FIGURE 5 - uploaded by Valerio Ramieri
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The patient at 5 months showing microcephaly, brachycephaly, round face, blepharophimosis, ptosis, epicantus inversus, hypotelorism, and short neck.
Source publication
The authors present the clinical case of a 5-month-old boy, affected by multimalformative syndrome with features of microdeletion 3q syndrome. In the literature so far, the real incidence is unknown because of its rarity. The goal of this study was to describe the salient findings of this rare malformative syndrome, which needs a multidisciplinary...
Citations
... 3q deletion syndrome is a genomic disorder characterized by a great variability of phenotypes associated to the extension of deletion. The clinical features of 3q deletion syndrome range from intellectual disability, motor developmental delay, congenital heart disease, renal and gastrointestinal malformations, autism, congenital hypothyroidism, epilepsy and brain anomalies (1,2). The corpus callosum is the primary commissural region of the brain consisting of white matter tracts connecting cerebral hemispheres. ...
Chromosome 3q syndrome is a well-known genetic condition caused by interstitial deletion in the long arm of chromosome 3. The phenotype of this syndrome is variable and the great variability in the extent of these deletions leads to a wide spectrum of clinical manifestations. Terminal 12p deletion represents one of the rarest subtelomeric imbalances; patients with distal monosomy 12p present different phenotypes ranging from muscular hypotonia to autism spectrum disorders. The present study reported a prenatal diagnosis of a male fetus presenting ultrasound evidence of corpus callosum dysplasia and ventriculomegaly showing a 3q13q21.2 deletion and a 12p13.33 microdeletion paternally inherited. Among several features previously attributed to the terminal deletion of 3q, corpus callosum dysplasia and ventriculomegaly have rarely been reported together. As the 12p13.33 microdeletion in the father was associated only with muscular hypotonia and joint laxity, the involvement of terminal 12p deletions in the clinical features of the fetus was not possible to verify during the prenatal period. The present case report may provide a reference for prenatal diagnosis and genetic counseling in patients who present 3q13q21.2 deletions and 12p13.33 microdeletion.
... Again, in 2008, Sasakin-Adam et al. 2 described a case of Dandy-Walker variant with PRS. In 2011, Ramieri et al. 10 described the case of a 5-month-old boy affected by multimalformative syndrome (PRS, Dandy-Walker variant, and Seckle syndrome) with features of microdeletion 3q syndrome. ...
Pierre Robin sequence (PRS) is a condition consisting of three essential components: micrognathia or retrognathia, cleft palate, and glossoptosis. It can be part of multiple congenital anomalies. We present the case and outcome of a 3-month-old clinically stable patient who has PRS with Dandy-Walker variant – which is a rare presentation in the literature – with a large right hemispheric brain abscess, treated with multiple minimally-invasive surgical drainage procedures with adjuvant antibiotics.
Resumo
A sequência de Pierre Robin (SPR) é uma condição que consiste em três componentes essenciais: micrognatia ou retrognatia, fenda palatina e glossoptose. Pode ser parte de várias anomalias congênitas. Apresentamos o caso e a evolução de um paciente clinicamente estável de 3 meses que tem PRS com variante de Dandy-Walker – uma apresentação rara na literatura – com um grande abscesso cerebral hemisférico direito, tratado com vários procedimentos de drenagem cirúrgica minimamente invasiva com antibióticos adjuvantes.
... In humans, some cases of DWM have been reported to coexist with chromosomal abnormalities including deletion of chromosome 3q24.3 (Ramieri et al., 2011). In Eurasier dogs, a single base deletion in the very low density lipoprotein receptor (VLDLR) gene was discovered in dogs that had been diagnosed with DWLM (Gerber et al., 2015). ...
An 88.5 cm long, 12.9 kg, 3-week-old stranded male Atlantic harbour seal (Phoca vitulina concolor) presented with cerebellar ataxia, delayed postural reactions, hyperaesthesia and nystagmus. The skull was enlarged and domed. Ultrasound through a persistent fontanelle in the frontal bone revealed hydrocephalus. Magnetic resonance imaging showed diffuse enlargement of the ventricular system, an absent cerebellar vermis, hypertrophy of the choroid plexus of the fourth ventricle and enlargement of the caudal fossa. Throughout rehabilitation, the seal failed to achieve milestones critical for successful release or placement in a managed care facility, including the ability to feed independently and haul out. Three months into rehabilitation it began to regurgitate and staff had difficulty administering food to the seal. The seal was euthanized due to a poor prognosis. Post-mortem examination confirmed a) aplasia of the dorsal cerebellar vermis and hypoplasia of the most dorsal portions of the right and left cerebellar hemispheres, b) severe, diffuse, congenital communicating hydrocephalus, and c) aplasia of the interthalamic adhesion and corpus callosum. This case represents the first report of Dandy–Walker-like malformation (DWLM) in a marine mammal and illustrates the importance of advanced imaging and thorough post-mortem examination in free-ranging pinnipeds that strand with evidence of neurological disease.
