Search

FOXC1 loss contributes to Dandy-Walker malformation (DWM), a common human cerebellar malformation. Previously, we found that complete Foxc1 loss leads to aberrations in proliferation, neuronal differentiation and migration in the embryonic mouse cerebellum (Haldipur et al., 2014). We now demonstrate that hypomorphic Foxc1 mutant mice have granule and Purkinje cell abnormalities causing subsequent disruptions in postnatal cerebellar foliation and lamination. Particularly striking is the presence of a partially formed posterior lobule which echoes the posterior vermis DW 'tail sign' observed in human imaging studies. Lineage tracing experiments in Foxc1 mutant mouse cerebella indicate that aberrant migration of granule cell progenitors destined to form the posterior-most lobule causes this unique phenotype. Analyses of rare human del chr 6p25 fetal cerebella demonstrate extensive phenotypic overlap with our Foxc1 mutant mouse models, validating our DWM models and demonstrating that many key mechanisms controlling cerebellar development are likely conserved between mouse and human., Competing Interests: The authors declare that no competing interests exist.

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors declare no conflict of interest., (© 2016 Wiley Periodicals, Inc.)

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder, which is characterized by congenital cataracts, cerebellar ataxia, progressive muscle weakness, and delayed psychomotor development. SIL1, which is located at 5q31.2, is the only gene known to cause MSS. Dandy-Walker syndrome (DWS) is defined by hypoplasia, upward rotation of the cerebellar vermis, and cystic dilation of the fourth ventricle; however, its genetic pathogeny remains unclear. Here, we report a Chinese consanguineous family with MSS and DWS. Whole exome sequencing identified a novel nonstop mutation in SIL1. Sanger sequencing revealed that the mutation was segregated in this family according to a recessive mode of inheritance. We found that the mutation changed a stop codon (TGA) to an arginine codon (CGA), and no in-frame termination codon in the 3' untranslated region (UTR) of SIL1 could be found. The mRNA levels of SIL1 were decreased by 56.6% and 37.5% in immortalized lymphoblasts of the patients respectively; the protein levels of SIL1 were substantially decreased. This case study is the first report on Chinese MSS patients, MSS complicated by DWS, and a nonstop mutation in SIL1. Our findings imply the pathogenetic association between DWS and MSS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To explore the outcome in fetuses with prenatal diagnosis of posterior fossa anomalies apparently isolated on ultrasound imaging., Methods: MEDLINE and EMBASE were searched electronically utilizing combinations of relevant medical subject headings for 'posterior fossa' and 'outcome'. The posterior fossa anomalies analyzed were Dandy-Walker malformation (DWM), mega cisterna magna (MCM), Blake's pouch cyst (BPC) and vermian hypoplasia (VH). The outcomes observed were rate of chromosomal abnormalities, additional anomalies detected at prenatal magnetic resonance imaging (MRI), additional anomalies detected at postnatal imaging and concordance between prenatal and postnatal diagnoses. Only isolated cases of posterior fossa anomalies - defined as having no cerebral or extracerebral additional anomalies detected on ultrasound examination - were included in the analysis. Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale for cohort studies. We used meta-analyses of proportions to combine data and fixed- or random-effects models according to the heterogeneity of the results., Results: Twenty-two studies including 531 fetuses with posterior fossa anomalies were included in this systematic review. The prevalence of chromosomal abnormalities in fetuses with isolated DWM was 16.3% (95% CI, 8.7-25.7%). The prevalence of additional central nervous system (CNS) abnormalities that were missed at ultrasound examination and detected only at prenatal MRI was 13.7% (95% CI, 0.2-42.6%), and the prevalence of additional CNS anomalies that were missed at prenatal imaging and detected only after birth was 18.2% (95% CI, 6.2-34.6%). Prenatal diagnosis was not confirmed after birth in 28.2% (95% CI, 8.5-53.9%) of cases. MCM was not significantly associated with additional anomalies detected at prenatal MRI or detected after birth. Prenatal diagnosis was not confirmed postnatally in 7.1% (95% CI, 2.3-14.5%) of cases. The rate of chromosomal anomalies in fetuses with isolated BPC was 5.2% (95% CI, 0.9-12.7%) and there was no associated CNS anomaly detected at prenatal MRI or only after birth. Prenatal diagnosis of BPC was not confirmed after birth in 9.8% (95% CI, 2.9-20.1%) of cases. The rate of chromosomal anomalies in fetuses with isolated VH was 6.5% (95% CI, 0.8-17.1%) and there were no additional anomalies detected at prenatal MRI (0% (95% CI, 0.0-45.9%)). The proportions of cerebral anomalies detected only after birth was 14.2% (95% CI, 2.9-31.9%). Prenatal diagnosis was not confirmed after birth in 32.4% (95% CI, 18.3-48.4%) of cases., Conclusions: DWM apparently isolated on ultrasound imaging is a condition with a high risk for chromosomal and associated structural anomalies. Isolated MCM and BPC have a low risk for aneuploidy or associated structural anomalies. The small number of cases with isolated VH prevents robust conclusions regarding their management from being drawn. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Partial deletion of the long arm of the chromosome 13, 13q deletion syndrome is a rare chromosomal disorder characterized by severe growth and mental retardation, microcephaly, facial dysmorphism, brain malformations (holoprosencephaly, Dandy-Walker malformation), distal limb defects, eye anomalies, genitourinary and gastrointestinal tract malformations (Hirschsprung's disease). Approximately 1.2 Mb region in 13q32 was suggested as minimal critical region which is responsible for severe mental and growth retardation and brain anomalies. Here we described a male patient with de novo interstitial deletion of 13q31.1-q34 associated with short stature, microcephaly, facial dysmorphism, clinodactyly, cryptorchidism, micropenis, epilepsy, HPE, DWM, and HSCR. According to the literature review, present case indicated that smallest deleted region associated with DWM and HPE might be located at the 13q32.3, limb defects 13q34, anogenital malformations 13q33.3-34, and HSCR 13q31.1-32.1.

