Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.
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Anophthalmos↗
Biomedical subjects
Férechté Encha-Razavi
Publications and source records attributed to Férechté Encha-Razavi.
Reassessment of holoprosencephaly-diencephalic hamartoblastoma (HDH) association.
We report on a 23-week fetus with a hypothalamic hamartoma, lobar holoprosencephaly, right anophthalmia, and facial asymmetry, features which are consistent with the holoprosencephaly-diencephalic hamartoblastoma (HDH) association. In an attempt to better delineate HDH, we reviewed 19 published patients with similar features. The HDH clinical spectrum ranges from classic holoprosencephaly with micro/anophthalmia, multiple additional findings in non-contiguous structures and early lethality, to isolated microforms of holoprosencephaly. Associated cephalic features mainly include cortical/neuronal migration defects (39%), meningeal anomalies (28%), brainstem/posterior fossa malformations (22%), dysmorphic ears (41%), facial asymmetry (35%), and hypoplastic mandible (29%). Fifty-three percent of patients have additional extra-cephalic malformations, for example, vertebral/rib segmentation defects (50%), hypo/aplastic lungs (38%), congenital heart defect (29%), and urinary anomalies (29%). HDH shows etiological heterogeneity, that is, teratogenic exposure, chromosome imbalances, autosomal recessive as well as dominant "de novo" mutations. Several features could directly result from a disruptive sequence caused by an early hamartoma which alters the development of forebrain, hindbrain, meninges, and 1st-2nd branchial arches, although the pleiotropic action of genetic/environmental factors cannot be excluded. HDH does not emerge as a distinct syndrome, but other hypotheses, including separate conditions within a common pathway and the developmental field defect theory, are discussed.
Abnormalities, Multiple↗
Bilateral periventricular heterotopias in an X-linked dominant transmission in a family with two affected males.
We report on the case of dizygotic twin boys, born prematurely to an asymptomatic mother. Bilateral periventricular heterotopias with enlarged ventricles were discovered at birth in both twins. One of the twins died prematurely of bronchopulmonary complications, and was shown to have several neuropathological anomalies (microgyria, thin corpus callosum, and reduced white matter). The surviving twin had mental retardation, without epilepsy. MRI of the mother showed asymptomatic periventricular heterotopias without ventricular enlargement. She had two affected daughters also with asymptomatic periventricular heterotopias. A point mutation in the last coding exon 48 of the Filamin A (FLNA) gene (7922c > t) was discovered on sequencing and segregated with the affected individuals. This family has a classical X-linked dominant BPNH pathology, with greater severity in males than females. The location of the FLNA mutation is discussed in light of the neuropathological anomalies and mental retardation in male patients.
Amino Acid Sequence↗
Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome.
Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.
Abnormalities, Multiple↗
Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different.
In type I or classical lissencephaly, two genetic causes, namely the LIS1 gene mapping at 17p13.3 and the DCX (doublecortin on X) gene mapping at Xq22.3 are involved. These are considered to act during corticogenesis on radial migratory pathways. The prevailing view is that heterozygous mutations in the LIS1 gene and hemizygous mutations in the DCX gene produce similar histological pattern. The present detailed neuropathological study in two unrelated fetuses with respectively a mutation in the LIS1 and the DCX genes do not confirm this view. In LIS1 mutation, the cortical ribbon displays a characteristic inverted organization, also called "four layered cortex" while in DCX mutation, the cortex displays a roughly ordered "six layered" lamination. Our hypothesis is that mutations of the LIS1 and DCX genes, may not affect the same neuronal arrangement in the neocortex. Because the pathology of proven XLIS is rarely documented, further detailed neuropathological analysis in other cases identified through molecular study would be of a great help in the recognition of neuronal population involved in these migrational disorders and their underlying molecular mechanism.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Molecular screening of the ZFHX1B gene in prenatally diagnosed isolated agenesis of the corpus callosum.
