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Purpose: This study aims to explore the correlation between fetal aberrant right subclavian artery (ARSA) and chromosomal disorders, with a specific focus on Down syndrome and DiGeorge syndrome., Methods: From November 2017 to February 2020, we conducted fetal anomaly screening and assessed the fetal heart in 8494 at our institution. The right subclavian artery tracing was assessed using Doppler ultrasonography following the 3-vessel and tracheal views (3VTV) in the fetal heart scan., Results: ARSA was found in 31 fetuses, which accounts for 0.36% of the total of 8494 fetuses. 96.8% of fetuses with ARSA were found to have normal chromosomal analysis. We identified only one case of trisomy 21 as the chromosomal condition present. In 80% of the identified ARSA, there were no additional associated findings., Conclusion: ARSA is a rare condition that often does not manifest any concomitant abnormalities. The majority of ARSA instances identified in the second trimester are euploid. If ARSA is the only sonographic finding during fetal anomaly screening and there are no maternal or laboratory risk factors, further evaluation with non-invasive diagnostics may be recommended. Non-invasive genetic testing may be used for additional investigation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Enlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra-cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.2 deletion syndrome., Methods: Case-control study of fetuses evaluated from 2016 to 2022. The study group included fetuses with laboratory confirmation of 22q11.2 deletion syndrome. The control group included pregnancies with conotruncal cardiac anomalies with normal microarray as well as structurally normal fetuses with normal microarray. The CSP and thymus were routinely measured during anatomical ultrasound in all patients at their initial visit at 27.1 ± 4.7 weeks. The CSP and thymus measurements were classified as abnormal if they were >95% or <5% for gestational age, respectively. The groups were compared using analysis of variance or Kruskal-Wallis for continuous variables and Fisher's exact test for categorical variables. Logistic regression was performed, and a Receiver Operating Characteristic (ROC) curve was constructed., Results: We identified 47 fetuses with 22q11.2 deletion syndrome and compared them to 47 fetuses with conotruncal anomalies and normal microarray and 47 structurally normal fetuses with normal microarray. 51% (24/47) of fetuses with 22q11.2 deletion syndrome had an enlarged CSP compared to 6% (3/47) of fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). Of the fetuses with 22q11.2 deletion syndrome, 83% (39/47) had a hypoplastic or absent thymus compared to 9% (4/47) of the fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). 87% (41/47) of the fetuses with 22q11.2 deletion syndrome had conotruncal cardiac anomalies. Logistic regression revealed that both enlarged CSP and hypoplastic/absent thymus were associated with 22q11.2 deletion syndrome. The area under the ROC curve for the two markers was 0.94., Conclusion: An enlarged CSP and hypoplastic/absent thymus appear to be part of the fetal phenotype of 22q11.2 deletion syndrome. These markers are associated with conotruncal anomalies in the setting of 22q11.2 deletion syndrome but not in normal controls or fetuses with conotruncal defects and normal microarrays., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Clinical features of 22q11.2 microdeletion syndrome (22q11.2DS) are highly variable between affected individuals and frequently include a subset of conotruncal and aortic arch anomalies. Many are diagnosed with 22q11.2DS when they present as a fetus, newborn or infant with characteristic cardiac findings and subsequently undergo genetic testing. The presence of an aortic arch anomaly with characteristic intracardiac anomalies increases the likelihood that the patient has 22q11.2 DS, but those with an aortic arch anomaly and normal intracardiac anatomy are also at risk. It is particularly important to identify the fetus at risk for 22q11.2DS in order to prepare the expectant parents and plan postnatal care for optimal outcomes. Fetal anatomy scans now readily identify aortic arch anomalies (aberrant right subclavian artery, right sided aortic arch or double aortic arch) in the three-vessel tracheal view. Given the association of 22q11.2DS with aortic arch anomalies with and without intracardiac defects, this review highlights the importance of recognizing the fetus at risk for 22q11.2 deletion syndrome with an aortic arch anomaly and details current methods for genetic testing. To assist in the prenatal diagnosis of 22q11.2DS, this review summarizes the seminal features of 22q11.2DS, its prenatal presentation and current methods for genetic testing., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories., (© 2024. The Author(s).)

