Chromosome 22q11 Deletion Syndrome Research Articles

CTEV WITH MEGA URINARY BLADDER: A CASE REPORT

Congenital talipes equino varus (CTEV), also known as congenital club foot is one of the common developmental deformities occurring at ankle, subtalar and metatarsal joints. Three elements comprise this deformity- equinus, inversion of foot and adduction of the forefoot relative to the hind-foot and equinus. The incidence of the deformity is 1 per 1000 live births. 20% of cases are associated with distal arthrogryposis, congenital myotonic dystrophy, myelomeningocele, amniotic band sequence and genetic syndromes such as trisomy 18 or chromosome 22q11 deletion syndrome, in the remaining cases the deformity is isolated and the exact etiology is unknown. We are presenting a case of aborted male fetus of 20 weeks with congenital talipes equino varus in left foot with enlarged urinary bladder. The purpose of this report is to document the association of CTEV with enlarged urinary bladder.

Prevalence and treatment of psychiatric disorders other than psychosis in children and adolescents with 22q11DS: Examining associations with social and role functioning

Individuals with chromosome 22q11 deletion syndrome (22q11DS) have high rates of psychotic disorders. Less is known about their psychopathology and how it is treated prior to the peak period of risk for psychotic disorder. There is also a lack of evidence on how functioning is impacted by psychopathology in this population. The aim of this study was to investigate the prevalence and treatment of non-psychotic psychiatric disorders, and how these factors are associated with psychosocial functioning in children and adolescents with 22q11DS. 126 individuals with 22q11DS aged 8–17 participated in the study. Participants were assessed for psychiatric diagnoses, social and role functioning, anxiety and depressive symptoms and IQ. Information on current treatments was collected. 52.4% of the sample presented with at least one psychiatric disorder. Mood and anxiety disorders were the most frequent, followed by behavioural disorder. Individuals with a psychiatric disorder had significantly lower general, role and social functioning. Only 27% of participants with a psychiatric diagnosis were receiving any mental health treatment at the time of assessment. Findings suggest the high prevalence of psychiatric disorders in youth with 22q11DS, which significantly impacts psychosocial functioning. Despite this, psychiatric disorders tend to remain untreated in this population.

染色体22q11欠失症：発見と合併心疾患

染色体22q11欠失症：発見と合併心疾患

Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge/22q11 Deletion Syndrome

ABSTRACTWe assessed feeding-related developmental anomalies in the LgDel mouse model of chromosome 22q11 deletion syndrome (22q11DS), a common developmental disorder that frequently includes perinatal dysphagia – debilitating feeding, swallowing and nutrition difficulties from birth onward – within its phenotypic spectrum. LgDel pups gain significantly less weight during the first postnatal weeks, and have several signs of respiratory infections due to food aspiration. Most 22q11 genes are expressed in anlagen of craniofacial and brainstem regions critical for feeding and swallowing, and diminished expression in LgDel embryos apparently compromises development of these regions. Palate and jaw anomalies indicate divergent oro-facial morphogenesis. Altered expression and patterning of hindbrain transcriptional regulators, especially those related to retinoic acid (RA) signaling, prefigures these disruptions. Subsequently, gene expression, axon growth and sensory ganglion formation in the trigeminal (V), glossopharyngeal (IX) or vagus (X) cranial nerves (CNs) that innervate targets essential for feeding, swallowing and digestion are disrupted. Posterior CN IX and X ganglia anomalies primarily reflect diminished dosage of the 22q11DS candidate gene Tbx1. Genetic modification of RA signaling in LgDel embryos rescues the anterior CN V phenotype and returns expression levels or pattern of RA-sensitive genes to those in wild-type embryos. Thus, diminished 22q11 gene dosage, including but not limited to Tbx1, disrupts oro-facial and CN development by modifying RA-modulated anterior-posterior hindbrain differentiation. These disruptions likely contribute to dysphagia in infants and young children with 22q11DS.

