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Find video protocols related to scientific articles indexed in Pubmed.
CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases.
Am. J. Med. Genet. A
PUBLISHED: 08-14-2014
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Mowat-Wilson syndrome (MWS) is characterized by moderate to severe intellectual disability and distinctive facial features in association with variable structural congenital anomalies/clinical features including congenital heart disease, Hirschsprung disease, hypospadias, agenesis of the corpus callosum, short stature, epilepsy, and microcephaly. Less common clinical features include ocular anomalies, craniosynostosis, mild intellectual disability, and choanal atresia. These cases may be more difficult to diagnose. In this report, we add 28 MWS patients with molecular confirmation of ZEB2 mutation, including seven with an uncommon presenting feature. Among the "unusual" patients, two patients had clinical features of charge syndrome including choanal atresia, coloboma, cardiac defects, genitourinary anomaly (1/2), and severe intellectual disability; two patients had craniosynostosis; and three patients had mild intellectual disability. Sixteen patients have previously-unreported mutations in ZEB2. Genotype-phenotype correlations were suggested in those with mild intellectual disability (two had a novel missense mutation in ZEB2, one with novel splice site mutation). This report increases the number of reported patients with MWS with unusual features, and is the first report of MWS in children previously thought to have CHARGE syndrome. These patients highlight the importance of facial gestalt in the accurate identification of MWS when less common features are present.
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Subthreshold psychotic symptoms in 22q11.2 deletion syndrome.
J Am Acad Child Adolesc Psychiatry
PUBLISHED: 06-19-2014
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Chromosome 22q11.2 deletion syndrome (22q11DS) confers 25% risk for psychosis and is an invaluable window for understanding the neurobiological substrate of psychosis risk. The Structured Interview for Prodromal Syndromes (SIPS) is well validated in nondeleted populations for detecting clinical risk but has only recently been applied to 22q11DS. We assessed the largest 22q11DS cohort to date and report on SIPS implementation and symptoms elicited.
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Perioperative Risk Factors in Patients With 22q11.2 Deletion Syndrome Requiring Surgery for Velopharyngeal Dysfunction.
Cleft Palate Craniofac. J.
PUBLISHED: 05-09-2014
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Objective :? To determine the prevalence of cardiac, cervical spine, and carotid artery abnormalities in patients with 22q11.2 deletion syndrome (22q11.2DS) undergoing surgery for velopharyngeal dysfunction (VPD), associations between the presence of these abnormalities, and whether these abnormalities caused changes in surgical management or perioperative complications. Design :? Retrospective review. Setting :? Tertiary pediatric hospital. Patients :? Seventy patients with 22q11.2DS with complete preoperative cervical vascular and spine imaging and cardiac evaluation between 1998 and 2011. Main Outcome Measures :? Incidence of cardiac, cervical spine, and vascular abnormalities; related perioperative complications; and resulting changes in surgical, anesthetic, or perioperative management plan. Results :? Cardiac abnormalities occurred in 45 patients (64.3%), and 8 patients required cardiac anesthesia. Thirty-eight patients (54.3%) had at least one vascular abnormality of the neck, and 14% had medial deviation of the internal carotid artery. Surgery was not performed in one patient, and the surgical plan was altered in three patients because of carotid anomalies. Cervical spine abnormalities were found in 24 patients (34.3%); 8 patients demonstrated radiographic evidence of cervical instability and were treated with spinal precautions during surgery. The presence of one anomaly was not predictive of any other finding, and there were no complications related to the heart, cervical spine, or carotid arteries. Conclusions :? Anomalies of the heart, cervical spine, and cervical vasculature occur frequently in 22q11.2DS, vary drastically in severity, and are impossible to predict based on other features of the syndrome. Preoperative diagnosis of these comorbidities with routine imaging can minimize the risk of avoidable surgical complications.
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22q11.2 Deletion syndrome and obstructive sleep apnea.
Int. J. Pediatr. Otorhinolaryngol.
PUBLISHED: 03-02-2014
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Otolaryngologic problems are common in the 22q11.2 deletion syndrome (DS) population. Structural anomalies and retrognathia may predispose these patients to obstructive sleep apnea (OSA). The current association of OSA in this population is not defined.
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Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome.
Am J Psychiatry
PUBLISHED: 03-01-2014
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Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants.
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Patient genotypes impact survival after surgery for isolated congenital heart disease.