22q11.2 Deletion Syndrome (22q11.2DS), the most common chromosomal microdeletion, presents as a heterogeneous phenotype characterized by an array of anatomical, behavioral, and cognitive abnormalities. Individuals with 22q11.2DS exhibit extensive cognitive deficits, both in overall intellectual capacity and focal challenges in executive functioning, attentional control, perceptual abilities, motor skills, verbal processing, as well as socioemotional operations. Heterogeneity is an intrinsic factor of the deletion's clinical manifestation in these cognitive domains. Structural imaging has identified significant changes in volume, thickness, and surface area. These alterations are closely linked and display region-specific variations with an overall increase in abnormalities following a rostral-caudal gradient. Despite the extensive literature developing around the neurocognitive and neuroanatomical profiles associated with 22q11.2DS, comparatively little research has addressed specific structure-function relationships between aberrant morphological features and deficient cognitive processes. The current review attempts to categorize these limited findings alongside comparisons to populations with phenotypic and structural similarities in order to answer to what degree structural findings can explain the characteristic neurocognitive deficits seen in individuals with 22q11.2DS. In integrating findings from structural neuroimaging and cognitive assessments, this review seeks to characterize structural changes associated with the broad neurocognitive challenges faced by individuals with 22q11.2DS.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis., Methods: Glx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms., Results: While no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers., Conclusions: We provide evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit impaired ability to process and understand emotions in others. We measured structural connectivity in children and adolescents with 22q11.2DS (n = 28) and healthy controls (n = 29). Compared to controls, those with 22q11.2DS had poorer social skills and more difficulty recognizing facial emotions. Children with 22q11.2DS also had higher fractional anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways. Right amygdala to fusiform gyrus fractional anisotropy values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. These findings provide insight into the neural origins of social skills deficits seen in 22q11.2DS and may serve as a biomarker for risk of future psychiatric problems., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Ki cer . There was an inverse linear effect of copy number variant number on striatal Ki cer value (B = -1.2 × 10 -3 , SE = 2 × 10 -4 , p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki cer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen's d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen's d = 2) groups. Moreover, Ki cer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers., (© 2021. The Author(s).)

Objectives: Recurrent chromosome 22q11.2 deletions cause 22q11 deletion syndrome (22q11DS), a multisystem disorder associated with high rates of schizophrenia. Neuroanatomical changes on brain MRI have been reported in relation to 22q11DS. However, to date no 22q11DS neuroimaging studies have examined cerebral blood flow (CBF). This exploratory case-control study seeks to identify differences in regional cerebral blood flow between 22q11DS subjects and controls, and their association with psychotic symptoms., Methods: This study of 23 adults used arterial spin labelling MRI to investigate voxel-wise CBF in 22q11DS individuals compared with age- and sex-matched healthy controls., Results: Four significant clusters, involving the right and left putamen, right fusiform gyrus and left middle temporal gyrus, delineated significantly elevated CBF in individuals with 22q11DS compared to controls. Post-hoc analysis determined that this elevation in CBF trended with psychotic symptom diagnosis within the 22q11DS group., Conclusions: These findings suggest possible relevance to schizophrenia risk and support further functional neuroimaging studies of 22q11DS with larger sample sizes to improve our understanding of the underlying pathophysiology.

Background: The 22q11.2 Deletion Syndrome (22q11.2DS) is considered the most reliable biological model to study genetic vulnerability to schizophrenia. It appears useful to investigate neuroanatomical characteristics of people with 22q11.2DS compared to chronic schizophrenia and healthy controls., Methods: The sample consisted of 16 individuals with a diagnosis of schizophrenia for over 10 years (SCZ>10), 14 with a diagnosis for less than 10 years (SCZ≤10), 11 patients with 22q11.2DS with no diagnosis of psychotic disorder (DEL, n=11) and 19 healthy controls (HCs, n=19). Global intelligence (IQ) was evaluated for all subjects. Voxel-Based Morphometry (VBM) was employed to investigate potential differences between groups in grey matter volumes., Results: VBM located the most significant difference between SCZ and HCs in the left medial frontal gyrus, where SCZ>10 group showed a significant reduction of grey matter volume; the same cluster resulted significantly decreased in DEL group compared to HCs as well. Despite the extensive grey matter abnormalities observed in 22q11.2DS, the DEL group showed the only significant differences compared to the SCZ>10 group in the right lingual gyrus volumes., Conclusions: Despite the small sample, our study identified a common area of grey matter loss both in idiopathic schizophrenia and 22q11.2DS.

Background: Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk of developing psychosis and cognitive impairments, which may be related to dopaminergic and glutamatergic abnormalities. Therefore, in this exploratory study, we examined the association between dopaminergic and glutamatergic functioning in 22q11DS. Additionally, the associations between glutamatergic functioning and brain volumes in 22q11DS and healthy controls (HC), as well as those between dopaminergic and cognitive functioning in 22q11DS, were also examined., Methods: In this cross-sectional, multimodal imaging study, glutamate, glutamine, and their combined concentration (Glx) were assessed in the anterior cingulate cortex (ACC) and striatum in 17 22q11DS patients and 20 HC using 7T proton magnetic resonance spectroscopy. Ten 22q11DS patients also underwent 18 F-fallypride positron emission tomography to measure dopamine D 2/3 receptor (D 2/3 R) availability in the ACC and striatum. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery., Results: No significant associations were found between ACC or striatal (1) glutamate, glutamine, or Glx concentrations and (2) D 2/3 R availability. In HC but not in 22q11DS patients, we found a significant relationship between ACC volume and ACC glutamate, glutamine, and Glx concentration. In addition, some aspects of cognitive functioning were significantly associated with D 2/3 R availability in 22q11DS. However, none of the associations remained significant after Bonferroni correction., Conclusions: Although our results did not reach statistical significance, our findings suggest an association between glutamatergic functioning and brain volume in HC but not in 22q11DS. Additionally, D 2/3 R availability seems to be related to cognitive functioning in 22q11DS. Studies in larger samples are needed to further elucidate our findings.