We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Ritscher-Schinzel syndrome (RSS)/3C (cranio-cerebro-cardiac) syndrome (OMIM#220210) is a rare and clinically heterogeneous developmental disorder characterized by intellectual disability, cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. A recent study of a Canadian cohort identified homozygous sequence variants in the KIAA0196 gene, which encodes the WASH complex subunit strumpellin, as a cause for a form of RSS/3C syndrome. We have searched for genetic causes of a phenotype similar to RSS/3C syndrome in an Austrian family with two affected sons. To search for disease-causing variants, whole-exome sequencing (WES) was performed on samples from two affected male children and their parents. Before WES, CGH array comparative genomic hybridization was applied. Validation of WES and segregation studies was done using routine Sanger sequencing. Exome sequencing detected a missense variant (c.1670A>G; p.(Tyr557Cys)) in exon 15 of the CCDC22 gene, which maps to chromosome Xp11.23. Western blots of immortalized lymphoblastoid cell lines (LCLs) from the affected individual showed decreased expression of CCDC22 and an increased expression of WASH1 but a normal expression of strumpellin and FAM21 in the patients cells. We identified a variant in CCDC22 gene as the cause of an X-linked phenotype similar to RSS/3C syndrome in the family described here. A hypomorphic variant in CCDC22 was previously reported in association with a familial case of syndromic X-linked intellectual disability, which shows phenotypic overlap with RSS/3C syndrome. Thus, different inactivating variants affecting CCDC22 are associated with a phenotype similar to RSS/3C syndrome.

Complex small supernumerary marker chromosomes (sSMC) constitute one of the smallest subgroups of sSMC in general. Complex sSMC consist of chromosomal material derived from more than one chromosome. We report a complex sSMC derived from chromosomes 9 and 8, characterized as der(8;9)(p10;p10) resulting from unbalanced transition of maternal balanced translocation. Besides dysmorphic face and mental-motor retardation, the patient had Dandy-Walker malformation (DWM) in cranial MR also. As far as we are concerned, this is the first complex sSMC case comprising short arms of 8th and 9th chromosomes.

We are beginning to understand the molecular biology of hydrocephalus and its related diseases. X-linked hydrocephalus (XLH), holoprosencephaly (HPE), Dandy-Walker malformation (DWM), and neural tube defect (NTD) can all be discussed with respect to their available molecular genetics knowledge base and its clinical applications. XLH is single gene disorder caused by mutations in the neural cell adhesion molecule-encoding L1CAM (L1) gene. Our knowledge of the molecular basis of XLH is already being applied clinically in disease diagnosis, disease classification, and prenatal diagnosis. However, the molecular mechanism underlying XLH-related hydrocephalus still needs to be clarified. Sixteen causative genes for HPE have been identified, of which mutations are most often found in SHH, ZIC2, SIX3, and TGIF. Genetic interactions, gene complexity, and the wide variety of HPE phenotypes and genotypes are topics for future study. For DWM, two important loci, 3q24, which includes the FOXC1 gene, and 6q25.3, which includes the ZIC1 and ZIC4 genes, were recently identified as causative areas. The planar cell polarity (PCP) genes CELSR1, CELSR2, VANGL1, and VANGL2 have been implicated in NTD; these genes have roles in neural tube closure and ependymal ciliary movement.