Ann. Thorac. Surg.
PUBLISHED: 02-21-2014
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Survival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children.
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Neurodevelopmental outcomes in preschool survivors of the Fontan procedure.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 01-02-2014
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The study objectives were to compare the neurodevelopmental outcomes of preschool survivors of the Fontan procedure with those of children with congenital heart disease undergoing biventricular repair and to investigate predictors of neurodevelopmental outcome for those with single ventricle congenital heart disease, including hypoplastic left heart syndrome.
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Asymmetric crying facies in the 22q11.2 deletion syndrome: implications for future screening.
Clin Pediatr (Phila)
PUBLISHED: 10-17-2013
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Asymmetric crying facies (ACF) is congenital hypoplasia of the depressor anguli oris muscle characterized by asymmetry of lower lip depression during crying. This has an overall incidence of 0.6%. This study determines the incidence of ACF in a large population of patients with 22q11.2 deletion.
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Contribution of congenital heart disease to neuropsychiatric outcome in school-age children with 22q11.2 deletion syndrome.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 09-23-2013
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Children with 22q11.2 deletion syndrome (22q11DS) present with congenital heart disease (CHD) and high prevalence of psychiatric disorders and neurocognitive deficits. Although CHD has been implicated in neurodevelopment, its role in the neuropsychiatric outcome in 22q11DS is poorly understood. We investigated whether CHD contributes to the high prevalence of psychiatric disorders and neurocognitive impairments in 22q11DS. Fifty-four children ages 8-14 years with 22q11DS and 16 age-matched non-deleted children with CHD participated. They were assessed using semi-structured interviews and a Computerized Neurocognitive Battery. CHD status was assessed using available medical records. Prevalence of psychiatric disorders and cognitive profiles were compared among the groups. There were no significant differences between the prevalence of psychiatric disorders in the 22q11DS with and without CHD. In 22q11DS with CHD, the prevalence rates were 41% anxiety disorders, 37% ADHD and 71% psychosis spectrum. In 22q11DS without CHD, the rates were 33% anxiety disorders, 41% ADHD and 64% psychosis spectrum. In comparison, the non-deleted CHD group had lower rates of psychopathology (25% anxiety disorders, 6% ADHD, and 13% psychosis spectrum). Similarly, the 22q11DS groups, regardless of CHD status, had significantly greater neurocognitive deficits across multiple domains, compared to the CHD-only group. We conclude that CHD in this sample of children with 22q11.2DS does not have a major impact on the prevalence of psychiatric disorders and is not associated with increased neurocognitive deficits. These findings suggest that the 22q11.2 deletion status itself may confer significant neuropsychiatric vulnerability in this population. © 2013 Wiley Periodicals, Inc.
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Report from the Society of Thoracic Surgeons National Database Workforce: clarifying the definition of operative mortality.
World J Pediatr Congenit Heart Surg
PUBLISHED: 06-27-2013
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Several distinct definitions of postoperative death have been used in various quality reporting programs. Some have defined postoperative mortality as the occurrence of death after a surgical procedure when the patient dies while still in the hospital, while others have considered all deaths occurring within a predetermined, standardized time interval after surgery to be postoperative mortality. While mortality data are still collected and reported using both these individual definitions, the Society of Thoracic Surgeons (STS) believes that either approach alone may be inadequate. Accordingly, the STS prefers a more encompassing metric, Operative Mortality. Operative Mortality is defined in all STS databases as (1) all deaths, regardless of cause, occurring during the hospitalization in which the operation was performed, even if after 30 days (including patients transferred to other acute care facilities); and (2) all deaths, regardless of cause, occurring after discharge from the hospital, but before the end of the 30th postoperative day. This article provides clarification for some uncommon but important scenarios in which the correct application of this definition may be challenging.
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Ablepharon macrostomia syndrome: A distinct genetic entity clinically related to the group of FRAS-FREM complex disorders.
Am. J. Med. Genet. A
PUBLISHED: 06-02-2013
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Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders. © 2013 Wiley Periodicals, Inc.
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Expanding the spectrum of microdeletion 4q21 syndrome: a partial phenotype with incomplete deletion of the minimal critical region and a new association with cleft palate and Pierre Robin sequence.
