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Biology Open Aug 2023G9a, also known as EHMT2, is essential for embryogenesis and has specific functions in multiple developmental processes. G9a inactivation affects development of the...
G9a, also known as EHMT2, is essential for embryogenesis and has specific functions in multiple developmental processes. G9a inactivation affects development of the nervous system, which is formed with contribution of descendants of progenitor cells expressing the transcription factor Isl1. However, the function of G9a in Isl1-expressing progenitors is unknown. Here, we show that G9a is required for proper development of multiple structures formed with contribution of Isl1-expressing progenitors. A Cre-dependent GFP reporter revealed that the recombinase activity of the Isl1-Cre used in this study to inactivate G9a was reduced to a subset of Isl1-expressing progenitor cells. G9a mutants reached endpoint by 7 weeks of age with cardiac hypertrophy, hydrocephalus, underdeveloped cerebellum and hind limb paralysis, modeling aspects of Dandy-Walker complex. Moreover, neuroepithelium of the lateral ventricle derived from Isl1-expressing progenitors was thinner and disorganized, potentially compromising cerebrospinal fluid dynamics in G9a mutants. Micro-computed tomography after iodine staining revealed increased volume of the heart, eye lens and brain structures in G9a mutant fetuses. Thus, altered development of descendants of the second heart field and the neural crest could contribute to multicomponent malformation like Dandy-Walker.
Topics: Dandy-Walker Syndrome; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Integrases; Stem Cells; X-Ray Microtomography; Animals
PubMed: 37470706
DOI: 10.1242/bio.059894 -
JPMA. the Journal of the Pakistan... Jul 2023Dandy-Walker Malformation (DWM) is a rare congenital anomaly of the posterior cranial fossa. Features of DWM include hypoplasia of the cerebellar vermis, enlargement of...
Dandy-Walker Malformation (DWM) is a rare congenital anomaly of the posterior cranial fossa. Features of DWM include hypoplasia of the cerebellar vermis, enlargement of the posterior fossa, and cystic dilatation of the fourth ventricle. MRI is the modality to confirm the diagnosis. Treatment is usually symptomatic and required when signs of hydrocephalus develop. Rare cases of asymptomatic DWM diagnosed incidentally are reported in literature. We report a case of DWM in a 60-year-old male who presented with haemorrhagic stroke and was later found to have DWM on brain imaging.
Topics: Male; Humans; Aged; Middle Aged; Female; Pregnancy; Dandy-Walker Syndrome; Hemorrhagic Stroke; Hydrocephalus; Brain; Prenatal Diagnosis; Magnetic Resonance Imaging; Stroke
PubMed: 37469077
DOI: 10.47391/JPMA.7379 -
Fa Yi Xue Za Zhi Apr 2023
Topics: Humans; Infant; Female; Dandy-Walker Syndrome; Tomography, X-Ray Computed; Craniocerebral Trauma
PubMed: 37277384
DOI: 10.12116/j.issn.1004-5619.2021.411104 -
Journal of Neurosurgical Sciences May 2023Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have...
BACKGROUND
Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated hydrocephalus associated loci. This study aims to identify potential genetic causation in cases of hydrocephalus, with or without spina bifida and Dandy Walker Syndrome (DWS), using family-based rare variant association analysis of whole exome sequencing.
METHODS
We performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with hydrocephalus (N.=27), with hydrocephalus with spina bifida (N.=21) and with DWS (N.=3), using Illumina HiSeq 2500 instrument.
RESULTS
No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known hydrocephalus loci in our subjects. However, after examining 73 known hydrocephalus genes previously identified from literature, we identified three potentially impactful variants from the cohort. Using a gene panel comprising variants in known neural tube defects loci, we identified a total of 1024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing.
CONCLUSIONS
We identified three potentially impactful variants from our cohort in 73 known hydrocephalus genes previously identified in literature.
PubMed: 37158713
DOI: 10.23736/S0390-5616.23.06010-1 -
BMC Pregnancy and Childbirth Jan 2023Dandy-Walker syndrome (DWS) is a rare congenital malformation of the central nervous system (CNS), characterized by underdevelopment or dysplasia of the cerebellar...