Sinus of Valsalva Aneurysm Rupture: An Unusual Presentation of Chromosome 22q11.2 Deletion: A Case Report

Sinus of Valsalva aneurysm (SVA) is defined as a weakness in the aortic valve wall, immediately above the attachments of each of the aortic cusps. This weakness can rupture and create an aortocardiac fistula. There are many congenital heart defects associated with chromosome 22q11 deletion, especially involving the aortic arch and its branches. SVA is not an anomaly usually associated with chromosome 22 deletion. We report the case of a 19-year-old female who presented to our institution with SVA rupture. She was subsequently diagnosed with chromosome 22q11 deletion syndrome. Despite dysmorphic facial features and a learning disability, our patient had not been diagnosed with the chromosome abnormality. SVA is a rare congenital heart defect and has only once previously been reported in a child with a chromosome 22q11 deletion. We report the first case where aneurysm rupture preceded the chromosomal findings. Chromosome 22q11 deletion could be missed due to either the unfamiliarity of physicians with the syndrome or the variability and subtlety of the phenotype. This was demonstrated by our patient who, at age 19 after presenting with an SVA rupture, prompted physicians to find an explanation for her coexisting dysmorphic features and her learning disability.

Delayed-Onset Hypoparathyroidism in an Adolescent with Chromosome 22Q11 Deletion Syndrome

To describe the first case of established chromosome 22q11 deletion syndrome with late onset presentation of hypocalcemia secondary to hypoparathyroidism. We present the history, clinical and laboratory investigations, and management of a 17-year-old adolescent boy who presented with 3 separate seizures secondary to hypocalcemia. This patient had an established diagnosis of chromosome 22q11 deletion syndrome at the time of the seizure presentations, but had previously normal calcium levels. Hypocalcemia was noted during each seizure, with corrected calcium levels ranging from 6.64 to 7.76 mg/dL (reference range, 8.52 to 10.52 mg/dL). The hypocalcemia was secondary to hypoparathyroidism, with parathyroid hormone levels < 2.75 pg/mL (reference range, 22.9 to 68.75 pg/mL). He was treated with calcitriol, 0.5 μg daily, and calcium carbonate, 2,400 mg daily, leading to normalization of serum calcium and resolution of seizures. Chromosome 22q11 deletion syndrome is a relatively common genetic disorder with a wide variety of phenotypic manifestations including cardiac abnormalities, abnormal facies, thymic dysfunction, cleft palate, and hypocalcemia. This case shows that medical practitioners should be aware that hypocalcemia can present after an established diagnosis, which has implications for the management of this disorder.

Social skills and associated psychopathology in children with chromosome 22q11.2 deletion syndrome: implications for interventions

Although distinctive neuropsychological impairments have been delineated in children with chromosome 22q11 deletion syndrome (22q11DS), social skills and social cognition remain less well-characterised. To examine social skills and social cognition and their relationship with neuropsychological function/behaviour and psychiatric diagnoses in children with 22q11DS. Sixty-six children with 22q11DS and 54 control participants underwent neuropsychological testing and were administered the Diagnostic Analysis of Non-Verbal Accuracy (DANVA) for face and auditory emotion recognition, a measure of social cognition: their parents/guardians were administered the Social Skills Rating System (SSRS) - parent version, Child Behavior Checklist (CBCL) - parent version and the Computerised Diagnostic Interview Schedule for Children (C-DISC). The 22q11DS group exhibited significantly lower social skills total score and more problem social behaviours, lower neurocognitive functioning, higher rates of anxiety disorders and more internalising symptoms than the control group. Participants with 22q11DS also exhibited significant deficits in their ability to read facial expressions compared with the control group, but performed no differently than the control participants in the processing of emotions by tone of voice. Within the 22q11DS group, higher social competency was correlated with higher global assessment of functioning and parental socio-economic status. Social competency was worse in those with anxiety disorders, attention deficit hyperactivity disorder, more than two psychiatric diagnoses on the C-DISC and higher internalising symptoms. No significant correlations of SSRS scores were seen with IQ, executive functions, attention, or verbal learning and memory. No correlations were found between social cognition and social skill scores. Our results indicate that social skills in children with 22q11DS are associated with behaviour/emotional functioning and not with neurocognition. Thus, treating the behaviour or emotional problems such as attention deficit hyperactivity disorder and anxiety disorders may provide a pathway for improving social skills in these children.