Am. J. Med. Genet. A
PUBLISHED: 04-25-2013
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Microdeletion 4q21 syndrome has been described in about a dozen patients with deletions ranging from 3.2 to 15.1 MB with similar features including the distinctive facial characteristics of broad forehead, hypertelorism, and prominent front teeth, with severe growth delay, developmental delay, and neonatal hypotonia. A 1.37 MB minimal critical region has been described that accounts for this shared phenotype and includes five known genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1. We report on two new patients found through single nucleotide polymorphism (SNP) microarray testing that expand the reported phenotype. Patient 1 has a novel deletion of 2.0 MB, the smallest reported deletion, which involves only a partial deletion of the minimal critical region, including the genes HNRNPD, HNRPDL, and ENOPH1. She shares much of the typical phenotype including moderate developmental delay, unusual facial features, small hands and feet, but not any growth delay or neonatal hypotonia. This patient allows further genotype-phenotype correlation of the genes in the minimal critical region, and supports that heterozygous loss of PRKG2 leads to the growth delay. Patient 2 has a novel 3.4 MB deletion that includes the entire critical region, and has typical features, but also presented with cleft palate and Pierre Robin sequence, which have not been previously described. A gene reported to be associated with inherited cleft palate, SCD5, is in the deleted region in this patient, which suggests it may be playing a role in palate formation. Taken together, these patients allow for an expansion of the microdeletion 4q21 syndrome and provide candidate genes for particular features of the phenotype.
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Congenital heart defects in oculodentodigital dysplasia: Report of two cases.
Am. J. Med. Genet. A
PUBLISHED: 02-24-2013
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Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations. © 2013 Wiley Periodicals, Inc.
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Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.
Am. J. Hum. Genet.
PUBLISHED: 01-31-2013
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Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.
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External validation of the Society of Thoracic Surgeons General Thoracic Surgery Database.
Ann. Thorac. Surg.
PUBLISHED: 01-27-2013
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The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) reports outstanding results for lung and esophageal cancer resection. However, a major weakness of the GTSD has been the lack of validation of this voluntary registry. The purpose of this study was to perform an external, independent audit to assess the accuracy of the data collection process and the quality of the database.
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The society of thoracic surgeons national database.
Heart
PUBLISHED: 01-18-2013
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The Society of Thoracic Surgeons (STS) National Database collects detailed clinical information on patients undergoing adult cardiac, paediatric and congenital cardiac, and general thoracic surgical operations. These data are used to support risk-adjusted, nationally benchmarked performance assessment and feedback; voluntary public reporting; quality improvement initiatives; guideline development; appropriateness determination; shared decision making; research using cross-sectional and longitudinal registry linkages; comparative effectiveness studies; government collaborations including postmarket surveillance; regulatory compliance and reimbursement strategies.
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Computerized neurocognitive profile in young people with 22q11.2 deletion syndrome compared to youths with schizophrenia and at-risk for psychosis.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 08-02-2011
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Adults with 22q11.2 Deletion syndrome (22q11DS) have increased prevalence of schizophrenia features. Our goal is to compare the neurocognitive profile in 22q11DS, schizophrenia and individuals at risk for schizophrenia. Twenty-one 22q11DS patients (8-32 years, mean 14.9 years, 15M, 6F) were matched to four comparison groups on age: low risk (n?=?21), first-degree family members of schizophrenia patients (genetic risk, n?=?20), individuals exhibiting putatively prodromal symptoms (clinical risk, n?=?19), and patients with schizophrenia (n?=?21). All participants received semi-structured interviews [Diagnostic Interview for Genetic Studies (DIGS) and the Structured Interview for Prodromal Syndromes (SIPS)], and a computerized neurocognitive battery (CNB) measuring the following domains: Abstraction and Mental Flexibility, Attention, Working Memory, Verbal Memory, Face Memory, Spatial Memory, Language, Spatial Processing, Sensorimotor Dexterity, and Emotion Processing. Sixty percent of 22q11DS participants met SIPS criteria for prodromal symptoms and one participant met criteria for paranoid schizophrenia. Thirty-eight percent met criteria for Depressive Disorders. All 22q11DS participants successfully completed the CNB. 22q11DS participants were significantly less accurate in nearly all domains, but had similar speed of response compared to the other groups. Their profile resembled that of the psychosis groups in accuracy and speed, except for more pronounced deficits in accuracy for face memory and emotion processing. Subthreshold psychotic symptoms are present in a high proportion of 22q11DS participants. Deficits shown in the CNB are more pronounced for accuracy than speed relative to the psychosis groups with similar profiles. Similar deficits have been described in the 22q11DS population using non-computerized measures, which require increased testing time.
