculation of the stillbirth rate. The quality assurance approach through mobilization of stakeholders is necessary to record reliable medical information and circumstances of occurrence that might be preventable. The PMSI is acquiring a new position in perinatal epidemiology.
No preview · Article · Mar 2015 · Revue de médecine périnatale
[Show abstract][Hide abstract] ABSTRACT: Objective
To describe investigate the outcomes of a pregnancy after a second- or third-trimester intrauterine fetal death (IUFD).
A prospective observational study was conducted at Trousseau Hospital (Paris, France) between 1996 and 2011. The first ongoing pregnancy in women who had had a previous IUFD was monitored. Management of their treatment was according to a standardized protocol. Recurrence of fetal death was the main outcome criterion.
The subsequent pregnancies of 87 women who had experienced at least one previous IUFD were followed up. The cause of previous IUFD was placental in 50 (57%) women, unknown in 19 (22%), adnexal in 12 (14%), metabolic in 2 (2%), and malformative in 4 (5%). Three (3%) participants had another stillbirth. Overall, obstetric complications occurred in 34 (39%) pregnancies (including 22 [25%] preterm births, 5 [6%] small for gestational age, and 6 [7%] maternal vascular complications). Obstetric complications were significantly more common among women whose previous stillbirth had been due to placental causes than among those affected by other causes (P = 0.02).
Most pregnancies after IUFD resulted in a live birth; however, adverse obstetric outcomes were more common when the previous stillbirth was due to placental causes.
Full-text · Article · Dec 2014 · International Journal of Gynecology & Obstetrics
[Show abstract][Hide abstract] ABSTRACT: Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).
[Show abstract][Hide abstract] ABSTRACT: The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.European Journal of Human Genetics advance online publication, 16 April 2014; doi:10.1038/ejhg.2014.62.
Full-text · Article · Apr 2014 · European journal of human genetics: EJHG
[Show abstract][Hide abstract] ABSTRACT: Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs) and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease-causing in MFDGA, due to heterozygous loss-of-function mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 loss-of-function. MFD, external ear anomalies and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/sec) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underly saltatory conduction of action potentials along myelinated axons, an important process for neuronal function. A homozygous missense mutation in Adenylate Cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the Peripheral Nervous System (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.
Full-text · Article · Dec 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Nevus sebaceous (NS) is a complex hamartoma most commonly found on the scalp, face and neck and is often present at birth although some may be diagnosed later in infancy. We report the first prenatal diagnosis of isolated NS that presented at 19 weeks' gestation as a large and exophytic tumors of the scalp. This case emphasizes the crucial role of ultrasound examination performed with high frequency probes, which revealed associated diffuse lesions of the face. Identification of such a facial involvement could have a dramatic prognostic impact. This article is protected by copyright. All rights reserved.
Full-text · Article · Dec 2013 · Prenatal Diagnosis
[Show abstract][Hide abstract] ABSTRACT: Anophthalmia and Microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes (GDF6, FOXE3, OTX2, PAX6, RAX, SOX2, and VSX2) in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21 % of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition 8 gene deletions (5 SOX2, 2 OTX2 and 1 RAX) were identified using a semi-quantitative multiplex PCR (QMPSF). The causative genetic defect was identified in 21 % of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.
[Show abstract][Hide abstract] ABSTRACT: In the context of prenatal diagnosis of malformation, knowledge of “similar” and resolved cases (i.e. previous cases with a diagnosis validated by fetus autopsy) is essential for diagnosis orientation. Therefore, access to biomedical data accumulated over the years by fetopathology experts specializing in the study of foetal malformations is crucial. This work addresses the imperious need to gather all the data and make it accessible easily for best use of this collective memory. Our research hypothesis is as follows: scanning electronic records will bring added value in terms of knowledge, allowing to build a knowledge-base of the domain. The files will be structured and enriched by indexing using ontological and terminological resources and their links with external knowledge (publications, databases). Such a database will provide access to similar cases.
[Show abstract][Hide abstract] ABSTRACT: L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.
[Show abstract][Hide abstract] ABSTRACT: Objectives
To evaluate the management of prenatally diagnosed cleft lip with or without cleft palate and the immediate postnatal outcome.
Material and methods
Retrospective study of all cases of cleft lip with or without cleft palate referred to our fetal medicine unit, between January 2005 and January 2011. The anatomical type of cleft, associated malformations, and the postnatal outcome were reviewed.
Forty-three cases of fetal cleft lip with or without cleft palate were reviewed. The mean gestational age at diagnosis was 24 weeks ± 4. The postnatal distribution of clefts was: 30 cleft lip and palate (70%) and 13 cleft lip (30%). The prenatal diagnosis of the cleft type was exact in 27 cases (62.8%). Nine cases had associated anomalies (21%), detected prenatally in three cases (37.5%). There was no karyotypical abnormality. Six pregnancies were terminated (14%). The immediate postnatal outcome was comparable with unselected newborns.
The prenatal diagnosis of cleft lip with or without cleft palate is correct, with two thirds of exact diagnoses. Large clefts palate are the best detected. Associated malformations cannot always be diagnosed by prenatal ultrasound, but have to be searched for because they modify the fetal outcome.
No preview · Article · Apr 2013 · Journal de Gynécologie Obstétrique et Biologie de la Reproduction
[Show abstract][Hide abstract] ABSTRACT: Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the «Joubert syndrome related disorders» (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyses of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD.
No preview · Article · Mar 2013 · European journal of medical genetics
[Show abstract][Hide abstract] ABSTRACT: Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.
Full-text · Article · Dec 2012 · The American Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: : Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated.
: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS).
: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.
No preview · Article · Dec 2012 · Journal of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: Background:
CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances.
Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed.
Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype-genotype correlation.
Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.
No preview · Article · Sep 2012 · Journal of Medical Genetics