OBJECTIVE: Agenesis of the corpus callosum (ACC) is the most common malformation of the central nervous system and may be associated with mental retardation. ACC is found in 40% of the cases of Mowat-Wilson syndrome (MWS), a polytopic embryonic defect including a distinctive facial gestalt, severe mental retardation, epilepsy and postnatal microcephaly as constant features. Other manifestations involve Hirschsprung disease, cardiac defects, renal abnormalities and hypospadias. Among this broad spectrum of malformations recently associated with haploinsufficiency of the zinc finger homeobox 1B gene (ZFHX1B), ACC can therefore be the only feature to be detected prenatally. Thus, we studied a group of 18 fetuses terminated for ACC and performed mutational analysis of the ZFHX1B gene in six selected cases. METHODS: Diagnosis of agenesis of the ACC was performed by prenatal echography survey. Screening for ZFHX1B deletions was performed by poly (CA) microsatellite markers studies and real-time semi-quantitative PCR. Mutational analysis was performed by single-strand conformation polymorphisms analysis (SSCP). RESULTS: Neither deletion encompassing the ZFHX1B locus nor mutation could be detected in any of the six fetuses analysed. CONCLUSION: ZFHX1B is not a major gene in isolated ACC. However, analysis of MWS should be considered in the differential diagnosis of ACC, especially when the facial features raise the possibility of MWS.
Agenesis of Corpus Callosum↗
Prenatal diagnosis of primary anophthalmia with a 3q27 interstitial deletion involving SOX2.
We report an interstitial deletion of chromosome 3q26-q28 in a fetus in which anophthalmia had been detected prenatally. FISH analysis, using BAC clones encompassing the SOX2 locus, showed that SOX2 gene was involved in the chromosomal breakpoint of the deletion. This case confirms that haploinsufficiency for SOX2 plays a crucial role in human eye development and emphasizes the necessity of careful chromosomal analysis, including FISH analysis of the 3q region, in case of prenatal discovery of anophthalmia.
Adult↗
Features of the developing brain.
INTRODUCTION: Fetal brain evaluation implies a perfect knowledge of the timing and characteristics of the developing nervous system during gestation. DISCUSSION: The first half of gestation corresponds to the neurulation, differentiation of primary cerebral vesicles, and neuronogenesis. The second half is characterized by the tremendous growth of the cerebral hemispheres and the settlement of gyral formation, while the ventricular system undergoes gradual narrowing. Gyral formation follows an invariable temporospatial schedule and is a good marker of fetal maturation. At the histological level, the fetal cortex displays transient developmental features, a superficial granular layer, and cells of Cajal-Retzius, which disappear at term. Neuroblasts formation has usually ceased by the 16th week of gestation, while neuronal migration continues until the extinction of the germinal layer. At this time, the remnant of the germinal layer constitutes, between the thalami and the caudate nucleus, an eminence of tightly packed cells, called the ganglionic eminence or germinal zone. They disappear by the age of 1 year.
Aging↗
Identification of brain malformations: neuropathological approach.
INTRODUCTION: The sophistication of prenatal brain imaging (US, MRI) has awakened interest in fetal neuropathology and changed the concept of brain malformations, defined until recently through descriptive terms and considered as senseless accidents of development. Usually, most CNS malformations are documented from a clinical and radiological point of view. However, only a detailed neuropathological study permits their exact phenotype to be established, which is instrumental for a precise diagnosis and cause analysis. DISCUSSION: After pregnancy termination for fetal malformations (or prenatal death) full autopsy and frozen tissue storage for DNA analysis are mandatory. The delay between death and autopsy should be limited because of the rapid autolysis of brain tissue. Detailed neuropathological and cause analysis have made it clear that each brain malformation is phenotypically "unique" and causally heterogeneous. Molecular studies have shown that mutations in different genes involved in a signaling pathway may result in a similar malformation. In addition, signaling pathways may be a possible target of toxic agents, which will mimic the genetic causes of malformations. These findings have raised growing interest in the early patterning of the developing nervous system in humans and its molecular controlling pathways. Consequently, brain malformations are now evaluated with special regard to their mechanism and cause analysis, considering fetal, maternal, and placental pathology. The predictive value of this multidisciplinary approach is now well demonstrated and has led, in some conditions, to gene identification, which is crucial for genetic counseling. It permits a prenatal molecular diagnosis as early as the 10-12th gestational week on chorionic villus sampling.