Objective: Trisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases of complete trisomy 9 that both present unusual phenotypic associations, and we analyze the genetic pathway involved in this chromosomal abnormality., Case Report: The first fetus investigated showed Dandy-Walker malformation, cleft lip, and cleft palate) at the second trimester scan. Cardiovascular abnormalities were characterized by a right-sided, U-shaped aortic arch associated with a ventricular septal defect (VSD). Symmetrical intrauterine growth restriction and multicystic dysplastic kidney disease were associated findings. The second fetus showed a dysmorphic face, bilateral cleft lip, hypoplastic corpus callosum, and a Dandy-Walker malformation. Postmortem examination revealed cardiovascular abnormalities such as persistent left superior vena cava draining into the coronary sinus, membranous ventricular septal defect, overriding aorta, pulmonary valve with two cusps and three sinuses, and the origin of the left subclavian artery distal to the junction of ductus arteriosus and aortic arch., Conclusion: Complete trisomy 9 may result in a wide spectrum of congenital abnormalities, and the presented case series contributes further details on the phenotype of this rare aneuploidy., (Copyright © 2014. Published by Elsevier B.V.)

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.

We report on a de novo 0.5 Mb triplication (partial tetrasomy) of chromosome 17q25.3 in a 10-year-old girl with severe intellectual disability, infantile seizures (West syndrome), moderate hearing loss, Dandy-Walker malformation, microcephaly, craniofacial dysmorphism, striking cutaneous syndactyly (hands 3-4, feet 2-3), joint laxity, and short stature. The triplication resulted from the unusual combination of a terminal duplication at 17qter and a cryptic translocation of an extra copy of the same segment onto chromosome 10qter. The breakpoint at 17q25.3 was located within the FOXK2 gene. SNP chip analysis suggested that the rearrangement occurred during paternal meiosis involving both paternal chromosomes 17., (© 2013 Wiley Periodicals, Inc.)

We have observed a male and a female, sibs of non-consanguineous parents, affected by severe myopia with characteristic retinal defects and Dandy-Walker variant. The peculiarity of the retinopathy consists of pathological myopia with anomalous vitreal fenestrated membranes in the retinal periphery. We suppose that these associations may configure a new genetic syndrome.

Background: Ritscher-Schinzel syndrome (RSS) is a clinically heterogeneous disorder characterised by distinctive craniofacial features in addition to cerebellar and cardiac anomalies. It has been described in different populations and is presumed to follow autosomal recessive inheritance. In an effort to identify the underlying genetic cause of RSS, affected individuals from a First Nations (FN) community in northern Manitoba, Canada, were enrolled in this study., Methods: Homozygosity mapping by SNP array and Sanger sequencing of the candidate genes in a 1Mb interval on chromosome 8q24.13 were performed on genomic DNA from eight FN RSS patients, eight of their parents and five unaffected individuals (control subjects) from this geographic isolate., Results: All eight patients were homozygous for a novel splice site mutation in KIAA0196. RNA analysis revealed an approximate eightfold reduction in the relative amount of a KIAA0196 transcript lacking exon 27. A 60% reduction in the amount of strumpellin protein was observed on western blot., Conclusions: We have identified a mutation in KIAA0196 as the cause of the form of RSS characterised in our cohort. The ubiquitous expression and highly conserved nature of strumpellin, the product of KIAA0196, is consistent with the complex and multisystem nature of this disorder.

Trisomy 9 is a lethal chromosomal abnormality that rarely progresses beyond the second trimester of pregnancy. Multiple central nervous system anomalies, including bifid choroid plexus, ventriculomegaly, and Dandy-Walker malformation, associated with multicystic dysplastic kidney disease in a trisomy 9 fetus are reported. The prenatal ultrasound diagnosis has been aided by novel three-dimensional ultrasound software., (Copyright © 2012 Wiley Periodicals, Inc.)

We performed whole-exome sequencing of a family with autosomal dominant Dandy-Walker malformation and occipital cephaloceles and detected a mutation in the extracellular matrix (ECM) protein-encoding gene NID1. In a second family, protein interaction network analysis identified a mutation in LAMC1, which encodes a NID1-binding partner. Structural modeling of the NID1-LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicate the ECM in the pathogenesis of Dandy-Walker spectrum disorders., (© 2013 WILEY PERIODICALS, INC.)

Mutations affecting the integrity and function of cilia have been identified in various genes over the last decade accounting for a group of diseases called ciliopathies. Ciliopathies display a broad spectrum of phenotypes ranging from mild manifestations to lethal combinations of multiple severe symptoms and most of them share cystic kidneys as a common feature. Our starting point was a consanguineous pedigree with three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas and developmental heart disease. By genome-wide linkage analysis, we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9 that encodes a kinase involved in ciliary dynamics and cell cycle progression. Missense mutations in NEK8/NPHP9 have been identified in juvenile cystic kidney jck mice and in patients suffering from nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay. In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype. We furthermore linked NEK8 with NPHP3, another NPH protein known to cause a very similar phenotype in case of null mutations. Both proteins interact and activate the Hippo effector TAZ. Taken together, our study demonstrates that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype.