Background: Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is the most frequent microdeletion syndrome and is mainly characterized by congenital cardiac defects, dysmorphic features, hypocalcemia, palatal dysfunction, developmental delay, and impaired immune function due to thymic hypoplasia or aplasia. Thyroid anomalies are frequently reported in patients with 22q11.2DS, although only a few well-structured longitudinal studies about autoimmune thyroid disease (ATD) have been reported., Aim: To longitudinally evaluate the frequency of thyroid anomalies and ATD in patients with 22q11.2DS., Patients and Methods: Pediatric patients with a confirmed genetic diagnosis of 22q11.2DS were recruited and followed up on longitudinally. Clinical, biochemical, and immunological data were collected, as well as thyroid function, autoimmunity, and thyroid sonographic data., Results: The study included 73 children with 22q11.2DS, with a mean follow-up duration of 9.51 ± 5.72 years. In all, 16 of the 73 enrolled patients (21.9%) developed ATD before 18 years of age (mean age 12.92 ± 3.66 years). A total of 20.5% developed Hashimoto's Thyroiditis (HT), of whom 50% required L-thyroxine treatment; 1.4% developed Graves Disease. Thyroid hypoplasia was found in 6/16 patients with ATD and left lobe hypoplasia in 9/16 patients. These features were also found in patients affected by 22q11.2DS without ATD. Among patients who developed ATD, at the first altered ultrasound scan, the most frequent anomalies suggestive of thyroiditis were inhomogeneous echotexture, diffuse or irregular hypo-echogenicity, and vascular overflow., Conclusion: We strongly recommend periodic screening of thyroid function and for autoimmunity in patients affected by 22q11.2DS. Along with blood tests, ultrasound scans of the thyroid gland should be performed periodically since some patients who go on to develop an ATD could have specific anomalies on ultrasound prior to any other anomaly.

Aim: The present study aimed to perform an initial validation of the Thymic-Thoracic Ratio as a sonographic marker of conotruncal defects in non-syndromic fetuses and to assess the possible correlation between the grade of thymic hypoplasia and the severity of conotruncal defects., Methods: The study was conducted between January and June 2018 on singleton pregnant women who underwent fetal echocardiography at our institution. Fetuses with a diagnosis of conotruncal defects without 22q11.2 deletion composed the study group, while healthy appropriate for gestational age fetuses composed the control group. The Thymic-Thoracic Ratio was measured in all included fetuses and compared between the study and control group. A ROC curve analysis to evaluate the diagnostic performance of Thymic-Thoracic Ratio toward the diagnosis of conotruncal defects was performed, with determination of sensitivity, specificity, PPV, NPV, positive likelihood ratio, and negative likelihood ratio. The severity of conotruncal defects was defined with the Aristotle score in each newborn who underwent a surgical operation. The correlation between Thymic-Thoracic Ratio and Aristotle score was assessed., Results: During the study period, 23 fetuses with conotruncal defects without 22q11.2 deletion constituted the study group, and 67 healthy appropriate for gestational age fetuses were included in the control group. The T-T ratio of the study group was significantly lower than the control group (0.32 ± 0.08 vs. 0.41 ± 0.08, p  < .001). The ROC curve analysis showed an AUC of 0.80 (95% CI, 0.71-0.89, p  < .001) and a T-T ratio cutoff value of 0.35 for the identification of a CTD, with a sensibility of 73.9% (95% CI: 51.6-89.8%), a specificity of 79.1% (95% CI: 67.4-88.1%) a PPV of 54.8% (95% CI: 41.8-67.3%), a NPV of 89.8% (95% CI: 81.5-94.7), a positive likelihood ratio of 3.54 (95% CI 2.09-5.98), and a negative likelihood ratio of 0.33 (95% CI 0.16-0.66). A negative correlation between Aristotle score and T-T ratio was found, with a Kendall-Tau coefficient of -0.41, p  = .04., Conclusion: T-T ratio measurement could be useful to identify fetuses at higher risk of conotruncal heart diseases, even without chromosomic deletion, with a cutoff of 0.35. Since a lower T-T ratio seems to be related to a worse surgical neonatal prognosis, it could be possible to provide effective counseling and refer patients to high-specialized centers for fetal echocardiography and cardiac surgery.

Hybrid single-stage repair of Kommerell's diverticulum in a right aortic arch.Aortic arch anomalies, isolated or associated with congenital heart defects, are cardiovascular manifestations frequently associated with 22q11.2 deletion syndrome. Kommerell's diverticulum in the context of a right aortic arch is an exceedingly rare congenital anomaly, consisting in aneurysmal degeneration of the origin of an aberrant left subclavian artery. Open surgical repair has been the treatment paradigm, but in recent years, hybrid and endovascular procedures have also been proposed. In this report we present the case of a patient affected by 22q11.2 deletion syndrome successfully treated for Kommerell's diverticulum associated with a right-sided aortic arch through a single-stage hybrid procedure, consisting of bilateral carotid-subclavian bypass, exclusion of the diverticulum by an endovascular thoracic stent graft, and aberrant left subclavian artery plug occlusion. This type of hybrid technique can be an excellent alternative to extensive open surgical repairs or when total endovascular repair is deemed unachievable, also in the context of a complex genetic syndrome.

