Chromosome 22q11.2 deletionsyndrome (22q11.2DS) results from a one point 5 to three-megabase deletion on the q11 band of chromosome 22 (Driscoll et al. 1993; Scambler 2000; Botto et al. 2003). Alongside physical, cognitive, and socioemotional impairments, 22q11.2DS confers a 25- to 30-fold increased risk for schizophrenia over the general population. Only the rare occurrence of having two parents or a monozygotic twin with schizo- phrenia confers a greater risk. In patients with a diagnosis of schizophrenia, there is a 20- to 80-fold elevated prevalence of the deletion compared to the general population (Murphy 2002; Bassett et al. 2003). There are no clear clinical phenotypic differences between schizo- phrenic patients with and without 22q11.2DS (Bassett et al. 2003; Arinami 2006). Early identification makes 22q11.2DS an ideal research population for prospectively investigating risk and protective factors for schizophrenia. Recently, Karayiorgou and colleagues (2010) highlight- ed the complexity of the pathogenesis and pathophysiology of 22q11.2DS, especially as it relates to predicting psychosis and further indicating the need for longitudinal studies. The single prospective study of children with 22q11.2DS (Gothelf et al. 2007) found that baseline anxiety and mood, lower verbal IQ, and psychotic symptoms, along with catechol-O-methyltransferase (COMT) genotype, pre- dicted young adult onset and severity of psychosis. Somewhat surprisingly, given the richly developed human and animal literature on the effects of anxiety and stress on brain development and risk of neuropsychiatric disease (Bremner et al. 1997; Heim and Nemeroff 2001; McEwen 2003; Marco et al. 2010) and schizophrenia in particular (Read et al. 2005; Morgan and Fisher 2007; Walker et al. 2008; Freeman and Fowler 2009), there has been no E. A. Beaton ( * ) : T. J. Simon
OBJECTIVES. CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome and chromo- some 22q11.2 deletionsyndrome 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.
 Schneider, M., Debbane, M., Bassett, A.S., Chow, E.W., Fung, W.L., van den Bree, M., Owen, M., Murphy, K.C., Niarchou, M., Kates, W.R., Antshel, K.M., Fremont, W., McDonald-McGinn, D.M., Gur, R.E., Zackai, E.H., Vorstman, J., Duijff, S.N., Klaassen, P.W., Swillen, A., Gothelf, D., Green, T., Weizman, A., Van Amelsvoort, T., Evers, L., Boot, E., Shashi, V., Hooper, S.R., Bearden, C.E., Jalbrzikowski, M., Armando, M., Vicari, S., Murphy, D.G., Ousley, O., Campbell, L.E., Simon, T.J. and Eliez, S. (2014) Psychiatric Disorders from Childhood to Adulthood in 22q11.2 De- letion Syndrome: Results from the International Consortium on Brain and Behavior in 22q11.2 DeletionSyndrome . American Journal of Psychiatry , 171, 627-639. https://doi.org/10.1176/appi.ajp.2013.13070864
Some patients present with asymptomatic hypocalcemia and inappropriately low parathyroid hormone levels that leads to fluorescence in situ hybridization and the diagno- sis of chromosome 22q11.2 deletionsyndrome [5,7,8]. The majority of patients are diagnosed soon after birth, when the transport of calcium from mother to fetus is abruptly interrupted. The low serum calcium level gener- ally improves over the first year of life as the parathyroid gland hypertrophies and the dietary calcium intake Result of FISH analysis using LSI probe (TUPLE 1) from DiGeorge/velocardiofacial syndrome critical region
This study investigated three conversational subskills in children with 22q11.2 deletionsyndrome (22q11.2DS, n = 8, ages 7–13) and Williams syndrome (WS, n = 8, ages 6– 12). We re-evaluated these subskills after 18 to 24 months and compared them to those of peers with idiopathic intellectual disability (IID) and IID and comorbid autism spectrum disorders (IID+ASD). Children with 22q11.2DS became less actively involved over time. Lower assertiveness than in children with IID was demonstrated. They seemed less impaired in terms of accounting for listener’s knowledge than children with IID+ASD. Children with WS showed greater difficulties with discourse management compared to children with IID and 22q11.2DS. They had similar levels of conversational impairments to children with IID+ASD but these were caused by different shortcomings. Over time taking account of listener’s knowledge became challenging for them. Findings suggest that children with 22q11.2DS and those with WS would benefit from conversational skills support and that regular re-evaluation is needed to anticipate conversational challenges.