BACKGROUND
Dandy-Walker syndrome (DWS) is a rare congenital malformation of the central nervous system (CNS), characterized by underdevelopment or dysplasia of the cerebellar vermis, expansion of the fourth ventricle and posterior fossa cistern. The incidence is aboutapproximately 1/25000-1/35000. At present, the etiology and pathogenesis of DWS are not completely clear. It is mostly considered to be a multifactorial genetic disease that is related to both genetic factors and environmental factors. There is no large sample size analysis of the chromosomal profile of DWS up to now. This study aims to provide clinical reference for prenatal diagnosis via summarizing the clinical features and pregnancy outcomes of Dandy-Walker syndrome.
METHODS
A total of 76 cases of foetal Dandy-Walker syndrome out of 19,506 pregnant women underwent cordocentesis or amniocentesis for genetic detection. Rapid prenatal karyotyping, single nucleotide polymorphism array (SNP-array) and BACs-on-Beads™ (BoBs) were performed for prenatal genetic diagnosis. The results of ultrasonography, genetic analysis and pregnancy outcome were recorded.
RESULTS
Of the 76 cases, 19 were isolated DWS, while 57 cases were accompanied by other ultrasound-visible abnormalities. Ultrasound abnormalities of the CNS were most frequently observed, accompanied by DWS. Twenty-five out of 76 cases had chromosomal abnormalities, and the rate of chromosomal abnormalities increased in pregnant women of advanced maternal age or in combination with other ultrasound abnormalities. Of the 19 cases in the isolated DWS group, nine pregnant women chose to terminate the pregnancy, while seven cases continued the pregnancy and all infants were normal. Among the 57 pregnant women with pathological ultrasound manifestations other than foetal DWS, 44 chose to terminate the pregnancy, while 12 cases continued the pregnancy. Further follow-up revealed one newborn with postnatal neurodevelopmental delay. A female term neonate presented with very severe sensorineural deafness, and an infant died 7 days after birth with abnormal development of multiple organs.
CONCLUSIONS
Pregnant women with DWS in foetal ultrasonic examination should be offered a careful and comprehensive foetal ultrasound scan and further prenatal genetic testing including karyotype analysis and SNP-array. The prognosis of the foetus without chromosomal aberration is good in isolated DWS pregnancies but poor in nonisolated DWS pregnancies.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Chromosome Aberrations; Dandy-Walker Syndrome; Nervous System Malformations; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 36653756
DOI: 10.1186/s12884-023-05367-1 -
Molecular Syndromology Dec 2022Pathogenic variants in the PIEZO family member 2 () gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5)....
INTRODUCTION
Pathogenic variants in the PIEZO family member 2 () gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic variants have been reported to show posterior fossa anomalies.
METHODS AND RESULTS
By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in . The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes.
CONCLUSION
Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous related disorders represent a continuum with overlapping phenotypic features.
PubMed: 36588752
DOI: 10.1159/000523956 -
Journal of Medical Case Reports Dec 2022Chromosome 13q deletion syndrome shows variable clinical features related to the different potential breakpoints in chromosome 13q. The severely malformed phenotype is... (Review)
Review
BACKGROUND
Chromosome 13q deletion syndrome shows variable clinical features related to the different potential breakpoints in chromosome 13q. The severely malformed phenotype is known to be associated with the deletion of a critical region in 13q32. However, esophageal atresia is a rare symptom and the relevant region is unknown. Thus, determining the association between accurate breakpoints and new clinical features is essential.
CASE PRESENTATION
A 28-year-old Japanese primigravid woman was referred for fetal growth restriction, absence of a gastric bubble, cerebellar hypoplasia, overlapping fingers, and polyhydramnios at 31 weeks gestation. At 38 + 0 weeks, she delivered a 1774 g female infant. The infant presented with isolated esophageal atresia (Gross type A), Dandy-Walker malformation, right microphthalmia, left coloboma, overlapping fingers, pleurocentrum in the thoracic vertebrae, reduced anogenital distance, and hearing loss. Her karyotype was diagnosed as 46,XX,del(13)(q32.1-qter) by amniocentesis, but array comparative genomic hybridization after birth revealed the deletion of 13q31.3-qter. At 48 days after birth, the infant underwent surgery for esophageal atresia and was later discharged from the hospital at 7 months of age.