This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, cortical surface area, and diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls. In addition, the studies report on significant associations between brain imaging metrics and disorder-related factors such as symptom severity and treatments. Visual comparison of effect size profiles shows that effect sizes are generally in the same direction and scale in severity with the disorders (in the order SZ > BD > MDD). The effect sizes for 22q11DS, a rare genetic syndrome that increases the risk for psychiatric disorders, appear to be much larger than for either of the complex psychiatric disorders. This is consistent with the idea of generally larger effects on the brain of rare compared to common genetic variants. Cortical thickness and surface area effect sizes for 22q11DS with psychosis compared to 22q11DS without psychosis are more similar to those of SZ and BD than those of MDD; a pattern not observed for subcortical brain structures and fractional anisotropy effect sizes. The observed similarities in effect size profiles for cortical measures across the psychiatric disorders mimic those observed for shared genetic variance between these disorders reported based on family and genetic studies and are consistent with shared genetic risk for SZ and BD and structural brain phenotypes., (© 2022 The Authors. Psychiatry and Clinical Neurosciences © 2022 Japanese Society of Psychiatry and Neurology.)

22q11.2 deletion syndrome is the most common microdeletion syndrome. This article reviews the different neurological manifestations of 22q11.2 deletion syndrome. The syndrome is associated with neurological disorders such as epilepsy and movement disorders. Patients with 22q11.2 DS have an increased incidence of provoked and unprovoked seizures. Provoked seizures include, amongst others, seizures due to hypocalcemia, surgery, perioperative hypoxia, antipsychotic medication, and fever. Both focal seizures, myoclonus and generalized tonic-clonic seizures occur in 22q11.2 DS. Generalized epilepsy occurs more often than in the background population. Furthermore, 22q11.2 DS is associated with a significantly increased risk of developing Parkinson's disease, and an increased incidence of dystonia has also been suggested. Abnormal neuroradiological findings - amongst them polymicrogyria - are common in 22q11.2.2 DS and reviewed in the article. The risk of psychiatric disorders, in particular schizophrenia, is increased in 22q11.2 DS., (© 2021. Fondazione Società Italiana di Neurologia.)

Purpose: We aimed to present the fetal ultrasound, cytogenetic/molecular testing and postmortem or postnatal clinical findings of cases with 22q11.2DS diagnosed prenatally., Materials and Methods: A retrospective medical record review of 48 prenatal cases diagnosed with 22q11.2DS were evaluated in our institution. Detailed ultrasound examination was performed on all fetuses. Postmortem and postnatal examinations were evaluated. The microdeletions were detected by karyotyping or microarray, then confirmed by FISH. Descriptive statistical analysis was performed., Results: Demographic data of 48 prenatal cases including 46 singletons and 1 dichorionic diamniotic twin pregnancy were evaluated. The most common extracardiac anomaly was skeletal system anomalies (25%), in which PEV was the most frequent one (20.8%). Polyhydramnios rate was detected as 31%, in 6.6% as an isolated finding. Microdeletion has been detected by karyotyping in 13 cases (13/47, 27.7%) (including 2 unbalanced translocations), by FISH in 28 cases (28/48, 58.3%), by microarray/a-CGH testing in 7 cases. Microarray analysis showed that in one case with unbalanced translocation had two consecutive deletions; one was proximal and other one distal to critical region and not encompassing TBX1 gene but CRKL and LZTR1 genes., Conclusion: The current study demonstrates the whole spectrum of atypical phenotypic and genotypic variations of 22q11.2DS in the largest prenatal case series reported to date. Therefore, differential diagnosis should be considered not solely in CHD, but also in the presence of isolated clubfeet and polyhydramnios. Establishing the diagnosis in the prenatal period may allow a postnatal multidisciplinary approach, as well as affect the actual prevalence of the disease., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

22q11.2 deletion syndrome (22q11DS), also known as velo-cardio-facial syndrome (VCFS) is the most common copy number variant (CNV) in humans caused by a microdeletion on chromosome 22q11.2. The phenotype encompasses heart anomalies, cleft palate and cognitive difficulties. Alongside brain differences in VCFS, such as reduced hippocampal volume, different cognitive developmental trajectories can be observed. The aim of this study was to explore the developmental trajectories of cognitive inhibition in memory using longitudinal data acquired in a large cohort of individuals with 22q11DS and the brain correlates to those developmental changes. 51 participants with 22q11DS (mean age: 13.75 ± 4.26, mean IQ score: 70.50 ± 10.75) and 43 typically developing individuals matched for age (M = 13.50 ± 4.91) and gender were recruited. To explore inhibition in memory, the Directed Forgetting paradigm was used. 30 words were presented, half were 'To be remembered items'(TBR) and the other half 'To be forgotten items' (TBF). To measure source memory, participants were asked during the recognition stage to say if the world was a TBR or a TBF item. Participants were tested during two consecutive visits, with a mean interval of 3 years. T1-weighted images were acquired using a 1.5 T Philips or a 3 T Siemens scanner at both visits. Both groups recognized more TBR than TBF items (Directed forgetting effect), however, participants with 22q11DS recognized fewer TBR items and did not show an increased recognition of TBR items with age. Furthermore, in participants with VCFS increased source memory errors with age was associated with a decline in hippocampal volume., (Copyright © 2021. Published by Elsevier B.V.)