Of approximately 300 patients followed at the University Medical Center Utrecht and the 1300 patients from Children’s Hospital of Philadelphia, 26 patients (52 ears), 14 males and 12 females, un- derwent radiologic imaging of the temporal bones (11 patients from the University Medical Center Utrecht, 15 patients from Children’s Hospital of Philadelphia). The indications for imaging were hearing loss that could not be explained by otoscopic find- ings (n ⫽ 10), chronic otitis media (n ⫽ 13), both unexplained hearing loss and chronic otitis media (n ⫽ 2), or aureal atresia (n ⫽ 1). MR imaging was performed in 1 patient; all other patients underwent CT of the temporal bones. One patient likely had a second genetic disorder, in addition to a microdeletion on chro- mosome 22q11.2.
Of the 58 subjects with 22q11DS imaged, 27 had incidental find- ings (47%). There were no statistically significant differences in age, sex, or race between subjects with and without incidentals (Table 1). CSP and WM abnormalities were the most common incidental findings (Table 2). Secondary review of the 11 individ- uals with CSP demonstrated that CSP et vergae was present in all reported cases (Fig 1). Representative examples of other common incidental findings are provided in Fig 2. Five individuals in the sample presented with multiple incidental findings: 1) CSP and ventricular prominence, 2) white matter hyperintensities and a 12-mm pineal cyst, 3) multiple white matter hyperintensities and a nonspecific hypointensity in the left thalamus, 4) CSP and ab- sent left ICA flow, and 5) ventricular asymmetry and a nonspecific white matter hyperintensity.
To assess if the temperament subscales at baseline pre- dicted the future emergence of a psychotic disorder in 22q11.2DS, we conducted a logistic regression with the presence/absence of a psychotic disorder at follow-up en- tered as the outcome variable. The predicting variables were gender, age, and full scale IQ at baseline assessment, and the three baseline EAS subscale scores that distin- guished between 22q11.2DS and controls (Shyness, Emo- tionality, and Activity). Of all the potential predictors, only baseline scores of Shyness were significantly associated with the presence of a psychotic disorder at follow-up (Odds Ratio = 1.8, P = 0.01), with this regression model ac- counting for 44% of the variance. The 22q11.2DS individ- uals who subsequently developed a psychotic disorder had significantly higher baseline Shyness scores than those who did not develop a psychotic disorder (Figure 2).
