Edward Moss

Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion

A microscopic deletion of chromosome 22q11.2 has been identified in most patients with the DiGeorge, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies. This study presents the neurodevelopmental outcome, including cognitive development, language development, speech, neuromuscular development, and behavioral characteristics of 40 preschool children (ages 13 to 63 months) who have been diagnosed with the 22q11.2 deletion. The impact of cardiac disease, cardiac surgery, and the palatal anomalies on this population was also studied. In the preschool years, children with a 22q11.2 deletion are most commonly found to be developmentally delayed, have mild hypotonia, and language and speech delays. The more significantly delayed children are at high risk to be subsequently diagnosed with mild or moderate mental retardation. The global delays and the variations in intelligence found are directly associated with the 22q11.2 deletion and are not explained by physical anomalies such as palatal defects or cardiac defects, or therapeutic interventions such as cardiac surgery. Our findings demonstrate that there is a pattern of significant speech disorders within this population. All of the children had late onset of verbal speech. Behavioral outcomes included both inhibition and attention disorders. Early intervention services are strongly recommended beginning in infancy to address the delays in gross motor skills, speech and language, and global developmental delays.

Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion.

Purpose: Patients with one of the 22q11.2 deletion syndromes provide a unique opportunity to research the interface between genetics and brain-behavior relationships. This study investigates the neuropsychological characteristics and behavioral phenotype of children with this deletion syndrome.Methods: We report updated findings from descriptive and nonparametric analyses of neuropsychological data from 80 children with the 22q11.2 deletion.Results: The subjects showed higher verbal than nonverbal IQ scores, assets in verbal memory, and deficits in the areas of attention, story memory, visuospatial memory, arithmetic performance relative to other areas of achievement, and psychosocial functioning.Conclusion: Children with 22q11.2 deletion syndromes exhibit a behavioral phenotype reflective of nonverbal learning disabilities, concomitant language deficits, and social-emotional concerns.

The Neurocognitive Phenotype of the 22Q11.2 Deletion Syndrome: Selective Deficit in Visual-Spatial Memory

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome) is associated with a high frequency of learning disabilities. Although previous work has demonstrated that verbal skills are typically better preserved than non-verbal skills on both IQ and academic achievement testing in children with this syndrome, such measures are not sufficiently specific to determine a selective cognitive deficit. As part of an ongoing prospective study of patients with this syndrome, 29 children aged 517 with confirmed 22q11.2 deletions were assessed with a comprehensive neuropsychological test battery, including matched tasks of verbal and visuospatial memory. Results indicate that 22q patients displayed a selective deficit in visual-spatial memory, which was mirrored by deficits in arithmetic and general visual-spatial cognition. Further, a dissociation between visual-spatial and object memory was observed, indicating further selectivity of this pattern of deficit, and providing evidence for the dissociability of these components of visual cognition. These results indicate that children with 22q11.2 deletions display a specific neurocognitive phenotype, and suggest that this region of Chromosome 22q11 may harbor a gene or genes relevant to the etiology of nonverbal learning deficits.

Research on behavioral phenotypes: velocardiofacial syndrome (deletion 22q11.2).

Recent molecular genetics research has established that most cases of velocardiofacial syndrome (VCF) and of DiGeorge syndrome result from a submicroscopic deletion at chromosome 22q11.21–3. The medical features of this disorder include hypocalcemia, immunodeficiency, cleft palate, subtle facial dysmorphism, ‘conotruncal’ cardiac malformations (e.g. truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, and certain types of ventricular septal defects), and other congenital malformations4. While none of these complications is found in all patients with the 22q11.2 microdeletion, each is sufficiently common to be considered part of the disorder’s medical phenotype. Recent research also has established the existence of a behavioral phenotype for VCF. Investigators from the fields of Developmental-Behavioral Pediatrics, Child Neuropsychology, Developmental Psychology, Child Psychiatry, and other fields all contributed to the description of this phenotype. Investigators employed multiple approaches for examining VCF, including psychometric and psychiatric diagnostic methods, as anticipated by Dykens5. The resultant phenotype spans multiple domains of behavior. In this paper, we review the behavioral phenotype research on VCF, and identify current and future directions for this work. This research has implications not only for the clinical care of patients with VCF, but also for broader issues related to developmental cognitive psychology and to the pathogenesis of psychiatric disease. The research on VCF also illustrates several important methodological considerations for behavioral phenotype research that others have noted5–7.