In this study, a case of Dandy-Walker variant syndrome associated with trisomy 22 in a 17-year-old man is described. This is the first account of this combination in a person surviving into adulthood, and the neuropsychological and behavioural presentation is described in detail and a clinical formulation is presented for the benefit of researchers and clinicians.

Background: The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM., Methods and Results: Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q., Conclusions: Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS.

The combination of Dandy-Walker malformation, other central nervous system anomalies, and postaxial polydactyly has been reported previously in two pairs of siblings. We propose the name 'Pierquin syndrome' for this combination and we report a new patient with this disorder.

Objective: Fetal pathology aims to recognize syndromal patterns of anomalies for goal-directed mutation analyses, genetic counseling, and early prenatal diagnosis in consecutive pregnancies. Here, we report on five fetuses with Peters' plus syndrome (PPS) from two distinct families aborted after prenatal ultrasound diagnosis of hydrocephaly., Method: We performed fetal autopsies and molecular analyses., Results: Among 44 fetuses with prenatally diagnosed hydrocephaly, four fetuses of 16 to 21 gestational weeks presented with additional cleft lip/palate and/or agenesis of the corpus callosum. Other features were growth retardation, hypertelorism, anomalies of the eyes, in part consistent with Peters' anterior chamber anomalies, mild brachymelia, brachydactyly, and also internal anomalies. Suspected PPS was confirmed by detection of B3GALTL mutation in these four fetuses and in one additional sib fetus, revealing homozygosity for the common c.660 + 1G > A donor splice site mutation in intron 8., Conclusions: Autosomal-recessive PPS has not yet been diagnosed prenatally. We want to alert ultrasonographers to the diagnosis of this disorder in growth-retarded fetuses with (recurrent) hydrocephaly, agenesis of the corpus callosum, and cleft lip/palate and stress the more severe fetal manifestation, describing a first such case with additional Dandy-Walker cyst and occult meningoencephalocele., (© 2012 John Wiley & Sons, Ltd.)

Purpose: The 6p25 deletion syndrome is a rare disorder characterized by Dandy-Walker malformation, congenital heart defects, developmental delay, dysmorphic facial features, and malformations of the anterior segment of the eye with a risk for glaucoma. Here we report a child harboring a cryptic de novo 6p25 deletion, bilateral optic disc coloboma and characteristic anterior segment anomalies. We review reported ophthalmic findings in patients with this syndrome., Materials and Methods: Retrospective case review of a 4-day-old male with Dandy-Walker malformation and cardiac defects who was referred with a suspected diagnosis of iris coloboma., Results: The ophthalmic examination showed bilateral corectopia associated with posterior embryotoxon. Fundus examination revealed bilateral optic disc excavation, which was diagnosed as colobomatous because of its configuration and stability over time. Because of the association of posterior embryotoxon with Dandy-Walker malformation, a terminal 6p deletion syndrome was clinically suspected. Array comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies revealed a 3.2 Mb deletion at 6p25.2p25.3 including the FOXC1 gene. Neither unaffected parent carried this deletion., Conclusions: Optic disc colobomas may be found in patients carrying a 6p25 deletion. This has the potential to confound assessment of affected children for glaucoma and intracranial hypertension.

FOXC1 deletion, duplication, and mutations are associated with Axenfeld-Rieger anomaly, and Dandy-Walker malformation spectrum. We describe the clinical history, physical findings, and available brain imaging studies in three fetuses, two children, and one adult with 6p25 deletions encompassing FOXC1. Various combinations of ocular and cerebellar malformations were found. In all three fetuses, necropsy including detailed microscopic assessments of the eyes and brains showed ocular anterior segment dysgenesis suggestive of Axenfeld-Rieger anomaly. Five 6p25 deletions were terminal, including two derived from inherited reciprocal translocations; the remaining 6p25 deletion was interstitial. The size and breakpoints of these deletions were characterized using comparative genomic hybridization arrays. All six deletions included FOXC1. Our data confirm that FOXC1 haploinsufficiency plays a major role in the phenotype of patients with 6p25 deletions. Histopathological features of Axenfeld-Rieger anomaly were clearly identifiable before the beginning of the third-trimester of gestation., (Copyright © 2012 Wiley Periodicals, Inc.)