Schizophrenia has been extensively associated with reduced cortical thickness (CT), and its neurodevelopmental origin is increasingly acknowledged. However, the exact timing and extent of alterations occurring in preclinical phases remain unclear. With a high prevalence of psychosis, 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that represents a unique opportunity to examine brain maturation in high-risk individuals. In this study, we quantified trajectories of CT maturation in 22q11DS and examined the association of CT development with the emergence of psychotic symptoms. Longitudinal structural MRI data with 1-6 time points were collected from 324 participants aged 5-35 years (N = 148 22q11DS, N = 176 controls), resulting in a total of 636 scans (N = 334 22q11DS, N = 302 controls). Mixed model regression analyses were used to compare CT trajectories between participants with 22q11DS and controls. Further, CT trajectories were compared between participants with 22q11DS who developed (N = 61, 146 scans), or remained exempt of (N = 47; 98 scans) positive psychotic symptoms during development. Compared to controls, participants with 22q11DS showed widespread increased CT, focal reductions in the posterior cingulate gyrus and superior temporal gyrus (STG), and accelerated cortical thinning during adolescence, mainly in frontotemporal regions. Within 22q11DS, individuals who developed psychotic symptoms showed exacerbated cortical thinning in the right STG. Together, these findings suggest that genetic predisposition for psychosis is associated with increased CT starting from childhood and altered maturational trajectories of CT during adolescence, affecting predominantly frontotemporal regions. In addition, accelerated thinning in the STG may represent an early biomarker associated with the emergence of psychotic symptoms., (© 2021. The Author(s).)

Deletions and duplications at the 22q11.2 locus are associated with significant neurodevelopmental and psychiatric morbidity. Previous diffusion-weighted magnetic resonance imaging (MRI) studies in 22q11.2 deletion carriers (22q-del) found nonspecific white matter (WM) abnormalities, characterized by higher fractional anisotropy. Here, utilizing novel imaging and processing methods that allow separation of signal contribution from different tissue properties, we investigate whether higher anisotropy is driven by (1) extracellular changes, (2) selective degeneration of secondary fibers, or (3) volumetric differences. We further, for the first time, investigate WM microstructure in 22q11.2 duplication carriers (22q-dup). Multi-shell diffusion-weighted images were acquired from 26 22q-del, 19 22q-dup, and 18 healthy individuals (HC). Images were fitted with the free-water model to estimate anisotropy following extracellular free-water elimination and with the novel BedpostX model to estimate fractional volumes of primary and secondary fiber populations. Outcome measures were compared between groups, with and without correction for WM and cerebrospinal fluid (CSF) volumes. In 22q-del, anisotropy following free-water elimination remained significantly higher compared with controls. BedpostX did not identify selective secondary fiber degeneration. Higher anisotropy diminished when correcting for the higher CSF and lower WM volumes. In contrast, 22q-dup had lower anisotropy and greater extracellular space than HC, not influenced by macrostructural volumes. Our findings demonstrate opposing effects of reciprocal 22q11.2 copy-number variation on WM, which may arise from distinct pathologies. In 22q-del, microstructural abnormalities may be secondary to enlarged CSF space and more densely packed WM. In 22q-dup, we see evidence for demyelination similar to what is commonly observed in neuropsychiatric disorders., (© 2021. The Author(s).)

22q11.2 deletion syndrome (22q11DS) is a severe genetic syndrome characterized by cognitive deficits and neuropsychiatric disorders, particularly schizophrenia. Neuroimaging alterations have been extensively reported in 22q11DS, both in gray and white matter structures. However, a considerable variability among the results affects the generalizability of the findings to date. Herein, we reviewed diffusion tensor imaging (DTI) findings in 22q11DS, their association with psychosis and cognition, and the implications of DTI studies on neurodevelopment in 22q11DS. We also investigated differences between 22q11DS and schizophrenic patients without 22q11DS. Using an online search of PubMed and Embase, we identified studies investigating DTI findings in 22q11DS. After selecting eligible studies in accordance with the preferred reporting items for systematic reviews and meta-analyses guideline, we included thirty-one studies. Overall, 22q11DS patients show altered structural connectivity and disrupted microstructural organization of most cortical and subcortical structures and white matter tracts. Moreover, despite a significant heterogeneity in the results, reduced diffusivity measures and elevated fractional anisotropy were observed. However controversial, compared to typically developing children, 22q11DS patients reached the peak of fractional anisotropy (FA) and the trough of radial diffusivity (RD) at an older age, which shows neurodevelopmental delay. DTI measures were also associated with psychotic symptoms and cognitive deficits. In conclusion, this study provides a comprehensive review of microstructural alterations in 22q11DS. Future larger investigations on this syndrome could potentially lead to the detection of early diagnostic imaging markers for genetically induced schizophrenia, thus improving the treatment and, ultimately, the outcome., Competing Interests: Declaration of Competing Interest None of authors has any financial and personal relationships with other people or organizations to report that could inappropriately influence or bias this work., (Copyright © 2021. Published by Elsevier B.V.)