Molecular Mechanisms in 22q11 Deletion Syndrome

It is now well recognized that as well as having a characteristic facial dysmorphology and a range of congenital abnormalities, individuals with chromosome 22q11 deletion syndrome (22q11DS) have a greatly increased risk of developing psychosis, in particular schizophrenia. The majority of deletions span a large 3Mb region at 22q11. However, the presence of affected individuals carrying smaller deletions have not been sufficient to satisfactorily reduce the critical region for the behavioral phenotype beyond a ~1.5Mb region that contains at least 28 genes. By having a shared genetic variant that greatly increases risk to psychosis, individuals with 22q11DS are a relatively homogeneous population to study psychiatric disease. Despite this, the large volume of research performed over the last 15 years suggest that the mechanism by which haploinsufficiency at 22q11 increases risk to psychiatric illness is likely to be complex and it remains uncertain why individuals carrying identical 22q11 deletions can present with such a wide range of neuropsychiatric phenotypes. This review will therefore consider the ways in which deletions at 22q11 are expected to increase risk to develop psychiatric disease by summarizing the work that has been done to investigate three of the most likely disease causing mechanisms: (a) gene dosage sensitivity; (b) unmasking of recessive alleles or functional polymorphism; and (c) position effect.

Progress on chromosome 22q11 deletion syndrome

Chromosome 22qll deletion syndrome(22q11DS) is a common chromosomal microdeletion syndrome. Its clinical manifestation is complex, comprising congenital heart disease, dysmorphic facial, immunodeficiency, endocrine dysfunction and so on. The syndrome has a population prevalence of approximately 1/2500-1/4000. There have been many recent advances in understanding of the clinical manifestation, behavior and psychiatric problems and the mechanisms leading to the specific phenotypic features in chromosome 22q11 deletion syndrome. Asymmetric recombination of homologous low copy repetitives in the deletion region causes the deletion of 22q11. TBX1 is the dominant gene contributing to the phenotype. Key words: 22q11 deletion syndrome; Chromosome 22; Genomic disorder

A case of juvenile idiopathic polyarticular arthritis complicated by IgA deficiency in 22q11 deletion syndrome

Chronic arthritis may occur in association with antibody deficiency and chromosomal aberrations. This report presents the case of a 6-year-old girl with chromosome 22q11 deletion syndrome and chronic arthritis. The onset of arthritis occurred at 4years of age. The chronic arthritis course has been the polyarticular type. Neither antinuclear antibody nor rheumatoid factor was detected. Serum IgA was extremely low. She was diagnosed with juvenile idiopathic polyarticular arthritis (JIA) complicated by IgA deficiency in the 22q11 deletion syndrome. There is an increased prevalence of chronic arthritis in association with 22q11 deletion syndrome with IgA deficiency, but the reasons for this association are unknown. This study evaluated the possible correlation between cytokines and the susceptibility to chronic arthritis in the 22q11 deletion syndrome with IgA deficiency. The expression of pro-inflammatory cytokines such as IL-8, IL-6, MIP-1β, and MCP-1 suggests that T and B cells, macrophages and neutrophils modulate joint inflammation by an immune response. And the presence of IL-10 and IL-5 might suggest that the synovitis is associated with JIA and IgA deficiency.

Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients

Patients with chromosome 22q11 deletion syndrome exhibit significant phenotypic variability. Epidemiologic data suggest a higher incidence in Hispanics, but limited clinical information is available from Latin-American patients. We describe the clinical features of Chilean patients with 22q11 deletion syndrome and compare their findings with those reported in large European, Japanese and US series. Data were obtained from 208 patients from five medical centers. Mean age at diagnosis was 5.2 years, with a median of 2.3 years. Congenital heart defects were present in 59.6%, lower than other large series that averaged 75.8%. Palate abnormalities were present in 79%, higher than previous reports averaging 56%. Patients with congenital heart disease were diagnosed earlier (median 0.3 years of age) than those without heart defects (median 5.6 years) and had greater mortality attributable to the syndrome (9.8% vs 2.4%, respectively). The differences in frequencies of major anomalies may be due to growing awareness of more subtle manifestations of the syndrome, differences in clinical ascertainment or the presence of modifier factors. These observations provide additional data useful for patient counseling and for the proposal of health care guidelines.