We present three foetuses with Dandy-Walker malformation, intra-uterine growth restriction and multiple congenital abnormalities, who were studied by array-based comparative genomic hybridization and revealed a novel locus on chromosome 7p21.3. The association of pure chromosome 7p aberrations with Dandy-Walker malformation has rarely been reported. The present study suggests that the critical region associated with Dandy-Walker malformation is restricted to 7p21.3, including the cerebellar disease associated genes NDUFA4 and PHF14., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate genetic etiology of Dandy-Walker syndrome with array-based comparative genomic hybridization (array-CGH)., Methods: Eight fetuses with Dandy-Walker malformations but normal karyotypes by conventional cytogenetic technique were selected. DNA samples were extracted and hybridized with Affymetrix cytogenetic 2.7 M arrays by following the manufacturer's standard protocol. The data were analyzed by special software packages., Results: By using array-CGH technique, common deletions and duplication on chromosome 7p21.3 were identified in three cases, within which were central nervous system disease associated genes NDUFA4 and PHF14., Conclusion: Copy number variations (CNVs) of chromosome 7p21.3 region are associated with Dandy-Walker malformations which may be due to haploinsufficiency or overexpression of NDUFA4 and PHF14 genes.

Ritscher-Schinzel also known as cranio-cerebello-cardiac (3C) syndrome is a very rare clinical entity. The striking features of this syndrome are cerebellar, cardiac and craniofacial abnormalities. Life threatening features of this syndrome are generally associated with cardiac abnormalities. We here present prolonged respiratory problems due to pulmonary hypertension in a preterm baby with Ritscher-Schinzel syndrome.

Dandy-Walker malformation (DWM) is the most common human cerebellar malformation, characterized by hypoplasia of the cerebellar vermis, cystic dilation of the fourth ventricle, and an enlarged posterior fossa with upward displacement of the lateral sinuses, tentorium, and torcular. Although its pathogenesis is not completely understood, there are several genetic loci related to DWM as well as syndromic malformations and congenital infections. Dandy-Walker malformation is associated with other central nervous system abnormalities, including dysgenesis of corpus callosum, ectopic brain tissue, holoprosencephaly, and neural tube defects. Hydrocephalus plays an important role in the development of symptoms and neurological outcome in patients with DWM, and the aim of surgical treatment is usually the control of hydrocephalus and the posterior fossa cyst. Imaging modalities, especially magnetic resonance imaging, are crucial for the diagnosis of DWM and distinguishing this disorder from other cystic posterior fossa lesions. Persistent Blake's cyst is seen as a retrocerebellar fluid collection with cerebrospinal fluid signal intensity and a median line communication with the fourth ventricle, commonly associated with hydrocephalus. Mega cisterna magna presents as an extraaxial fluid collection posteroinferior to an intact cerebellum. Retrocerebellar arachnoid cysts frequently compress the cerebellar hemispheres and the fourth ventricle. Patients with DWM show an enlarged posterior fossa filled with a cystic structure that communicates freely with the fourth ventricle and hypoplastic vermis. Comprehension of hindbrain embryology is of utmost importance for understanding the cerebellar malformations, including DWM, and other related entities.

Neonatal onset of carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive, often lethal disorder of the mitochondrial beta-oxidation of long-chain fatty acids. It is a rare multiorgan disease which includes hypoketotic hypoglycemia, severe hepatomuscular symptoms, cardiac abnormalities, seizures and lethargy, as well as dysmorphic features. Until now, only 22 affected families have been described in the literature. An increasing number of mutations are being identified in the CPT2 gene, with a distinct genotype-phenotype correlation in most cases. Herein we report a new case of neonatal CPT II deficiency associated with Dandy-Walker syndrome and sudden death at 13 days of life. CPT II deficiency was suggested by acylcarnitine analysis of dried-blood on filter paper in the expanded newborn screening. Genetic analysis of the CPT2 gene identified the presence of a previously described mutation in homozygosity (c.534_558del25bpinsT). All lethal neonatal CPT II deficiency patients previously described presented severe symptoms during the first week of life, although this was not the case in our patient, who remained stable and without apparent vital risk during the first 11 days of life. The introduction of tandem mass spectrometry to newborn screening has substantially improved our ability to detect metabolic diseases in the newborn period. This case illustrates the value of expanded newborn screening in a neonate with an unusual clinical presentation, combining hydrocephalus and sudden death, that might not commonly lead to the suspicion of an inborn error of metabolism., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Fibroblast growth factors (FGFs) are important signaling molecules which act during early vertebrate central nervous system development. FGF17, together with FGF8, is a key factor in the patterning of the mid-hindbrain region with a complex picture of spatiotemporal gene expression during the various stages of cerebellar development. Disruption or reduced expression of fgf17 in mice has been associated with cerebellar vermis abnormalities. We have identified a de novo 2.3-Mb deletion of chromosome 8p21.2-p21.3 in a girl with severe growth retardation, seizures, and classical Dandy-Walker malformation. Analysis of gene expression in blood lymphocytes and skin fibroblasts revealed markedly reduced levels of FGF17, which is located 1 Mb from the proximal deletion breakpoint. This is the first report of a human cerebellar malformation associated with transcriptional downregulation of the FGF17 gene.