Background and Purpose: MR imaging studies and neuropathologic findings in individuals with 22q11.2 deletion syndrome show anomalous early brain development. We aimed to retrospectively evaluate cerebral abnormalities, focusing on gray matter heterotopia, and to correlate these with subjects' neuropsychiatric impairments., Materials and Methods: Three raters assessed gray matter heterotopia and other morphologic brain abnormalities on 3D T1WI and T2*WI in 75 individuals with 22q11.2 deletion syndrome (27 females, 15.5 [SD, 7.4] years of age) and 53 controls (24 females, 12.6 [SD, 4.7] years of age). We examined the association among the groups' most frequent morphologic findings, general cognitive performance, and comorbid neuropsychiatric conditions., Results: Heterotopia in the white matter were the most frequent finding in individuals with 22q11.2 deletion syndrome ( n = 29; controls, n = 0; between-group difference, P < .001), followed by cavum septi pellucidi and/or vergae ( n = 20; controls, n = 0; P < .001), periventricular cysts ( n = 10; controls, n = 0; P = .007), periventricular nodular heterotopia ( n = 10; controls, n = 0; P = .007), and polymicrogyria ( n = 3; controls, n = 0; P = .3). However, individuals with these morphologic brain abnormalities did not differ significantly from those without them in terms of general cognitive functioning and psychiatric comorbidities., Conclusions: Taken together, our findings, periventricular nodular heterotopia or heterotopia in the white matter (possibly related to interrupted Arc cells migration), persistent cavum septi pellucidi and/or vergae, and formation of periventricular cysts, give clues to the brain development disorder induced by the 22q11.2 deletion syndrome. There was no evidence that these morphologic findings were associated with differences in psychiatric or cognitive presentation of the 22q11.2 deletion syndrome., (© 2021 by American Journal of Neuroradiology.)

Language difficulties of children with Developmental Language Disorder (DLD) have been associated with multiple underlying factors and are still poorly understood. One way of investigating the mechanisms of DLD language problems is to compare language-related brain activation patterns of children with DLD to those of a population with similar language difficulties and a uniform etiology. Children with 22q11.2 deletion syndrome (22q11DS) constitute such a population. Here, we conducted an fMRI study, in which children (6-10yo) with DLD and 22q11DS listened to speech alternated with reversed speech. We compared language laterality and language-related brain activation levels with those of typically developing (TD) children who performed the same task. The data revealed no significant differences between groups in language lateralization, but task-related activation levels were lower in children with language impairment than in TD children in several nodes of the language network. We conclude that language impairment in children with DLD and in children with 22q11DS may involve (partially) overlapping cortical areas., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia., Methods: We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups., Results: Relative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms., Conclusions: Our findings suggest a critical period of prefrontal cortex-hippocampal-striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The 22q11.2 deletion syndrome (22q11DS) is a developmental genetic syndrome associated with a 30% risk for developing schizophrenia. Lateral ventricles and subcortical structures are abnormal in this syndrome as well as in schizophrenia. Here, we investigated whether these structures are related in young adults with 22q11DS with and without prodromal symptoms (PS) for schizophrenia and whether abnormalities in volumes are associated with global functioning. MR images were acquired on a 3T scanner from 51 individuals with 22q11DS and 30 healthy controls (mean age: 21±2 years). Correlations were performed to evaluate the relationship between ventricular and subcortical volumes, with Global Assessment of Functioning (GAF) and Premorbid Adjustment Scale (PAS) in each group. Lateral ventricular volumes correlated negatively with subcortical volumes in individuals with 22q11DS. In individuals with 22q11DS with PS only, GAF correlated positively with volumes of the lateral ventricles and negatively with subcortical volumes. PAS correlated negatively with lateral ventricle volumes, and positively with volumes of subcortical structures. The results suggest a common neurodevelopmental mechanism related to the growth of these brain structures. Further, the ratio between the volumes and clinical measures could potentially be used to characterize individuals with 22q11DS and those from the general population for the risk of the development of schizophrenia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

