Wanda Fremont

Velo-cardio-facial syndrome

Purpose of review Velo-cardio-facial syndrome has emerged from obscurity to become one of the most researched disorders this past decade. It is one of the most common genetic syndromes in humans, the most common contiguous gene syndrome in humans, the most common syndrome of cleft palate, and the most common syndrome of conotruncal heart malformations. Velo-cardio-facial syndrome has an expansive phenotype, a factor reflected in the wide range of studies that cover both clinical features and molecular genetics. In this review, we cover multiple areas of research during the past year, including psychiatric disorders, neuroimaging, and the delineation of clinical features. Recent findings The identification of candidate genes for heart anomalies, mental illness, and other clinical phenotypes has been reported in the past year with a focus on TBX1 for cardiac and craniofacial phenotypes and COMT and PRODH for psychiatric disorders. The expansive phenotype of velo-cardio-facial syndrome continues to grow with new behavioral and structural anomalies reported. Treatment issues are beginning to draw attention, although most authors continue to focus on diagnostic issues. Summary Its high population prevalence, estimated to be as common as 1:2000 has sparked a large amount of research, as has the model the syndrome serves for identifying the causes of mental illness and learning disabilities, but it is obvious that more information is needed. Intensive scrutiny of velo-cardio-facial syndrome will undoubtedly continue for many years to come with the hope that researchers will turn more of their attention to treatment and treatment outcomes.

Childhood reactions to terrorism-induced trauma: a review of the past 10 years.

OBJECTIVE To summarize the literature about the clinical presentation and treatment interventions of childhood reactions to terrorism-induced trauma. METHOD The literature on childrens responses to terrorist activities was reviewed. RESULTS Over the past 10 years, more research has emerged on the subject of terrorism in children. Many of the effects of terrorism-induced trauma are similar to the effects of natural and man-made trauma. Childrens responses include acute stress disorder, posttraumatic stress disorder, anxiety, depression, regressive behaviors, separation problems, sleep difficulties, and behavioral problems. However, several aspects of terrorist attacks result in unique stressors and reactions and pose specific challenges for treatment. The unpredictable, indefinite threat of terrorist events, the profound effect on adults and communities, and the effect of extensive terrorist-related media coverage exacerbates underlying anxieties and contributes to a continuous state of stress and anxiety. Intervention strategies include early community-based interventions, screening of children at risk, triage and referral, and trauma-loss-focused treatment programs. CONCLUSIONS Advances have been made in the research of childhood reactions to terrorism-induced trauma. Further research is needed to identify children at risk and to determine the long-term impact on childrens development. Although the preliminary results of interventions developed to help children are promising, outcome data have not been examined, and further research is needed to evaluate their effectiveness.

A gender-moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo-cardio-facial syndrome (22q11.2 deletion syndrome)

Caused by a microdeletion at the q11.2 locus of chromosome 22, velo‐cardio‐facial syndrome (also known as VCFS, 22q11 deletion syndrome, DiGeorge sequence, and conotruncal anomalies face syndrome) is associated with a distinctive physical, neurocognitive, and psychiatric phenotype. Increasing interest has centered on identifying the candidate genes within the deleted region that may contribute to this phenotype. One attractive candidate gene is catechol‐O‐methyltransferase (COMT) because it encodes for a protein that degrades dopamine. Variability in COMT activity is related to a Val158Met polymorphism that has been implicated in prefrontal lobe cognitive and neuropsychiatric function. We examined the effect of this polymorphism on prefrontal anatomy and frontally‐mediated neuropsychological function in 58 children with VCFS, 26 who were hemizygous for the Met allele and 32 for the Val allele. We found an allele by gender interaction effect on the volumes of the dorsal prefrontal and orbital prefrontal cortices. We did not find significant allele or gender by allele effects on neuropsychological tasks, although girls with the Met allele tended to perform better on the Wisconsin card sorting task. These data suggest that this functional COMT polymorphism may play a gender‐moderated role in determining the neuroanatomic phenotype of individuals with VCFS. Longitudinal evaluation of these children is essential in order to identify potential clinical implications of this allele by gender interaction.