Ritscher-Schinzel (cranio-cerebello-cardiac, 3C) syndrome is a multiple congenital anomaly syndrome that is considered to be autosomal recessive although no genetic defect has yet been identified. In a consanguineous Saudi family, we have identified four patients who meet the diagnostic criteria of 3C syndrome and who also have alopecia, camptodactaly and significant renal involvement. Interestingly, two otherwise normal female siblings have unilateral renal agenesis only. This report expands the phenotypic spectrum of 3C syndrome., (Copyright © 2011 Wiley-Liss, Inc.)

We report a case carrying a de novo interstitial deletion of chromosome 3q22-q25. The clinical phenotype of this case included blepharophimosis/ptosis/epicanthus inversus syndrome, Dandy-Walker malformation, and global developmental delay. Contiguous heterozygous deletion of FOXL2, ATR, ZIC1, and ZIC4 was postulated as the causative mechanism of the clinical phenotype. The association of blepharophimosis, ptosis, and epicanthus inversus syndrome with developmental delay or mental retardation may be an indication for the use of brain imaging and chromosomal analysis capable of detecting chromosomal rearrangements encompassing several candidate genes.

Complex chromosome rearrangements are constitutional structural rearrangements involving three or more chromosomes or having more than two breakpoints. These are rarely seen in the general population but their frequency should be much higher due to balanced states with no phenotypic presentation. These abnormalities preferentially occur de novo during spermatogenesis and are transmitted in families through oogenesis.Here, we report a de novo complex chromosome rearrangement that interests eight chromosomes in eighteen-year-old boy with an abnormal phenotype consisting in moderate developmental delay, cleft palate, and facial dysmorphisms.Standard G-banding revealed four apparently balanced translocations [corrected] involving the chromosomes 1;13, 3;19, 9;15 and 14;18 that appeared to be reciprocal. Array-based comparative genomic hybridization analysis showed no imbalances at all the breakpoints observed except for an interstitial microdeletion on chromosome 15. This deletion is 1.6 Mb in size and is located at chromosome band 15q14, distal to the Prader-Willi/Angelman region. Comparing the features of our patient with published reports of patients with 15q14 deletion this finding corresponds to the smallest genomic region of overlap. The deleted segment at 15q14 was investigated for gene content.

Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh-downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1(+/-);Zic4(+/-) background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1(-/-);Zic4(-/-) mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1(+/-);Zic4(+/-);Shh(+/-), we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM.

The Klippel-Feil deformity is a complex of osseous and visceral anomalies, which include low hairline, platybasia, fused cervical vertebrae with a short neck, and deafness. Associated central nervous system abnormalities include occipital cephalocele, Chiari I malformation, syrinx, microcephaly, and hydrocephalus. Herein, we report a case with Klippel-Feil syndrome and Dandy-Walker malformation.

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation., (Copyright © 2010 Wiley-Liss, Inc.)

Trisomy 18 is the second most common chromosomal syndrome and has multiple dysmorphic features. However, ocular findings in trisomy 18 are rarely reported. Retinal folds are the most common ocular finding described to date, although retinal hypopigmentation, dysplasia, and areas of hemorrhage and gliosis are also found in trisomy 18. Dandy-Walker syndrome is a brain malformation that has been reported in association with numerous chromosomal abnormalities, although it has rarely been reported in association with trisomy 18. Here, we present a case of trisomy 18 with ocular pathology and variant of Dandy-Walker syndrome, a combination that has not previously been reported., (Copyright © 2010 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Objective: To present the prenatal diagnosis and molecular cytogenetic characterization of de novo partial trisomy 7p (7p15.3→pter) and partial monosomy 13q (13q33.3→qter) associated with Dandy-Walker malformation (DWM), abnormal skull development, microcephaly and multiple congenital anomalies., Materials, Methods and Results: A 42-year-old woman, gravida 6, para 1, was referred for amniocentesis at 18 weeks of gestation because of her advanced maternal age. Amniocentesis revealed an aberrant derivative chromosome 13, or der(13). The parental karyotypes were normal. Spectral karyotyping showed that the der(13) was derived from a translocation of chromosomes 7 and 13. Fluorescence in situ hybridization using subtelomeric probes revealed three signals of 7pTEL and only one signal of 13qTEL, indicating a translocation between 7p and 13q in the der(13). Array-based comparative genomic hybridization demonstrated partial trisomy 7p (7p15.3-p22.3) and partial monosomy 13q (13q33.3-q34). The karyotype was 46,XY,der(13)t(7;13)(p15.3;q33.3). Polymorphic DNA marker analysis revealed the paternal origin of the aberrant chromosome. Level II ultrasound at 24 weeks of gestation revealed microcephaly, an irregular-shaped skull, DWM, nuchal edema and transposition of the great arteries., Conclusion: Spectral karyotyping, fluorescence in situ hybridization and array-based comparative genomic hybridization are useful for prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 7p (7p15.3→pter) and partial monosomy 13q (13q33.3→qter) can be associated with DWM, microcephaly, abnormal skull development, nuchal edema and cardiovascular defects on prenatal ultrasound., (Copyright © 2010 Taiwan Association of Obstetric & Gynecology. Published by Elsevier B.V. All rights reserved.)