deficits. Consistent exposure to stressful stimuli leads to increased blood pressure and heart rate will later lead to heart disease, hypertension, and a weakened immune system, among other outcomes (Baum & Posluszny, 1999; McEwen, 2003). Cognitively, increased allostatic load is associated with synaptic and dendritic changes and suppressed neurogenesis, which results in a weakened ability for the body to properly respond to stressors (Arnsten, 2009; Brown, Rush, & McEwen, 1999; Juster, McEwen, & Lupien, 2010). Interleukin 6 (IL-6), a pro-inflammatory cytokine, acts to incite immune response after trauma. It plays a crucial role in preparing the body to react to illness as it mediates fever by increasing the body’s temperature. In response to chronic stress exposure, though, the body overproduces IL-6. As an individual increases in age, this exaggerated production is associated with osteoporosis, arthritis, type 2 diabetes, and certain cancers (Kiecolt-Glaser et al., 2003). Inflammation is seen in a variety of patient populations including schizophrenia, autism spectrum disorder, Alzheimer’s disease, and in those with chronic anxiety, depression, and stress (de Pablos et al., 2006; Maes et al., 1998; Rojo,
Abstract: The 22q11.2 deletionsyndrome (22q11DS) is caused by an autosomal dominant microdeletion of chromosome 22 at the long arm (q) 11.2 band. The 22q11DS is among the most clinically variable syndromes, with more than 180 features related with the deletion, and is associated with an increased risk of psychiatric disorders, accounting for up to 1%–2% of schizophrenia cases. In recent years, several genes located on chromosome 22q11 have been linked to schizophrenia, including those encoding catechol-O-methyltransferase and proline dehydrogenase, and the interaction between these and other candidate genes in the deleted region is an important area of research. It has been suggested that haploinsufficiency of some genes within the 22q11.2 region may contribute to the characteristic psychiatric phenotype and cognitive functioning of schizophrenia. Moreover, an extensive literature on neuroimaging shows reductions of the volumes of both gray and white matter, and these findings suggest that this reduction may be predictive of increased risk of prodromal psychotic symptoms in 22q11DS patients. Experimental and standardized cognitive assessments alongside neuroimaging may be important to identify one or more endophenotypes of schizophrenia, as well as a predictive prodrome that can be preventively treated during childhood and adolescence. In this review, we summarize recent data about the 22q11DS, in particular those addressing the neuropsychiatric and cognitive phenotypes associated with the deletion, underlining the recent advances in the studies about the genetic architecture of the syndrome.
Background: Chromosome 22q11.2 deletionsyndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention. Methods: Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices.
Chromosome 22q11.2 deletionsyndrome, also called velocardiofacial syndrome or DiGeorge syndrome, is caused by a microdeletion on the long arm of chromosome 22 at band 11.2. 1 Phenotypic presentation is variable, including congenital heart disease, velopharyngeal abnormalities, immunodeficiency, and cognitive impairment. 2 Anxiety, depressive disorders, and attention deficit hyperactivity disorder (ADHD) are prevalent in childhood, 3 and by adulthood, up to 30% of patients with 22q11deletionsyndrome develop psychosis. 4 Additionally, children with 22q11deletionsyndrome have brain structural abnormalities, including reduced gray matter and white matter volumes and abnormal white matter connectivity, which have been associated with the neuropsychological impairments. 5 The neurocognitive phenotype of 22q11deletionsyndrome includes impaired verbal working memory. 6 Working memory, the mental system permitting a person to retain and manipulate a limited amount of information for a limited time, 7 is necessary for reading comprehension 8 and predicts general fluid intelligence. 9 The importance of working memory in cognition makes understanding its neural underpinnings imperative to delineating the pathogenesis of cognitive impairments in 22q11deletionsyndrome. Adults performing working memory tasks during functional magnetic resonance imaging (fMRI) typically show blood oxygenation level dependent signal in both hemispheres in prefrontal areas (dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, frontal operculum, frontal pole, rostral prefrontal cortex); premotor cortex and supplementary motor area; dorsal cingulate; parietal areas (precuneus, inferior parietal lobule, and posterior parietal cortex); thalamus; 10 and inferior temporal lobe. 11 Similar areas are activated in children, 12 but extent of activation changes as a function of development from childhood to early adulthood. 13
Chromosome 22q11.2 deletionsyndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletionsyndrome. We describe two further cases of chromosome 22q11.2 deletionsyndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletionsyndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS.