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A prospective study of influenza vaccination and a comparison of immunologic parameters in children and adults with chromosome 22q11.2 deletion syndrome (digeorge syndrome/velocardiofacial syndrome).
J. Clin. Immunol.
PUBLISHED: 06-01-2011
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Prior to the advent of cardiac bypass, most children with congenital cardiac anomalies and chromosome 22q11.2 deletion syndrome died. With improved technology, there is now a wave of young adults with chromosome 22q11.2 deletion syndrome requiring clinical care. Fifteen young children and 20 adults with chromosome 22q11.2 deletion had flow cytometry, functional T cell analyses, and functional B cell analyses to characterize their immune system. Subjects were vaccinated with the annual inactivated influenza vaccine, and responses were evaluated by hemagglutination inhibition titer assessment. The pattern of T cell subset abnormalities was markedly different between pediatric and adult patients. In spite of the cellular deficits observed in adults, titers produced after influenza vaccine administration were largely intact. We conclude that disruption to T cell production appears to have secondary consequences for T cell differentiation and B cell function although the clinical impact remains to be determined.
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Genotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.
Hum. Mutat.
PUBLISHED: 04-15-2011
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Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype-enrichment groups. Nine common SNPs (minor allele frequency, MAF > 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome.
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Ablepharon-Macrostomia syndrome--extension of the phenotype.
Am. J. Med. Genet. A
PUBLISHED: 01-12-2011
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Ablepharon-Macrostomia syndrome (AMS) is a rare collection of findings characterized by absent or hypoplastic eyelids, fusion defects of the mouth with unfused lateral commissures, abnormal ears, ambiguous genitalia, skin differences including dry and coarse skin or redundant folds of skin, and developmental delay. Fewer than 20 patients have been reported to date. These include a parent and two children and a recent report of a father and daughter, therefore suggesting autosomal dominant inheritance. Here we present one additional sporadic case with an expanded phenotype. This patient has more significant hand and foot anomalies than previously reported.
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Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).
Medicine (Baltimore)
PUBLISHED: 01-05-2011
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Chromosome 22q11.2 deletion syndrome is a common syndrome also known as DiGeorge syndrome and velocardiofacial syndrome. It occurs in approximately 1:4000 births, and the incidence is increasing due to affected parents bearing their own affected children. The manifestations of this syndrome cross all medical specialties, and care of the children and adults can be complex. Many patients have a mild to moderate immune deficiency, and the majority of patients have a cardiac anomaly. Additional features include renal anomalies, eye anomalies, hypoparathyroidism, skeletal defects, and developmental delay. Each childs needs must be tailored to his or her specific medical problems, and as the child transitions to adulthood, additional issues will arise. A holistic approach, addressing medical and behavioral needs, can be very helpful.
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Metopic craniosynostosis due to mutations in GLI3: A novel association.
Am. J. Med. Genet. A
PUBLISHED: 06-29-2010
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We report on the novel association of trigonocephaly and polysyndactyly in two unrelated patients due to mutations within the last third (exon 14) and first third (exon 6) of the GLI3 gene, respectively. GLI3 acts as a downstream mediator of the Sonic hedgehog signal-transduction pathway which is essential for early development; and plays a role in cell growth, specialization, and patterning of structures such as the brain and limbs. GLI3 mutations have been identified in patients with Pallister-Hall, Grieg cephalopolysyndactyly syndrome (GCPS), postaxial polydactyly type A1, preaxial polydactyly type IV, and in one patient with acrocallosal syndrome (ACLS). Furthermore, deletions including the GLI3 gene have been reported in patients with features of GCPS and ACLS. To date, trigonocephaly has not been associated with abnormalities of GLI3 and craniosynostosis is not a feature of GCPS. However, Hootnick and Holmes reported on a father with polysyndactyly and son with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum, considered GCPS thereafter. Guzzetta et al. subsequently described a patient with trigonocephaly, polysyndactyly, and agenesis of the corpus callosum postulating a diagnosis of GCPS, later considered ACLS. In retrospect, these two patients, evaluated prior to mutational analysis, and our patients, with confirmed mutations, likely fall within the GLI3 morphopathy spectrum and may provide a bridge to better understanding those patients with overlapping features of GCPS and ACLS. Based on this observation, we suggest GLI3 studies in patients presenting with this constellation of findings, specifically metopic craniosynostosis with polysyndactyly, in order to provide appropriate medical management and genetic counseling.