Identification of Candidate Genes for Congenital Ventricular Septal Defects With HSA22q11 Loss of Heterozygosity

Ventricular septal defect (VSD) is one of the major forms of congenital heart disease (CHD) in individuals with Homo sapiens chromosome 22q11 (HSA22q11) deletion syndrome. The objective was to identify candidate genes associated with VSD located within HSA22q11 by analyzing loss of heterozygosity (LOH) using microsatellite genotyping and by gene dosage analysis in seven candidate genes. The study involved 82 families with CHD, which included 261 individuals (85 patients and 176 siblings and parents). All were screened for LOH in the HSA22q11 region by microsatellite (n=10) genotyping. Bioinformatic strategies were used to characterize seven candidate genes located within this region in greater detail. Quantitative polymerase chain reaction analysis was used to determine the dosages of the seven candidate genes in 16 patients with LOH of HSA22q11. Overall, 42 out of 85 patients (49.4%) with CHD had at least one LOH in the HSA22q11 region. Moreover, LOH of HSA22q11 was found in 17 out of 29 patients with a VSD and in three out of four families with two offspring affected by CHD. Dosage analysis of the seven candidate genes showed recurrent heterozygous deletion of HIRA, GNB1L and TUBA8 genes in 16 VSD patients with a LOH of HSA22q11. Microsatellite genotyping identified LOH of HSA22q11 in several types of CHD. Heterozygous deletion of HIRA, GNB1L or TUBA8 genes might play an important role in ventricular septum development. Since CHD can be a familial disease, screening the siblings of a proband for LOH of HSA22q could be valuable for early diagnosis and treatment.

Unambiguous molecular detections with multiple genetic approach for the complicated chromosome 22q11 deletion syndrome

BackgroundChromosome 22q11 deletion syndrome (22q11DS) causes a developmental disorder during the embryonic stage, usually because of hemizygous deletions. The clinical pictures of patients with 22q11DS vary because of polymorphisms: on average, approximately 93% of affected individuals have a de novo deletion of 22q11, and the rest have inherited the same deletion from a parent. Methods using multiple genetic markers are thus important for the accurate detection of these microdeletions.MethodsWe studied 12 babies suspected to carry 22q11DS and 18 age-matched healthy controls from unrelated Taiwanese families. We determined genomic variance using microarray-based comparative genomic hybridization (array-CGH), quantitative real-time polymerase chain reaction (qPCR) and multiplex ligation-dependent probe amplification (MLPA).ResultsChanges in genomic copy number were significantly associated with clinical manifestations for the classical criteria of 22q11DS using MPLA and qPCR (p < 0.01). An identical deletion was shown in three affected infants by MLPA. These reduced DNA dosages were also obtained partially using array-CGH and confirmed by qPCR but with some differences in deletion size.ConclusionBoth MLPA and qPCR could produce a clearly defined range of deleted genomic DNA, whereas there must be a deleted genome that is not distinguishable using MLPA. These data demonstrate that such multiple genetic approaches are necessary for the unambiguous molecular detection of these types of complicated genomic syndromes.

Supportive Evidence for Reduced Expression of GNB1L in Schizophrenia

Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia.

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P=6.1 x 10(-6)). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed P<or=0.01). Our approach--of screening genes involved in a particular pathway for association--resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.

A patient with both Gilles de la Tourette's syndrome and chromosome 22q11 deletion syndrome: clue to the genetics of Gilles de la Tourette's syndrome?

This is the first published case description of the association of Gilles de la Tourette's syndrome (GTS) and chromosome 22q11.2 deletion syndrome (22q11DS; previously referred to as CATCH-22 syndrome). The co-occurrence of GTS, 22q11DS, and their behavioral/neuropsychiatric abnormalities may be due to the common endophenotypic mechanisms shared by these disorders, rather than due to specificity for GTS. Research into this genomic region may lead to advancement in neurobehavioral/neuropsychiatric genetics, which will help us in further explicating a broader perspective of gene–brain–behavior interrelationships and of the genetic underpinnings of various developmental psychopathologies and behavioral/neuropsychiatric disorders that are common to both GTS and 22q11DS. Our report should warrant further genetic investigations of the chromosome 22q11.2 deletion site using alternative strategies to the quantitative trait loci endophenotype-based approach, which would be useful for establishing the biological and molecular underpinnings of obsessive–compulsive disorder, attention-deficit/hyperactivity disorder, and GTS.