Comparing phenotypes in patients with idiopathic autism to patients with velocardiofacial syndrome (22q11 DS) with and without autism

At least three research groups have reported that autism is diagnosed in up to 20% of children with velocardiofacial syndrome (VCFS). However the degree of phenotypic overlap between VCFS‐affected children with autism and those with idiopathic autism has not been established. The purpose of this study was to define and differentiate the behavioral phenotype of autism in samples of children with either (VCFS) or idiopathic autism. Five groups of children ages 5–15 were included in the between‐group design. Parent report of autism behaviors (based on the Autism Diagnostic Interview‐Revised, ADI‐R) were compared between children with VCFS, children with VCFS and autism (VCFS + autism), siblings of the children with VCFS, a community control group, and a group of children with idiopathic autism. Autism diagnoses were based according to the ADI‐R. Parental responses to the ADI‐R indicated that relative to children with VCFS‐only, children with idiopathic autism and children with VCFS + autism exhibited less make believe play and more rituals, motor stereotypies and repetitive use of objects. However several other core autism behaviors, including difficulties sharing attention, deficits in gestural communication and initiating conversation, and presence of circumscribed interests, appear to be phenotypic VCFS behaviors, characterizing children with VCFS regardless of an autism diagnosis. Accordingly, the autism phenotype in VCFS differs to some extent from that of idiopathic autism. Several features of idiopathic autism are spared in VCFS, and other features appear to be a function of the VCFS phenotype independent of autism. These findings carry implications for clinicians who diagnose and treat VCFS or autism, and for researchers who study genotype–phenotype associations in autism.

The Neurocognitive Phenotype in Velo-Cardio-Facial Syndrome: A Developmental Perspective.

Although research has focused primarily on the wide range of variability in the cognitive phenotype between individuals with velo-cardio-facial syndrome (VCFS), we know relatively little about the extent to which within-individual expressions of the cognitive phenotype remain stable throughout development. General cognitive functioning in the low borderline range is the most consistent cognitive finding. Stronger reading decoding and spelling skills as well as auditory/verbal rote memory skills have been reported to be areas of relative strength. Conversely, significant visuospatial dysfunction, diminished math attainment, and executive dysfunction have all been reported as phenotypic. We propose several considerations that could advance our knowledge of developmental changes in the VCFS cognitive phenotype. The most salient of these is the need for more longitudinal designs with carefully matched control participants.

Behavior and corpus callosum morphology relationships in velocardiofacial syndrome (22q11.2 deletion syndrome)

Velocardiofacial syndrome (VCFS) is a neurodevelopmental disorder caused by a microdeletion on chromosome 22q11.2 that predisposes affected individuals to learning disabilities and psychiatric conditions. Previous research has indicated that compared with comparison children, children with VCFS have larger corpus callosal areas. Children with VCFS are often diagnosed with comorbid attention deficit hyperactivity disorder (ADHD), and previous research has indicated that children with ADHD often have smaller corpus callosal areas than controls. The present study investigated two hypotheses: children with VCFS would have larger callosal areas than controls, and children with VCFS+ADHD would have smaller callosal areas than children with VCFS. Corpus callosum area was obtained from the mid-sagittal slice and was assessed in children with VCFS (n=60) and age- and gender-matched control participants (n=52). Results indicated that all of the corpus callosum measures were significantly different between the two groups except for the genu. Across all measures, children with VCFS demonstrated a larger corpus callosum area. Within the VCFS sample, children with VCFS+ADHD (n=30) had smaller total callosal, splenium, and genu areas than children with VCFS alone. Although children with VCFS+ADHD had smaller total callosal areas than children with VCFS, relative to control participants, these children had larger total callosal and subregion areas except for the genu. In addition to other anatomic anomalies, corpus callosal abnormalities appear to be another variable to consider when analyzing brain/behavior relations in this population.