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Is cardiac diagnosis a predictor of neurodevelopmental outcome after cardiac surgery in infancy?
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 04-27-2010
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To determine whether a cardiac diagnosis is a predictor of neurodevelopmental outcomes after infant cardiac surgery.
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Not silent, invisible: literatures chance encounters with deaf heroes and heroines.
Am Ann Deaf
PUBLISHED: 04-27-2010
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Literature is both a rich resource and a blunt instrument in conveying the complexities of identity, in particular, the elusive deaf identity. The rarity of the fully realized deaf person in memoir and fiction shapes the way readers regard deaf people and throws up fresh challenges in redesigning stories of deafness free of the taint of triumphalism or complaint. Competing but authentic representations of deafness and deaf peoples experiences allow readers to variously witness, immerse themselves in, and navigate their way through those experiences. Consequently, establishing universal truths about deaf lives is a risky business and an improbable goal.
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A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.
Nat. Genet.
PUBLISHED: 01-15-2010
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We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
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The natural history of patients treated for TWIST1-confirmed Saethre-Chotzen syndrome.
Plast. Reconstr. Surg.
PUBLISHED: 12-03-2009
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Patients with Saethre-Chotzen syndrome have a heterogeneous phenotype. The purpose of this study was to use the genotypic diagnosis of the authors series of patients with TWIST1-confirmed Saethre-Chotzen syndrome to describe their natural history and long-term surgical outcomes.
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Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2.
Am. J. Med. Genet. A
PUBLISHED: 11-06-2009
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We report on three unrelated patients with the 22q11.2 microdeletion syndrome (del22q11) who have phenotypic anomalies compatible with oculo-auriculo-vertebral spectrum (OAVS). Hemifacial microsomia, unilateral microtia, hearing loss, congenital heart/aortic arch arteries defects, and feeding difficulties were present in all three patients. Additional anomalies occasionally diagnosed included coloboma of the upper eyelid, microphthalmia, cerebral malformation, palatal anomalies, neonatal hypocalcemia, developmental delay, and laryngomalacia. Several clinical features characteristic of OAVS have been described in patients with del22q11 from the literature, including ear anomalies, hearing loss, cervical vertebral malformations, conotruncal cardiac defects, renal malformations, feeding and respiratory difficulties. Atretic ear with facial asymmetry has been previously described in one patient. Thus, clinical expression of hemifacial microsomia and microtia resembling OAVS should now be included within the wide phenotypic expression of del22q11. The occurrence of this manifestation in del22q11 is currently low. Nevertheless, patients with hemifacial microsomia and microtia associated with clinical features typically associated with del22q11 should now have for specific cytogenetic testing.
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A 3.1-Mb microdeletion of 3p21.31 associated with cortical blindness, cleft lip, CNS abnormalities, and developmental delay.
Eur J Med Genet
PUBLISHED: 11-03-2009
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We report a 3.1-Mb de novo deletion of 3p21.31 in a 3.5-year-old female with cortical blindness, cleft lip, CNS abnormalities, and gross developmental delays. Examination of the region showed approximately 80 genes to be involved in the deletion. Functional analysis of the deleted genes suggests that several of them may be important in normal neuronal maturation and function. Thus, haploinsufficiency of one or more of these genes could potentially contribute to the observed phenotype. Our patient does not have clinical features that overlap completely with either proximal or distal 3p deletions, suggesting that the deletion seen in our patient leads to a distinct clinical phenotype not described previously.
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CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome: a comparison of immunologic and nonimmunologic phenotypic features.
Pediatrics
PUBLISHED: 05-01-2009
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CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromosome 22q11.2 deletion syndrome are known to have significant clinical overlap including cardiac anomalies, ear abnormalities, hearing loss, developmental delay, renal abnormalities, and cleft palate. Immunodeficiency has been well documented in 22q11.2 deletion, but there has been limited recognition of this potentially serious complication in CHARGE syndrome. The goals of our study were to identify clinical features unique to CHARGE syndrome or 22q11.2 deletion and to describe the spectrum of immunodeficiency found in patients with CHARGE syndrome.
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Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome.
Birth Defects Res. Part A Clin. Mol. Teratol.
PUBLISHED: 04-15-2009
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The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion.