Symptomatic anal anomalies in chromosome 22q11 deletion syndrome: a report of three patients

Deletion of chromosome 22q11 is a common genetic condition with varying clinical presentation ranging from neonatal fatality to patients whose presentation to medical services will be prompted after a few years by speech delay or mild developmental concerns. While most published data relating to patients with 22q11 deletions has focused on the "classical" presentation of the condition with cardiac manifestations, hypocalcaemia and velopharyngeal insufficiency, a much wider range of clinical presentations can characterise this syndrome. Anal anomalies, comprising imperforate anus and symptomatic anal stenosis, are a rarely described presentation of this multisystem disorder. In this report we document three patients presenting to paediatric services with symptoms attributed initially to symptomatic anal stenosis/atresia.

Anesthetic management of a child with chromosome 22q11 deletion syndrome

Chromosome 22q11 deletion syndrome (22q11DS) is a congenital anomaly characterized by cardiovascular, oropharyngeal, immunologic, endocrine, and neurodevelopmental abnormalities. We successfully managed a 6-year-old girl with 22q11DS with general anesthesia. Potential problems in anesthetic management of patients with 22q11DS are reviewed.

A method for accurate detection of genomic microdeletions using real-time quantitative PCR

BackgroundQuantitative Polymerase Chain Reaction (qPCR) is a well-established method for quantifying levels of gene expression, but has not been routinely applied to the detection of constitutional copy number alterations of human genomic DNA. Microdeletions or microduplications of the human genome are associated with a variety of genetic disorders. Although, clinical laboratories routinely use fluorescence in situ hybridization (FISH) to identify such cryptic genomic alterations, there remains a significant number of individuals in which constitutional genomic imbalance is suspected, based on clinical parameters, but cannot be readily detected using current cytogenetic techniques.ResultsIn this study, a novel application for real-time qPCR is presented that can be used to reproducibly detect chromosomal microdeletions and microduplications. This approach was applied to DNA from a series of patient samples and controls to validate genomic copy number alteration at cytoband 22q11. The study group comprised 12 patients with clinical symptoms of chromosome 22q11 deletion syndrome (22q11DS), 1 patient trisomic for 22q11 and 4 normal controls. 6 of the patients (group 1) had known hemizygous deletions, as detected by standard diagnostic FISH, whilst the remaining 6 patients (group 2) were classified as 22q11DS negative using the clinical FISH assay. Screening of the patients and controls with a set of 10 real time qPCR primers, spanning the 22q11.2-deleted region and flanking sequence, confirmed the FISH assay results for all patients with 100% concordance. Moreover, this qPCR enabled a refinement of the region of deletion at 22q11. Analysis of DNA from chromosome 22 trisomic sample demonstrated genomic duplication within 22q11.ConclusionIn this paper we present a qPCR approach for the detection of chromosomal microdeletions and microduplications. The strategic use of in silico modelling for qPCR primer design to avoid regions of repetitive DNA, whilst providing a level of genomic resolution greater than standard cytogenetic assays. The implementation of qPCR detection in clinical laboratories will address the need to replace complex, expensive and time consuming FISH screening to detect genomic microdeletions or duplications of clinical importance.

Altered functioning of the cingulate gyrus in two cases of chromosome 22q11 deletion syndrome

The 22q11 microdeletion syndrome (22q11-DS) is strongly associated with schizophreniform disorders and, in turn, the 22q11 deletion region harbours several candidate genes for schizophrenia. Here, we present the case of an adolescent female patient with 22q11-DS associated with impaired cognitive abilities and behavioural abnormalities. The patient was studied with magnetic resonance imaging (MRI) and positron emission tomography (PET) as well as extensive neurophysiological investigations. Although no structural or functional abnormalities were found in MRI and PET, assessment of event-related potentials elicited during the Continuous Performance Test revealed a lack of NoGo anteriorisation. The latter was replicated in a second case of 22q11-DS with schizoaffective disorder but devoid of a severe somatic syndrome. This electrophysiological finding, which indicates modified functioning of the cingulate gyrus, has previously been demonstrated only in patients suffering from schizophrenia and attention deficit/hyperactivity disorder, two psychopathological conditions frequently associated with 22q11-DS. We conclude that more extensive study of NoGo anteriorisation as a potential endophenotype of 22q11-DS patients at risk for 22q11-associated psychiatric conditions is warranted.