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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 -
Journal of Human Genetics Sep 2023WLS (Wnt ligand secretion mediator or Wntless) orchestrates the secretion of all Wnt proteins, a family of evolutionary conserved proteins, involved in Wnt signaling...
WLS (Wnt ligand secretion mediator or Wntless) orchestrates the secretion of all Wnt proteins, a family of evolutionary conserved proteins, involved in Wnt signaling pathway that has many essential biological functions including the regulation of development, cell proliferation, migration and apoptosis. Biallelic variants in WLS have recently been described in 10 patients with pleiotropic multiple congenital anomalies (MCA) known as Zaki syndrome. We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly. These features were reminiscent of Zaki syndrome although variable clinical severity was observed. In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation. As such, we extend the phenotype linked to Zaki syndrome. This study further highlights the importance of a thorough clinical evaluation to delineate the phenotypic spectrum associated with WLS variants and suggests that genotype-phenotype correlations due to variant localization seems likely. However, future work on additional patients and more functional studies may give further insights into genotype-phenotype correlations and the complex function of WLS.
Topics: Apoptosis; Phenotype; Receptors, G-Protein-Coupled; Wnt Proteins; Wnt Signaling Pathway; Humans
PubMed: 37106064
DOI: 10.1038/s10038-023-01152-2 -
Neuroradiology Jun 2023Congenital melanocytic naevus (CMN) syndrome, previously termed neurocutaneous melanosis, is a rare disease caused by postzygotic mosaic mutations occurring during... (Review)
Review
Congenital melanocytic naevus (CMN) syndrome, previously termed neurocutaneous melanosis, is a rare disease caused by postzygotic mosaic mutations occurring during embryogenesis in precursors of melanocytes. The severity of neurological manifestations in CMN patients is related to central nervous system abnormalities found at magnetic resonance imaging. The association between CMN and Dandy-Walker malformation (DWM) has been described in the literature, but recent advances in imaging and genetics lead to diagnostic criteria revision. In this paper, we aim to re-evaluate the proposed association by reviewing the available literature and present a patient with CMN and a large posterior fossa cyst.
Topics: Humans; Dandy-Walker Syndrome; Nevus, Pigmented; Melanosis; Neurocutaneous Syndromes; Magnetic Resonance Imaging
PubMed: 37093228
DOI: 10.1007/s00234-023-03150-9 -
Neurosurgery Sep 2023Hydrocephalus frequently occurs with midline posterior fossa cystic collections. The classification of this heterogeneous group of developmental anomalies, including...
The Management of Hydrocephalus in Midline Posterior Fossa Cystic Collections: Surgical Outcome From a Retrospective Single-Center Case Series of 54 Consecutive Pediatric Patients.
BACKGROUND
Hydrocephalus frequently occurs with midline posterior fossa cystic collections. The classification of this heterogeneous group of developmental anomalies, including Dandy-Walker malformation, persisting Blake's pouch, retrocerebellar arachnoid cysts, and mega cisterna magna, is subject of debate. The absence of diagnostic criteria is confusing regarding the ideal management of PFCC-related hydrocephalus.
OBJECTIVE
To decipher the surgical strategy for the treatment of children with PFCC-related hydrocephalus through a retrospective analysis of the surgical outcome driven by their clinical and radiological presentation.
METHODS
This study enrolled patients operated of symptomatic PFCC-related hydrocephalus. Clinical and MRI features were examined, as well as the surgical outcome. Unbiased subgroup classification of the patients was performed with multiple component analysis as a function of imaging characteristics and hierarchical clustering on principal component. Outcome was assessed with binomial logistic regression and Kaplan-Meier analysis.
RESULTS
Fifty-four patients were included between 2007 and 2021. Multiple component analysis suggested that cerebellar and vermian hypoplasia, vermian rotation, basal-tentorial angle, and fastigial angle were strongly correlated. Hierarchical clustering and the distribution of the patients in the bidimensional plot showed the clear segregation of 3 major clusters, which correlated with the radiological diagnosis ( P < .01). Binomial logistic regression and survival analysis showed that endoscopic third ventriculostomy was an effective treatment for patients with persisting Blake's pouch, while failing to control hydrocephalus in most of patients with Dandy-Walker malformation.
CONCLUSION
Preoperative MRI in patients with PFCC-related hydrocephalus is essential to better define the diagnosis. The choice of treatment strategy notably relies on correct radiological diagnosis.
Topics: Humans; Child; Dandy-Walker Syndrome; Retrospective Studies; Hydrocephalus; Arachnoid Cysts; Cerebellum; Magnetic Resonance Imaging; Cranial Fossa, Posterior
PubMed: 36921245
DOI: 10.1227/neu.0000000000002450 -
Canadian Journal of Ophthalmology.... Aug 2023
Topics: Humans; Adult; Dandy-Walker Syndrome; Eye; Face
PubMed: 36716793
DOI: 10.1016/j.jcjo.2023.01.008 -
European Journal of Medical Genetics Apr 2023The combination of Dandy-Walker malformation and occipital cephalocele is a rare autosomal dominant condition, known as ADDWOC, and caused by mutations in NID1 or LAMC1....
The combination of Dandy-Walker malformation and occipital cephalocele is a rare autosomal dominant condition, known as ADDWOC, and caused by mutations in NID1 or LAMC1. We present a three-generation family with variable manifestations of Dandy-Walker malformation and occipital cephalocele. They all have normal psychomotor development and lack neurological manifestations. Mutation analysis revealed a likely pathogenic missense variant in NID1 (c.3336T > G, p.Asn1112Lys), affecting an amino acid residue crucial in the nidogen/laminin interaction.
Topics: Humans; Encephalocele; Dandy-Walker Syndrome; Membrane Glycoproteins; Mutation
PubMed: 36702440
DOI: 10.1016/j.ejmg.2023.104713 -
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 -
Child's Nervous System : ChNS :... May 2023Dandy-Walker malformation (DWM) is a posterior fossa malformation characterized by a huge posterior fossa cyst in communication with the fourth ventricle. Hydrocephalus...
BACKGROUND
Dandy-Walker malformation (DWM) is a posterior fossa malformation characterized by a huge posterior fossa cyst in communication with the fourth ventricle. Hydrocephalus is associated with more than 80% of cases and is usually treated by shunting. Despite infection being a common complication of the shunt, abscess formation within the cyst was reported only once.
CASE REPORT
A neonate affected by DWM developed a posterior fossa abscess following a shunt infection. The purulent collection was refractory to standard treatment (antibiotics and burr hole drainage); therefore, an endoscopic approach was performed in order to remove the purulent collection under direct vision. This material was aspirated with the help of an endoscopic ultrasonic aspirator. The outcome was favorable, with a resolution of infection and re-implantation of the ventriculo-peritoneal shunt. Surprisingly, post-operative radiological examination showed substantial modification of the anatomy of the posterior fossa with disappearing of the Dandy-Walker cyst. To the best of our knowledge, this is the first documented report of a true Dandy-Walker malformation that modified its anatomical appearance over time.
DISCUSSION AND CONCLUSION
Endoscopic aspiration of intracranial purulent collection should be considered a valid option to manage complicated cases. An endoscopic ultrasonic aspirator may make the procedure more effective and faster.
Topics: Infant, Newborn; Humans; Dandy-Walker Syndrome; Abscess; Ultrasonics; Ventriculostomy; Cysts; Magnetic Resonance Imaging
PubMed: 36574013
DOI: 10.1007/s00381-022-05811-1 -
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