How the brain's white-matter anatomy constrains brain activity is an open question that might give insights into the mechanisms that underlie mental disorders such as schizophrenia. Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder with an extremely high risk for psychosis providing a test case to study developmental aspects of schizophrenia. In this study, we used principles from network control theory to probe the implications of aberrant structural connectivity for the brain's functional dynamics in 22q11DS. We retrieved brain states from resting-state functional magnetic resonance images of 78 patients with 22q11DS and 85 healthy controls. Then, we compared them in terms of persistence control energy; that is, the control energy that would be required to persist in each of these states based on individual structural connectivity and a dynamic model. Persistence control energy was altered in a broad pattern of brain states including both energetically more demanding and less demanding brain states in 22q11DS. Further, we found a negative relationship between persistence control energy and resting-state activation time, which suggests that the brain reduces energy by spending less time in energetically demanding brain states. In patients with 22q11DS, this behavior was less pronounced, suggesting a deficiency in the ability to reduce energy through brain activation. In summary, our results provide initial insights into the functional implications of altered structural connectivity in 22q11DS, which might improve our understanding of the mechanisms underlying the disease., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Computer-assisted pattern recognition platforms, such as Face2Gene® (F2G), can facilitate the diagnosis of children with rare genetic syndromes by comparing a patient's features to known genetic diagnoses. Our work designed, implemented, and evaluated an innovative model of care in clinical genetics in a heterogeneous and multicultural patient population that utilized this facial phenotyping software at the point-of-care. We assessed the performance of F2G by comparing the suggested diagnoses to the patient's confirmed molecular diagnosis. Providers' overall experiences with the technology and trainees' educational experiences were assessed with questionnaires. We achieved an overall diagnostic yield of 57%. This increased to 82% when cases diagnosed with syndromes not recognized by F2G were removed. The mean rank of a confirmed diagnosis in the top 10 was 2.3 (CI 1.5-3.2) and the mean gestalt score 37.6%. The most commonly suggested diagnoses were Noonan syndrome, mucopolysaccharidosis, and 22q11.2 deletion syndrome. Our qualitative assessment revealed that clinicians and trainees saw value using the tool in practice. Overall, this work helped to implement an innovative patient care delivery model in clinical genetics that utilizes a facial phenotyping tool at the point-of-care. Our data suggest that F2G has utility in the genetics clinic as a clinical decision support tool in diverse populations, with a majority of patients having their eventual diagnosis listed in the top 10 suggested syndromes based on a photograph alone. It shows promise for further integration into clinical care and medical education, and we advocate for its continued use, adoption and refinement along with transparent and accountable industrial partnerships., (© 2021 Wiley Periodicals LLC.)

Abstract: The surgical management of velopharyngeal incompetence (VPI) in children with 22q11.2 deletion syndrome (22q11.2 DS) is challenging. There are numerous approaches and children often undergo more than one operation. Our aim was to develop a method using images from routine lateral videofluoroscopy to study the dimensions of the velopharynx in this cohort.We analyzed 22 pre-operative lateral videofluoroscopy recordings of children with 22q11.2 DS and VPI. Fourteen had a submucous cleft palate (SMCP) and 8 had no obvious palatal abnormality but who were subsequently labelled as having an occult submucous cleft palate (OSMCP). The control data were 10 historic records of children with cleft lip and an intact palate. The authors identified key points on radiographs of the velum at rest and when elevated to measure the total velar length, functional velar length and pharyngeal depth and compared them ratiometrically.The intra-observer reliability was > 0.9 whereas the inter-observer reliability was > 0.74. The velopharyngeal depth/total velar length was significantly greater in 22q11.2 DS than the control group P < 0.001. There was no difference between SMCP and OSMCP patients, P = 0.556. There was no difference in the functional velar length/total velar length between 22q11.2 DS and controls (P = 0.763).In this study, the authors demonstrate a reliable method to gain useful ratiometric measurements of the velopharynx. This may help with treatment planning. Children with 22q11.2 DS and VPI have a larger velopharyngeal depth/total velar length ratio that may explain some of the difficulty in management., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H+\H-) reveals no change in MMN response in 22q11.2DS (H+ and H-) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH+ as compared to 22q11.2DSH- and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6-31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

Introduction: Patients with 22q11.2 deletion syndrome (22q11.2DS) have a variety of anatomic anomalies. For surgeons operating in proximity to the retropharynx, the most pertinent is medial displacement of the internal carotid arteries. The purpose of this study is to describe the preoperative use of magnetic resonance angiography (MRA) in surgical planning and update the incidence rate of medial carotid displacement in patients with 22q11.2DS., Methods: This is a retrospective cohort study of patients with a confirmed diagnosis of 22q11.2 deletion and preoperative MRA <18 years old who underwent tonsillectomy, adenoidectomy, Furlow palatoplasty (FPP), posterior pharyngeal flap (PPF), sphincter pharyngoplasty (SPP), or submucosal cleft palate (SMCP) repair between January 1st, 2008 and December 31st, 2019., Results: Ninety patients who met the inclusion criteria underwent 133 procedures. The majority identified as Caucasian (84.4%); 52.2% were female. Cervical MRA was more likely to be ordered before a PPF (80.9%) and tonsillectomy (72.7%) over a FPP (47.6%) or adenoidectomy (11.1%). Carotid medialization was visualized in 23 patients (25.6%) and was mild in 11 cases, moderate in 7 cases, and significant in 5 cases. There was no association between sex, race/ethnicity, or genetic diagnosis with carotid medialization. Flap shortening was necessary in 20% of PPF cases to avoid injuring the medialized vessel., Conclusion: Patients with 22q11.2DS may have higher rates of medialization of the carotid arteries than previously thought. Given the risk for complications in these patients during pharyngeal operations, there may be a critical place for MRA in surgical planning for patients with 22q11.2DS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Low hippocampal volume is a consistent finding in schizophrenia and across the psychosis spectrum. However, there is a lack of studies investigating longitudinal hippocampal development and its relationship with psychotic symptoms. The 22q11.2 deletion syndrome (22q11DS) has proven to be a remarkable model for the prospective study of individuals at high risk of schizophrenia to unravel the pathophysiological processes predating the onset of psychosis. Repeated cerebral MRIs were acquired from 140 patients with 22q11DS (53 experiencing moderate-to-severe psychotic symptoms) and 135 healthy controls aged from 6 to 35 years and with up to 5 time points per participant. Hippocampal subfield analysis was conducted using FreeSurfer-v.6 and FIRST-FSL. Then, whole hippocampal and subfield volumes were compared across the groups. Relative to controls, patients with 22q11DS showed a remarkably lower volume of all subfields except for CA2/3. No divergent trajectories in hippocampal development were found. When comparing patients with 22q11DS exhibiting psychotic symptoms to those without psychosis, we detected a volume decrease during late adolescence, starting in CA1 and spreading to other subfields. Our findings suggested that hippocampal volume is consistently smaller in patients with 22q11DS. Moreover, we have demonstrated that patients with 22q11DS and psychotic symptoms undergo a further decrease in volume during adolescence, a vulnerable period for the emergence of psychosis. Interestingly, CA2/3, despite being affected in patients with psychotic symptoms, was the only area not reduced in patients with 22q11DS relative to controls, thus suggesting that its atrophy exclusively correlates with the presence of positive psychotic symptoms.