CONCLUSION
This case report and the literature reviews supports the previous findings on the pathological roles of haploinsufficiency of the ZIC2/ZIC5 in Dandy-Walker malformation and the EFBN2 haploinsufficiency in eye malformation and hearing loss. Furthermore, the possible involvement of IRS2, COLA1, and COLA2 in eye malformation were identified. This is the first case of 13q deletion syndrome with esophageal atresia (Gross A), but it may be a symptom of VATER/VACTER association (vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects), as in the previous cases. These symptoms might also be associated with EFBN2 haploinsufficiency, although further research is required.
Topics: Pregnancy; Female; Humans; Esophageal Atresia; Dandy-Walker Syndrome; Comparative Genomic Hybridization; Chromosome Deletion; Prenatal Diagnosis; Fetus; DNA-Binding Proteins; Transcription Factors
PubMed: 36572904
DOI: 10.1186/s13256-022-03713-z -
Taiwanese Journal of Obstetrics &... Nov 2022We present a female neonate with de novo trisomy 9p24.3-q21.2 presented with a neurological anomaly.
OBJECTIVE
We present a female neonate with de novo trisomy 9p24.3-q21.2 presented with a neurological anomaly.
CASE REPORT
Her birth length was 41 cm (<3rd percentile), birth body weight was 1600 g (<5th percentile), and head circumference was 29.5 cm (<5th percentile). She had low-set ears, deep and wide-set eyes with downslanting palpebral fissures, and a full nasal bridge with a globular nose. In addition, a rocker bottom foot was noted after further evaluation. Congenital heart anomalies, including patent ductus arteriosus (0.43 cm), large atrial septal defect, and malalignment ventricular septal defect (0.64 cm) were also confirmed. Brain magnetic resonance imaging showed partial agenesis of the cerebellum and corpus callosum. Furthermore, severe bilateral communicating hydrocephalus was found. CTG-banded chromosome analysis revealed 47, XX, +mar.
CONCLUSION
DNA analysis may be mandatory for small gene segments. In trisomy 9p, we proposed further delineation of the critical region correlating to neurological malformations.
Topics: Humans; Infant, Newborn; Female; Dandy-Walker Syndrome; Trisomy; Abnormalities, Multiple; Hydrocephalus
PubMed: 36427979
DOI: 10.1016/j.tjog.2022.05.018 -
Medicine Nov 2022Dandy-Walker syndrome (DWS) is a group of brain malformations which occasionally accompanied by psychotic symptoms. The co-occurrence of DWS and epilepsy in children is... (Review)
Review
BACKGROUNDS
Dandy-Walker syndrome (DWS) is a group of brain malformations which occasionally accompanied by psychotic symptoms. The co-occurrence of DWS and epilepsy in children is quite rare.
CASE DESCRIPTION
We reported a 14-year-old male who presented with a 8-month history of inconsistent upper limb tremor and accidental seizure. The MRI showed the typical alterations of DWS: cystic dilatation of the fourth ventricle, vermian hypoplasia, enlarged posterior fossa. He received the ventriculoperitoneal shunting (VPS) placement for hydrocephalus and had a symptom-free period for 8 days. Then he experienced a recurrence of involuntary upper limb tremor and behavior disturbance after decreasing the pressure of cerebrospinal fluid (CSF) from 150 to 130 mm Hg. After being treated with Olanzapine 10 mg/d, Clonazepam 3 mg/qn and Valproate acid (VPA) 500 mg/bid for nearly a month, his mental status and psychotic symptoms fluctuated. A search of Pub Med showed little report of hydrocephalus and DWS comorbidity with seizure and psychosis. Here we presented the whole process of a rare disease from the very beginning with all his symptoms, examinations and treatments.
CONCLUSION
VPS placement surgery at an earlier stage may be an effective way to avoid inevitable brain damage so as to improve the clinical outcomes for patients with DWS. Continued treatment with regard to DWS condition may include shunt placement, but it mainly focus on developmental concerns, with occupational and physical therapy along with ongoing supportive psychotherapy to improve the coping skills and quality of life.
Topics: Humans; Male; Child; Adolescent; Dandy-Walker Syndrome; Quality of Life; Tremor; Hydrocephalus; Seizures
PubMed: 36401431
DOI: 10.1097/MD.0000000000031421