Communication issues in 22q11.2 deletion syndrome: children at risk.

Purpose: The purpose of this investigation is to describe the communication profile of children with the 22q11.2 deletion syndrome from infancy through school age and to examine the influence of other medical aspects, such as palate anomalies, learning disorders, and cardiac defects of the syndrome to communication.Methods: Seventy-nine children were examined using standardized tests of speech and language and perceptual measures of resonance and voice.Results: Results show significant delay in emergence of speech and language milestones with delay/disorder in speech-language processes persisting into the school aged years, including those children diagnosed with nonverbal learning disabilities. Persistent articulation and resonance disorders were also present, presumed to be related in part to palatal anomalies. No correlation was found between cardiac status, learning disorders, palate anomalies and communication disorders.Conclusion: The need for early identification and management of communication skills is crucial in the care of children with the 22q11.2 deletion.

Communication disorders in the 22Q11.2 microdeletion syndrome

The 22q11.2 microdeletion syndrome is a genetic disorder that is being recognized with increasing frequency. Confirmation of the diagnosis can be made using fluorescence in situ hybridization. Many medical and developmental problems are present in children with this syndrome. Communication disorders are among the most common features of this syndrome and include articulation, language, resonance, and voice problems. The purpose of this paper is to provide a description of the communicative and developmental features in a sample of children with the 22q11.2 microdeletion syndrome seen for evaluation. Because communication and feeding disorders may be presenting features of this syndrome, speech and language pathologists must be familiar with this syndrome and its various characteristics. Awareness of these features and a multidisciplinary approach are necessary for the identification and treatment of the complex communicative and medical problems present in this population.

Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.

Cognitive development in VCFS

Abstract The 22q11.2 microdeletion (velocardiofacial syndrome, VCFS) results in a complex pattern of psychoeducational and neurocognitive deficits. Mean full-scale IQ scores are in the range of borderline intellectual function, but academic achievement scores are generally in the low–normal range. A dichotomy is often found between higher Verbal IQ scores and lower Performance IQ, paralleled by relative strength in Reading and Spelling, but weakness in Math. Language skills are also typically delayed and remain impaired later in life, and psychiatric disorders can be found in both children and adults with the syndrome. On-going neurocognitive research suggests that the impairment in mathematical ability may be associated with poor visual–spatial skills. This would be consistent with theoretical models that link arithmetic skills with visual attention and spatially referenced representations of magnitude. Neuroimaging investigations indicate that these skills may all depend critically on the inferior parietal lobes, and lead to our hypothesis that these may be dysfunctional in the 22q11.2 syndrome. Early reports find no association between cognitive ability in the syndrome and the presence of cardiac malformations.

Neurodevelopmental outcome in 22q11.2 deletion syndrome and management

The 22q11.2 deletion syndrome (22q11.2 DS) places affected individuals at an increased risk for neurodevelopmental/cognitive, behavioral and social–emotional difficulties. Poor cognitive functioning and intellectual disabilities, attention and executive functioning deficits, learning disorders, emotional dysregulation and impairments in social processing are common among individuals with 22q11.2 DS. Identifying risk and protective/resilience factors that can be detected in early life and can predict neurodevelopmental outcomes for people with 22q11.2 DS is of significant clinical relevance and might allow for early detection and intervention. Given the focus of this review, we will discuss the possible contributing factors that influence the neurodevelopmental outcome in 22q1.2 DS, the cognitive phenotype in 22q11.2 DS, the different developmental trajectories across life span, and the implications for clinical practice and management.

PSYCHO-EDUCATIONAL CHARACTERIZATION OF PATIENTS WITH A 22Q11.2 DELETION. 878

The majority of patients with DiGeorge / velocardiofacial syndrome have a 22q11.2 microdeletion, demonstrable by fluorescent in-situ hybridization. As part of a prospective study of patients with such deletions, Wechsler IQ measures were administered to 13 subjects (8 female, 5 male; age range 3y1m-20y10m). Full-scale IQ (FS-IQ) averaged 74.8 ± 9.8 (mean ± standard deviation), with 4/13 subjects scoring in the low-average or average ranges. A significant discrepancy was found between mean Verbal IQ (V-IQ) and Performance IQ (P-IQ) scores (82.8 ± 12.1 vs. 70.5 ± 9.2, Wilcoxon signed rank test, z=2.76, p P-IQ profile, and this discrepancy was statistically significant in 7 subjects.