Coffine-Siris syndrome or "fifth digit" syndrome is a multiple congenital anomaly-mental retardation syndrome with severe developmental delay, coarse facial features, hirsutism and absent fifth fingernails or toenails or fifth distal phalanges. The etiology of this syndrome remains uncertain. Here we report a stillborn male baby born from consanguineous parents who might represent a very severe form of Coffine-Siris syndrome with cardiac defect and multiple brain malformations including corpus callosum agenesis and Dandy Walker malformation. To the best of our knowledge, it is the first case leading to intrauterine death. Karyotype and array comparative genomic hybridization were normal; these results give additional support to mendelian inheritance for this syndrome. In our family, the most likely mode of inheritance is autosomal recessive and the recurrence is probably as high as 25%., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: Although pineoblastoma is the main brain abnormality associated with hereditary retinoblastoma, recent studies suggest an association with pineal cysts. This association is important because some pineoblastomas mimic pineal cysts. If there is a relationship, then radiologists should be aware of it because diagnostic confusion is possible. Mental retardation and congenital brain anomalies are also reported in patients with retinoblastoma, mostly in combination with 13q deletion syndrome. In this retrospective study, the presence of brain abnormalities on MR images in a large group of consecutive patients with retinoblastoma is evaluated., Materials and Methods: Brain MR images of 168 patients with retinoblastoma from 1989 to 2009 were evaluated by 2 radiologists for tumors, structural anomalies, myelinization, and coincidental findings. Clinical records were reviewed for laterality, heredity, and the presence of the 13q deletion syndrome., Results: The hereditary group (patients with bilateral and unilateral proved RB1-germline mutation) included 90 (54%) of 168 patients. Seven patients had 13q deletion syndrome. Normal findings on brain MR images were seen in 150 (89%) patients. Five pineoblastomas were detected, all in patients with hereditary retinoblastoma (5.5% in the hereditary subgroup). Nine pineal cysts were detected (2.2% in the hereditary subgroup). Corpus callosum agenesis was found in 1 patient and a Dandy-Walker variant in 1 patient, both in combination with 13q deletion syndrome., Conclusions: Pineoblastoma is associated with hereditary retinoblastoma, and structural brain abnormalities are restricted to patients with the 13q deletion syndrome. The incidence of pineal cysts in patients with retinoblastomas is similar to that in healthy children and is not associated with hereditary retinoblastoma.

We report on a girl with mild dysmorphic facial features, Dandy-Walker malformation (DWM), iris coloboma, profound hearing loss, and hyperlaxity of skin and joints, whose karyotype is 46,XX,t(6;13)(q23;q32)dn and who has a cryptic imbalance at the 13q32 translocation breakpoint assessed by array-CGH. Our patient has many clinical manifestations in common with those of the previously reported cases of 13q32 deletions, which suggests that at least part of the abnormal phenotype is probably due to the imbalance. The recurrent finding of DWM among patients with 13q deletions has led to the suggestions that candidate gene/s for its development are on chromosome 13. We describe the smallest 13q deletion associated to DWM, which allows further narrowing of the previously established critical region for this brain malformation to 13q32.2-32.3. Among the few genes of the deleted region, ZIC2 and ZIC5 seem the most plausible candidates, which is in keeping with some previous reports. This work also illustrates the usefulness of array-CGH platforms in the identification of cryptic imbalances in carriers of apparently balanced rearrangements with abnormal phenotypes.

We report on two sibs with a lethal form of bone dysplasia with distinctive skeletal findings including rhizomelic and mesomelic limb shortening, hooked clavicles, dumbbell femurs, and absence of talus and calcaneus ossification. Other clinical features include Dandy-Walker malformation, congenital heart defects, joint contractures, genital hypoplasia, and distinctive facial features. These sibs appear to have a previously undescribed skeletal dysplasia, which is most likely inherited in an autosomal recessive fashion.