... In addition, some subchromosomal microdeletions and microduplications had recurrent CNVs, such as 1p36, 3q, 11q23, and 22q11.2 deletion syndromes, with conserved breakpoints that were almost identical even in unrelated individuals [28][29][30][31]. In this study, we found 13 (36.11%) ...
Background
Noninvasive prenatal testing (NIPT) for fetal aneuploidies by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a first-tier aneuploidy screening test in clinical practices. With the development of whole-genome sequencing technology, small subchromosomal deletions and duplications that could not be detected by conventional karyotyping are now able to be detected with NIPT technology.
Methods
In the present study, we examined 8141 single pregnancies with NIPT to calculate the positive predictive values of each of the chromosome aneuploidies and the subchromosomal microdeletions and microduplications.
Results
We confirmed that the positive predictive values (PPV) for trisomy 13, trisomy 18, trisomy 21, and sex chromosome aneuploidy were 14.28%, 60%, 80%, and 45.83%, respectively. At the same time, we also found 51 (0.63%) positive cases for chromosomal microdeletions or microduplications but only 13 (36.11%) true-positive cases. These results indicate that NIPT for trisomy 21 detection had the highest accuracy, while accuracy was low for chromosomal microdeletion and microduplications.
Conclusions
Therefore, it is very important to improve the specificity, accuracy, and sensitivity of NIPT technology for the detection of subchromosomal microdeletions and microduplications.
... 19 Multiple types of neoplasms and neurocutaneous disorders have also been observed in variable frequencies. 20,21 In addition, other genetic syndromes 22 and chromosomal anomalies, such as 3q Syndrome (the location of the DWS-affected genes, known as ZIC1 and ZIC4) 1,23 and trisomy 18, 24 may coexist. However, despite many observations, the sporadic nature of the disease and the expectation that it is now relatively well understood in Europe and North America have impeded research in large case series to explore clinically significant comorbidities, and most of the above observations are derived from low-evidence case reports. ...
Objective:
Dandy-Walker syndrome (DWS) is a rare neurologic multi-entity malformation. This review aimed at reporting its main nonneurologic comorbidities.
Methods:
Following PRISMA guidelines, search in Medline was conducted (2000-2014, keyword: dandy-walker). Age, sex, country, DWS type, consanguinity or siblings with DWS, and recorded coexistent conditions (by ICD10 category) were extracted for 187 patients (46.5% male, 43% from Asia) from 168 case reports.
Results:
Diagnosis was most often set in <1 year old (40.6%) or >12 years old (27.8%). One-third of cases had a chromosomal abnormality or syndrome (n = 8 PHACE), 27% had a cardiovascular condition (n = 7 Patent Ductus Arteriosus), 24% had a disease of eye and ear (n = 9 cataract); most common malignancy was nephroblastoma (n = 8, all Asian). Almost one-fifth had a mental illness diagnosis; only 6.4% had mild or severe intellectual disability.
Conclusion:
The spread of comorbidities calls for early diagnosis and multidisciplinary research and practice, especially as many cases remain clinically asymptomatic for years.
... In Figure 2 these seven patients with clinical diagnosis of WS and additional cases of 3q deletion, without a clinical diagnosis of WS are shown along with our case to aid in narrowing the WS critical region Lim et al., 2011;Ramieri et al., 2011;Weber et al., 2011]. Patient 12 has a deletion that distally overlaps with ours, but apparently no clinical diagnosis of WS . ...
We report on a patient with a 6.5 Mb interstitial de novo deletion in 3q24q25.2, characterized by array CGH. The patient is a 4-year and 2-month-old girl, who presented to us with mild developmental delay, absence of language, facial dysmorphism, hirsutism, strabismus, and Dandy–Walker Malformation. The main clinical signs typical of WS (Wisconsin syndrome) are evident in the patient. The molecular mapping of WS in 3q23q25 allowed geneticists to define the syndrome more accurately. Comparing the present patient's phenotype with that of cases with a molecular characterization so far reported, it was possible to narrow the critical region for WS to an interval of 750 Kb, where two genes (MBNL1 and TMEM14E) are harbored. The potential role of MBNL1 in causing the WS phenotype is discussed.
... þ ¼ present, À ¼ absent.malformation.6,18 There have subsequently been at least 7 additional cases reported with features of Dandy-Walker malformation and associated 3q deletions affecting ZIC1 and ZIC4.[4][5][19][20][21][22] A comparison of the 15 total cases is presented inTable 1. ...
Interstitial deletions affecting the long arm of chromosome 3 have been associated with a broad phenotype. This has included the features of blepharophimosis–ptosis–epicanthus inversus syndrome, Dandy-Walker malformation, and the rare Wisconsin syndrome. The authors report a young female patient presenting with features consistent with all 3 of these syndromes. This has occurred in the context of a de novo 3q22.3q24 microdeletion including FOXL2, ZIC1, and ZIC4. This patient provides further evidence for the role of ZIC1 and ZIC4 in Dandy-Walker malformation and is the third reported case of Dandy-Walker malformation to have associated corpus callosum thinning. This patient is also only the seventh to be reported with the rare Wisconsin syndrome phenotype.