60. Schneider M, Debbané M, Bassett AS, Chow EWC, Fung WLA, van den Bree MBM, Owen M, Murphy KC, Niarchou M, Kates WR, Antshel KM, Fremont W, McDonald-McGinn DM, Gur RE, Zackai EH, Vorstman J, Duijff SN, Klaassen PWJ, Swillen A, Gothelf D, Green T, Weizman A, Van Amelsvoort T, Evers L, Boot E, Shashi V, Hooper SR, Bearden CE, Jalbrzikowski M, Armando M, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletionsyndrome: results from the international consortium on brain and behavior in 22q11.2 deletionsyndrome. Am J Psychiatry. 2014;171(6):627 – 39. 61. Armando M, Girardi P, Vicari S, Menghini D, Digilio MC, Pontillo M, Saba R,
Abstract: Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete prog- ress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.2 microdeletions, and more recently in large-scale, genome-wide case-control studies. These advances promise to help many families afflicted with this disease. In this review, we critically appraise recent developments in the field of schizophrenia genetics through the lens of immediate clinical applicability. Much work remains in translating the recent surge of genetic research discoveries into the clinic. The epidemiology and basic genetic parameters (such as penetrance and expres- sion) of most genomic disorders associated with schizophrenia are not yet well characterized. To date, 22q11.2 deletionsyndrome is the only established genetic subtype of schizophrenia of proven clinical relevance. We use this well-established association as a model to chart the pathway for translating emerging genetic discoveries into clinical practice. We also pro- pose new directions for research involving general genetic risk prediction and counseling in schizophrenia.
DNA was extracted from blood samples collected on all subjects. Fluorescence in situ hybridisation (FISH) (Oncor Inc, Gaithersburg, MD, USA) confirmed 3 Mb 22q11.2 deletion in 22q11DS cases while chromosome 22q11.2 deletion was excluded in all controls. The COMT Val 158 Met polymorphism was genotyped using the SNaPshot technique of single base extension (Applied Biosystems, Foster City, CA, USA). The initial PCR reaction was performed using a Touchdown-PCR-protocol, with the following primers: forward: 5 ′ -ACTGTGGCTACTCAGCTGTG-3 ′ and reverse: 5′-CCTTTTTCCAGGTCTGACAA-3′. The allele at the single nucleotide polymorphism (SNP) position was deter- mined by use of a 30 bp extension primer (5 ′ -ATCACC CAGCGGATGGTGGATTTCGCTGGC-3′). All alleles were resolved on an ABI 3100 sequencer (Applied Biosystems, Foster City, CA, USA).
Fluorescence in situ hybridization (FISH) is the current method of choice for detecting 22q11.2 microdeletions. FISH is a highly accurate and reliable test that can also be used for prenatal diagnosis. However, it is limited to a single target sequence within the proximal 22q11.2 deletion region, and some atypical deletions do not include the region analyzed using FISH with commonly used probes (such as TUPLE1). A polymerase chain reaction-based assay (multiplex ligand- dependent probe amplification) is used widely in Europe, and is becoming accepted increasingly in the US because it has a rapid turnaround time, it is more cost-effective, and
fects. Parents waited immediately outside the testing room for their children and were available to the chil- dren as needed. For all administrations, the order of the booklets (1-4) was maintained. In some cases, UPSIT smell test booklets were administered between other subtests or on consecutive mornings. During testing, some children asked for clarification of particular stim- ulus items, and testers provided analogous response op- tions. Response options that were queried most fre- quently included turpentine, “like paint cleaner”; menthol or wintergreen, “like some cough drops”; cedar, “like a Christmas tree”; and leather, “like new shoes.” No UPSIT items included response options that belonged to similar odor classes (eg, 2 types of mint), so these anal- ogies were enough to trigger recognition while not invali- dating particular items. All children who were included in these analyses were healthy, without upper respiratory infection, and unmedicated at the time of testing.
Background: The 22q11.2 deletion (22qDS) is a microdeletion syndrome which commonly leads to an uneven profile of Learning difficulties (LD), with superior verbal compared to nonverbal intellectual and memory functions in children and adolescents. However, in adult samples these differences reduce. There are two accounts of the reduction in the verbal-nonverbal discrepancy with age. The dominant hypothesis is that normative measures of verbal intelligence decline and so approximate nonverbal intelligence. The other is that normative nonverbal intelligence increases while verbal intelligence remains stable. Few studies have investigated this longitudinally and none with a UK sample. Aim: The aim was to examine longitudinally the pattern of developmental cognitive changes in verbal and nonverbal intellectual and memory functions. Method: Twenty-four participants with 22qDS, who were previously cognitively assessed between 2004- 2008 were re-examined in 2011. Intellectual, memory and executive functions were assessed.