Sex differences in cognitive functioning in velocardiofacial syndrome (VCFS)

Sex differences in cognitive functioning were investigated in children with velocardiofacial syndrome (VCFS), a genetic defect caused by a microdeletion on chromosome 22q.11. The study population consisted of six groups: 50 boys with VCFS (M = 11.1, SD = 2.7), 40 girls with VCFS (M = 10.8, SD = 2.5), 13 male siblings of the participant with VCFS (M = 12.3, SD = 1.9), 17 female siblings of the participant with VCFS (M = 12.2, SD = 1.9), and a race- and gender-ratio-matched sample of 28 boy community control participants (M = 10.7, SD =2.4) and 19 girl community control participants (M = 9.2, SD =2.3). Each participant received a psychological assessment including intellectual and academic achievement as well as structural magnetic resonance imaging of his or her brain. Our results indicate that boys with VCFS may be more cognitively affected than girls. In addition, and although cross-sectional in nature, our results document a negative association between age and cognitive functioning in girls with VCFS but not in boys. Sex differences in frontal lobe volume are generally seen in the general population between boys and girls (boys > girls) and across all three samples, this trend emerged. Relative to boys with VCFS, girls with VCFS may be less cognitively affected, although age is negatively associated with cognitive functioning in girls with VCFS but not boys, suggesting that girls with VCFS may fail to maintain this cognitive advantage over boys.

22q11.2 Deletion Syndrome: Genetics, Neuroanatomy and Cognitive/Behavioral Features Keywords

This paper presents a conceptual review of the genetic underpinnings of 22q11.2 Deletion Syndrome. The neuroanatomical, neuropsychological, behavioral, and psychiatric phenotype associated with 22q11.2 Deletion Syndrome is also explored, including variables that are thought to affect symptom expression. The history of the deletion syndrome is described, and future directions for continued research are discussed.

Comfort Level of Pediatricians and Family Medicine Physicians Diagnosing and Treating Child and Adolescent Psychiatric Disorders

Context: Twelve to twenty-one percent of children and adolescents have psychiatric disorders with at least mild functional impairment. Pediatricians and family medicine physicians prescribe 85% of psychotropic medications taken by children. However, little is known about the comfort level of these physicians with the diagnosis and treatment of psychiatric disorders in children. Objective: To determine the comfort level of physicians in diagnosing and treating psychiatric disorders in children. Method: An anonymous survey was sent to pediatricians and family medicine physicians in upstate New York. Of 483 surveys, 200 surveys were returned. Outcome Measures: To compare differences between pediatricians and family medicine physicians in comfort in diagnosing and prescribing medications for psychiatric disorders. Results: After controlling for age, race, and years since residency, pediatricians were more comfortable in diagnosing (O.R. = 3.05, C.I. = 1.40–6.63) and prescribing stimulants for (O.R. = 4.16, C.I. = 1.96–8.84) Attention Deficit Disorder. Family medicine physicians were more comfortable in diagnosing (O.R. = .28, C.I. = .14-.57) and prescribing medication for (O.R. = .44, C.I. = .22-.87) anxiety and depression. Despite the differences in comfort, there were no differences in the percentage of each group prescribing the different medications. Of those who were comfortable in making the diagnoses, 13%−64% were not comfortable in prescribing medications, although they did prescribe. Conclusions: Pediatricians and family medicine physicians who prescribe the majority of psychotropic medications for children report disconcerting degrees of discomfort with the diagnosis and treatment of childrens psychiatric disorders. The authors discuss the multiple factors that may impact primary care physicians comfort in diagnosing and treating children and adolescents with psychiatric disorders.

Atlas-Based White Matter Analysis in Individuals With Velo-Cardio-Facial Syndrome (22q11.2 Deletion Syndrome) and Unaffected Siblings

BackgroundVelo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning.MethodsThirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (pFDR < 0.05), we assessed the correlations between DTI and neuropsychological measures.ResultsIn VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of the internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD with measures of executive function, IQ, working memory, and/or social cognition.ConclusionsOur results suggest that individuals with VCFS display abnormal WM connectivity in a widespread cerebro-anatomical network, involving tracts from/to all cerebral lobes and the cerebellum. Future studies could focus on the WM developmental trajectory in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate 22q11.2 genes on WM anomalies.