... In another patient, in which the deletion did not contain ZIC1 and ZIC4, the expression level of both genes was found to be halved, suggesting a position effect [6]. Following this report, at least six additional cases with features of the DWM spectrum have been published, who carried a 3q chromosomal deletion encompassing the ZIC1 and ZIC4 genes [7][8][9][10][11][12]. ...
... The three patients described here were found to carry overlapping deletions of the long arm of chromosome 3. We performed SNP array analysis also in a 3q deleted patient with DWM and blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), whose detailed clinical features have been recently published [8]. This patient was found to carry a 19.2 Mb deletion of the region 3q22.1q25.1, from 132381260 bp (CN_995516) to 151675126 bp (CN_998137), including the FOXL2, ZIC1 and ZIC4 genes. ...
... Here we report two novel patients (CCM067 and CCM095) with a severe DWM phenotype and large deletions encompassing both ZIC1 and ZIC4 genes. Furthermore, six additional DWM patients with 3q deletions have been published since the original report [7][8][9][10][11][12], defining a critical region clearly implicated in DWM pathogenesis (DWM-CR in Figure 3). In a patient (LR01-325) [6], whose deletion did not encompass ZIC1-ZIC4, their expression levels were significantly reduced compared to controls, implying a position effect, possibly exerted by distally located regulatory elements. ...
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.
... In addition to the 22 cases of interstitial 3q deletions that Ramieri et al. (2011) cited, there are at least four more cases with deletions limited to 3q13.1-q13.33 (Lawson-Yuen et al., 2006;Shimojima et al., 2009;Simovich et al., 2008), and 19 more cases involving at least part of 3q21-q23 (with some extending to 3q13) (Almenrader et al., 2008;Arai et al., 1982;Brueton et al., 1989;Callier et al., 2009;Croft and Turnpenny, 2008;De Baere et al., 2001, 2005Engelen et al., 2002;Genuardi et al., 1994;Jenkins et al., 1985;Mackie Ogilvie et al., 1998;McMorrow et al., 1986;Okada et al., 1987;Sargent et al., 1985;Tohyama et al., 2010;Willemsen et al., 2010;Zahanova et al., 2012;Zhou et al., 2010), with a few more microdeletions associated with apparently balanced translocations. ...
We describe a boy with a de novo deletion of 15.67 Mb spanning 3q22.1q24. He has bilateral micropthalmia, ptosis, cleft palate, global developmental delay and brain, skeletal and cardiac abnormalities. In addition, he has bilateral inguinal hernia and his right kidney is absent. We compare his phenotype with seven other patients with overlapping and molecularly defined interstitial 3q deletions. This patient has some phenotypic features that are not shared by the other patients. More cases with smaller deletions defined by high resolution aCGH will enable better genotype-phenotype correlations and prioritizing of candidate genes for the identification of pathways and disease mechanisms.
Background
To evaluate the accuracy and feasibility of noninvasive prenatal testing (NIPT) according to the results of NIPT and pregnancy outcomes with different indications.
Methods
Between October 2014 and December 2020, 20,626 pregnant women who received NIPT were included in this study. The positive predictive value (PPV) of trisomy 21, 18, and 13 (T21, T18, T13), sex chromosome abnormalities (SCAs), other chromosomal aneuploidies, and chromosomal microdeletion/microduplication were calculated. The positive results of NIPT were confirmed by amniocentesis, Karyotype analysis, and chromosome microarray analysis (CMA).
Results
In total, 263 positive cases (263/20,626, 1.28%) were detected by NIPT, of which T21, T18, and T13 were 69, 26, and 9 cases, respectively. Sex chromosome abnormalities (SCAs), other chromosomal aneuploidies, and copy number variants (CNVs) were 69, 12, and 38 cases, respectively. There were true positive in 49 of T21, 13 of T18, 1 of T13, 32 of SCAs, 1 of other chromosomal aneuploidies, and 15 of CNVs. The NIPT sensitivity of T21, T18, T13, SCAs, other chromosomal aneuploidies, and CNVs was all 100%, the specialty was 99.90%, 99.94%, 99.96%, 99.82%, 99.95%, 99.89%, and the PPV was 71.01%, 50.00%, 11.11%, 46.38%, 8.33%, 39.47%, respectively. The PPV was high in T21, moderate in T18 and SCAs, and low in T13 and other chromosomal abnormalities.
Conclusion
NIPT has high accuracy, specificity and and can effectively avoid the occurrence of birth defects, but it cannot replace prenatal diagnosis. The accuracy, specificity, and sensitivity of NIPT in detecting sex chromosomes, chromosome microdeletion/microduplication, and other chromosomal abnormalities should be improved.