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Aortic root dilation in patients with 22q11.2 deletion syndrome.
Am. J. Med. Genet. A
PUBLISHED: 04-09-2009
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The 22q11.2 deletion syndrome is characterized by a highly variable phenotype including a range of cardiac malformations. The most common cardiovascular features include a subset of conotruncal defects, perimembranous ventricular septal defects and aortic arch anomalies. This report describes a series of patients with 22q11.2 deletion syndrome with the novel cardiac finding of mild aortic root dilation. A chart review was performed on 93 patients with documented 22q11.2 deletion without significant congenital heart disease to determine the number of patients with aortic root dilation. Patients ranged in age from 1 to 13 years of age. Of these 93 patients, 10 patients were found to have aortic root dilation on a screening echocardiogram. Seven of these patients did not have any additional risk factors while three patients had a bicuspid aortic valve (BAV). Four of 10 patients had additional minor cardiac anomalies including repaired ventricular septal defect (1), patent ductus arteriosus(1), arch anomalies (1), and left pulmonary artery stenosis (1). Three patients had isolated cases of aortic root dilation. Interestingly, several of these patients did not have aortic root dilation on their initial echocardiograms. The purpose of this study is to draw attention to a novel cardiac finding in patients with 22q11.2 deletion that may be of clinical importance. Further long-term study is warranted to assess the need for echocardiographic screening in the 22q11.2 deleted population for aortic root dilation into adolescence and adulthood.
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Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations.
Am. J. Hum. Genet.
PUBLISHED: 03-27-2009
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Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis.
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Alterations in midline cortical thickness and gyrification patterns mapped in children with 22q11.2 deletions.
Cereb. Cortex
PUBLISHED: 03-10-2009
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The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome) is a neurogenetic condition associated with visuospatial deficits, as well as elevated rates of attentional disturbance, mood disorder, and psychosis. Previously, we detected pronounced cortical thinning in superior parietal and right parieto-occipital cortices in patients with this syndrome, regions critical for visuospatial processing. Here we applied cortical pattern-matching algorithms to structural magnetic resonance images obtained from 21 children with confirmed 22q11.2 deletions (ages 8-17) and 13 demographically matched comparison subjects, in order to map cortical thickness across the medial hemispheric surfaces. In addition, cortical models were remeshed in frequency space to compute their surface complexity. Cortical maps revealed a pattern of localized thinning in the ventromedial occipital-temporal cortex, critical for visuospatial representation, and the anterior cingulate, a key area for attentional control. However, children with 22q11.2DS showed significantly increased gyral complexity bilaterally in occipital cortex. Regional gray matter volumes, particularly in medial frontal cortex, were strongly correlated with both verbal and nonverbal cognitive functions. These findings suggest that aberrant parieto-occipital brain development, as evidenced by both increased complexity and cortical thinning in these regions, may be a neural substrate for the deficits in visuospatial and numerical understanding characteristic of this syndrome.
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Affective disorders and other psychiatric diagnoses in children and adolescents with 22q11.2 Deletion Syndrome.
J Affect Disord
PUBLISHED: 02-09-2009
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22q11.2 Deletion Syndrome (22qDS) is a common chromosome deletion syndrome that has been associated with severe psychopathology, including bipolar disorder and schizophrenia, in adults. Assessment of psychiatric diagnoses in children and adolescents with 22qDS is in the early stages of investigation.
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Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region.
Hum. Mol. Genet.
PUBLISHED: 02-03-2009
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Deletions of the 22q11.2 region distal to the 22q11.21 microdeletion syndrome region have recently been described in individuals with mental retardation and congenital anomalies. Because these deletions are mediated by low-copy repeats (LCRs), located distal to the 22q11.21 DiGeorge/velocardiofacial microdeletion region, duplications are predicted to occur with a frequency equal to the deletion. However, few microduplications of this region have been reported. We report the identification of 18 individuals with microduplications of 22q11.21-q11.23. The duplication boundaries for all individuals are within LCRs distal to the DiGeorge/velocardiofacial microdeletion region. Clinical records for nine subjects reveal shared characteristics, but also several examples of contradicting clinical features (e.g. macrocephaly versus microcephaly and upslanting versus downslanting palpebral fissures). Of 12 cases for whom parental DNA samples were available for testing, one is de novo and 11 inherited the microduplication from a parent, three of whom reportedly have learning problems or developmental delay. The variable phenotypes and preponderance of familial cases obfuscate the clinical relevance of the molecular data and emphasize the need for careful parental assessments and clinical correlations.