Unlabelled: Unbalanced translocation 6p/16q in one fetus is a very rare event and the prenatal sonographic findings have never been published before. We will give a short overview of the literature along with a case report focussing on prenatal ultrasound features and molecular cytogenetic analysis., Case Description: A 21-year-old primigravid woman presented with a singleton pregnancy at 19 weeks' gestation. The fetus revealed a mild hydrocephalus, a ventricular septal defect (VSD), a Dandy-Walker malformation as well as an intrauterine growth retardation (IUGR) and limb anomalities. MLPA analysis from amniotic fluid cells showed an unbalanced translocation from the subtelomeric region of chromosome 6p to the subtelomeric region of chromosome 16q. Karyotype of the fetus was 46, XX.ishder(6)t(6;16)(p2?5;q?13)(pVYS246A+, pVYS228B-, pVYS229A+). Despite the karyotype the mother decided not to interrupt pregnancy. The fetus died in utero within the 39th week of gestation and was delivered vaginally after labour induction, with a birth weight of 1815g. Prenatal FISH and MLPA studies can be very important to help outline the chromosomal area of deletion and duplication and the sonographic findings forebode the cytogenetic region of interest. Subsequent to the processing of the case, a complete Medline search was conducted to review previous cases with similar genetic alterations., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Three cases of Usher syndrome associated with a variant of Dandy-Walker malformation in three siblings from consanguineous Turkish parents are described. The siblings had retinitis pigmentosa and hearing loss. Two of the siblings also had mental retardation, which is not a constant finding in Usher syndrome. Dandy-Walker malformation might have contributed to the mental retardation in two of these patients and might be a coincidental finding with Usher syndrome., (Copyright 2010, SLACK Incorporated.)

Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans. Both environmental and genetic factors have been identified to play a role in the HPE phenotype. Previous studies of the genetic bases of HPE have taken a phenotype-first approach by examining groups of patients with HPE for specific mutations or deletions in known or candidate HPE genes. In this study, we characterized the presence or absence of HPE or a microform in 136 individuals in which microarray-based comparative genomic hybridization (aCGH) identified a deletion of one of 35 HPE loci. Frank holoprosencephaly was present in 11 individuals with deletions of one of the common HPE genes SHH, ZIC2, SIX3, and TGIF1, in one individual with a deletion of the HPE8 locus at 14q13, and in one individual with a deletion of FGF8, whereas deletions of other HPE loci and candidate genes (FOXA2 and LRP2) expressed microforms of HPE. Although individuals with deletions of other HPE candidates (DISP1, LSS, HHIP, SMO, BMP4, CDON, CDC42, ACVR2A, OTX2, and WIF1) had clinically significant features, none had frank HPE or a microform. A search for significant aCGH findings in individuals referred for testing for HPE revealed a novel association of a duplication involving GSK3B at 3q13.33 with HPE or a microform, seen in two unrelated individuals.

The Keratitis-Ichthyosis-Deafness syndrome (KIDS) is an autosomal dominant ectodermal dysplasia characterized by ocular, skin, and ear anomalies, including keratitis, palmoplantar keratoderma, and congenital hearing loss. Most cases are due to mutations in the GJB2 gene encoding connexin 26. The Dandy-Walker malformation (DWM) is a developmental anomaly of the midline of the cerebellum with complete or partial agenesis of the vermis and cystic dilatation of the fourth ventricle. The association of KID syndrome with DWM has been reported a few times, but thought to be coincidental. We report 4 additional patients with KIDS and DWM, supporting the possibility that this is an association and not a coincidental finding. This also suggests that the GJB2 gene may have a role in other cases with DWM of, as yet, unknown etiology.

We report a case of a 23-year-old pregnant woman, who underwent amniocentesis after ultrasound (US) examination in the first trimester which revealed a nuchal translucency thickness of 2.9 mm. Cytogenetic analysis revealed complete tetrasomy of the short arm of chromosome 9. Further US evaluation in the second trimester revealed Dandy-Walker malformation, ventriculomegaly, bilateral clubfoot, lip and palate clefts, arthrogryposis and hyperechoic kidneys with bilateral pelvic dilatation. At 30 weeks of gestation, a placental abruption was noted and a Cesarean section was performed. The infant died shortly after birth. A review of previous cases of tetrasomy 9p shows that the remarkable sonographic findings are ventriculomegaly, intrauterine growth restriction, genitourinary anomaly, Dandy-Walker malformation, cleft lip/palate and limb malformation, but the association of tetrasomy 9p and increased nuchal translucency had not been reported.

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.