Brain↗
Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation.
A 4-base pair deletion in the neuronal serine protease neurotrypsin gene was associated with autosomal recessive nonsyndromic mental retardation (MR). In situ hybridization experiments on human fetal brains showed that neurotrypsin was highly expressed in brain structures involved in learning and memory. Immuno-electron microscopy on adult human brain sections revealed that neurotrypsin is located in presynaptic nerve endings, particularly over the presynaptic membrane lining the synaptic cleft. These findings suggest that neurotrypsin-mediated proteolysis is required for normal synaptic function and suggest potential insights into the pathophysiological bases of mental retardation.
Adolescent↗
Mosaic trisomy 9 and lobar holoprosencephaly.
The main features of trisomy 9 syndrome in mosaic and non-mosaic forms have been thoroughly described. Characteristic traits are low-set malformed ears, micrognathia, broad nose with bulbous tip, abnormal brain, congenital heart defects, abnormal hands and feet, genital abnormalities, and early death. We report a case of mosaic trisomy 9 with holoprosencephaly (HPE). The propositi was born at 37 weeks, with intra-uterine growth retardation, hypotelorism and single nostril, ventricular septal defect, anterior placement of anus, clenched hands with thumb adduction and ulnar deviation. Facial anomalies characteristic of trisomy 9 included deeply set eyes and short palpebral fissures, flat face with maxillary hypoplasia, small mouth, and low-set posteriorly angulated ears. Cytogenetic analysis showed mosaic trisomy 9 with 17% trisomic cells. Pathology confirmed lobar HPE. In literature, isolated arrhinia, related to the HPE spectrum, was reported in one case of mosaic trisomy 9. Our case raises the question of the causative role of trisomy 9 in full blown HPE.
Brain↗
Expression of the SMADIP1 gene during early human development.
The smad binding protein 1 gene (SMADIP1, MIM 605802) has been recently identified as a disease causing gene in a polytopic embryonic defect (MIM 235730) including midline anomalies, facial dysmorphic features and enteric nervous system malformation (Hirschsprung disease). To confirm the pleiotropic role of SMADIP1 during embryogenesis and investigate its role in neural crest cell derivatives differentiation, we performed RNA in situ hybridization at early stages of human development. According to the spectrum of malformations observed in patients, expression of SMADIP1 is observed in neural crest derived cells (peripheric nervous system, enteric nervous system, facial neurectoderm and cranial nerve ganglia), central nervous system, genital tubercle, muscles and kidneys. Surprisingly, SMADIP1 expression is also found in limbs and developing eye. Although congenital heart defects are frequently observed in patients with either a SMADIP1 large scale deletion or truncating mutation, no SMADIP1 expression could be detected in the developing heart at the stages studied.
Gene Expression↗
The spectrum of type III lissencephaly: a clinicopathological update.
A third type of lissencephaly that does not fufil diagnostic criteria of type I ("classical") and type II ("cobblestone") lissencephaly was described by our group as a new entity identified as OMIM 601160. This lethal familial syndrome comprises micrencephaly/lissencephaly and a spectrum of abnormalities lined to a severe fetal akinesia deformation sequence. Neuropathological findings suggest severe neurodegeneration leading to a marked neuronal dropout of the entire central nervous system and atrophy. Similar neuropathological findings have been described in the Neu-Laxova syndrome (NLS), an apparently different lethal malformation syndrome. Neuropathological similarities between OMIM 601160 and NLS raise the question of clinicopathological variability and genetic heterogeneity of type III lissencephaly. To answer this question, we compared our clinicopathological findings in a series of fetuses with OMIM 601160 to pathological data reported in NLS. In the study, 5 unrelated families with 7 affected fetuses were included. Interestingly, we found striking clinicopathological similarities between OMIM 601160 and NLS, which may represent a variability of a single neurodegenerative disease with early prenatal onset. Molecular studies in multiplex families defined through detailed clinicopathological screening are needed to clarify the distinction, if any, between these two entities.
Abnormalities, Multiple↗