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Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS.
J. Med. Genet.
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22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder, affecting an estimated 1?:?2000-4000 live births. Patients with 22q11.2DS have a broad spectrum of phenotypic abnormalities which generally includes congenital cardiac abnormalities, palatal anomalies, and immunodeficiency. Additional findings, such as skeletal anomalies and autoimmune disorders, can confer significant morbidity in a subset of patients. 22q11.2DS is a contiguous gene DS and over 40 genes are deleted in patients; thus deletion of several genes within this region contributes to the clinical features. Mutations outside or on the remaining 22q11.2 allele are also known to modify the phenotype.
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A candidate gene approach to identify modifiers of the palatal phenotype in 22q11.2 deletion syndrome patients.
Int. J. Pediatr. Otorhinolaryngol.
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Palatal anomalies are one of the identifying features of 22q11.2 deletion syndrome (22q11.2DS) affecting about one third of patients. To identify genetic variants that increase the risk of cleft or palatal anomalies in 22q11.2DS patients, we performed a candidate gene association study in 101 patients with 22q11.2DS genotyped with the Affymetrix genome-wide human SNP array 6.0.
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Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.
Am. J. Med. Genet. A
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Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000-1/4,000 live births. Approximately 9-11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, we hypothesized that DNA variants in the remaining allele of TBX1 may confer risk to CP in patients with 22q11DS. To test the hypothesis, we evaluated TBX1 exon sequencing (n = 360) and genotyping data (n = 737) with respect to presence (n = 54) or absence (n = 683) of CP in patients with 22q11DS. Two upstream SNPs (rs4819835 and rs5748410) showed individual evidence for association but they were not significant after correction for multiple testing. Associations were not identified between DNA variants and haplotypes in 22q11DS patients with CP. Overall, this study indicates that common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant.
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Diagnosis of 22q11.2 deletion syndrome and artemis deficiency in two children with T-B-NK+ immunodeficiency.
J. Clin. Immunol.
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Two infants are described who presented with 22q11.2 deletion and a T(-)B(-)NK(+) immune phenotype. For both infants, the initial diagnosis was athymia secondary to complete DiGeorge anomaly. The first infant underwent thymus transplantation but 6 months after transplantation had circulating thymus donor T cells; the patient did not develop recipient naïve T cells. Genetic analyses revealed that both patients had Artemis deficiency, a rare form of severe combined immunodeficiency (SCID). Both infants have subsequently undergone bone marrow transplantation. These cases illustrate the importance and paradox of differentiating SCID from complete DiGeorge anomaly because hematopoietic stem cell transplantation (HSCT) is the preferred treatment for SCID but is ineffective for complete DiGeorge anomaly. However, if the thymus is completely absent, donor stem cells from a HSCT would not be able to be educated.
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Syndrome-specific growth charts for 22q11.2 deletion syndrome in Caucasian children.
Am. J. Med. Genet. A
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Growth faltering occurs frequently in infancy in the 22q11 Deletion syndrome (22q11 DS). The subsequent course of growth in childhood and outcome for final adult height lacks consensus. We analyzed 5,149 growth data points from 812 Caucasian subjects with 22q11 DS, from neonates to 37 years old. Charts were constructed for height, weight, body mass index, and head circumference (OFC) using the LMS Chart Maker program. These charts were compared with the WHO birth to 4 years growth standard and US CDC 2000 growth reference between 5 and 20 years. Starting from the 50th centile at birth, by 6-9 months of age boys mean height and weight had fallen to the 9th centile, as did girls height but their weight fell less markedly, to the 25th centile. Feeding difficulties were non-contributory. In children under 2 years old with congenital heart disease (CHD) mean weight was -0.5 SD lighter than no CHD. Catch up growth occurred, more rapid in weight than height in boys. Up to 10 years old both sexes tracked between the 9th and 25th centiles. In adolescence, the trend was to overweight rather than obesity. At 19 years mean height was -0.72 SD for boys, -0.89 SD girls. OFC was significantly smaller than the WHO standard in infancy, between the 9th and 25th centile, rising to the 25th centile by 5 years old. Thereafter the mean was close to the 9th centile of the OFC UK growth reference, more prolonged and marked than in previous studies.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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