Aims: 22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly 'shifting' the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge., Methods: Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined., Results: No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC ( η 2 = 0.094 ) but not striatal glutamate concentrations as well as ACC GABA concentrations ( η 2 = 0.176 ) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients., Discussion: We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

Background: 22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported., Methods: We profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically matched healthy control subjects. To determine whether brain-behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains., Results: Cognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD subdomains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally measured positive and negative symptoms were elevated in deletion carriers. Finally, healthy control subjects showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups., Conclusions: 22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability., (Copyright © 2020 Society of Biological Psychiatry. All rights reserved.)

Objective: In patients with velocardiofacial syndrome (VCFS), medial displacement of the internal carotid arteries (ICAs) may increase the risk of vascular injury during the surgical correction of velopharyngeal dysfunction (VPD). Some surgeons advocate the use of vascular imaging studies prior to surgery. Nevertheless, the role of preoperative imaging is still controversial. This study aimed to review the current practice of the UK cleft units and also examine our own practice at the Evelina London Children's Hospital in relation to children with VCFS undergoing speech surgery over the previous 7 years., Design: A questionnaire was sent to all UK cleft surgeons to enquire about the management and use of preoperative vascular imaging in patients with VPD and VCFS. A retrospective study was also conducted of the unit's 7-year series of patients with VPD and VCFS., Results: Thirty-four completed questionnaires were returned (response rate 100%). Most UK surgeons (73.5%) do not regularly order preoperative vascular imaging for patients with VCFS although some reportedly would consider it if a posterior pharyngeal wall pulsation was visible. In our unit, between 2013 and 2019, a total of 40 patients affected by VCFS have been assessed for VPD. A magnetic resonance angiography (MRA) was performed for 23 patients. Medial deviation of the ICAs was identified in 7 (30%) patients., Conclusions: The results of the national survey showed no consensus on routine use of preoperative vascular imaging. Our retrospective study showed a 30% prevalence of medialized ICAs in our patient cohort. In these patients, the MRA findings influenced the choice of speech surgery.

BACKGROUND The 22q11.2 deletion syndrome (22q11.2DS) is the most common identified microdeletion in humans. Anomalies of the vestibular system can occur with great frequency and are reported in the radiology literature. Fewer reports exist regarding vestibular function or its clinical features. CASE REPORT We present a case report of a competitive gymnast with 22q11.2DS who was noted to be having specific issues related to balance under conditions of competition, specifically on the balance beam. Comprehensive balance assessment provided evidence of the absence of lateral semicircular canal function, correlating with computed tomography findings and her symptoms. Counselling and targeted training greatly improved her performance. CONCLUSIONS Comprehensive balance testing correlated with clinical and radiographic findings in a competitive gymnast with 22q11.2DS. Results demonstrated the functional aspect of this anomaly but also displayed the extent to which the complex interactions of all components of balance can work together to overcome balance issues under intense vestibular stress.

Background: The 22q11.2 deletion syndrome (22q11DS) is caused by a deletion on chromosome 22 locus q11.2. This copy number variant results in haplo-insufficiency of the catechol-O-methyltransferase (COMT) gene, and is associated with a significant increase in the risk for developing cognitive impairments and psychosis. The COMT gene encodes an enzyme that primarily modulates clearance of dopamine (DA) from the synaptic cleft, especially in the prefrontal cortical areas. Consequently, extracellular DA levels may be increased in prefrontal brain areas in 22q11DS, which may underlie the well-documented susceptibility for cognitive impairments and psychosis in affected individuals. This study aims to examine DA D2/3 receptor binding in frontal brain regions in adults with 22q11DS, as a proxy of frontal DA levels., Methods: The study was performed in 14 non-psychotic, relatively high functioning adults with 22q11DS and 16 age- and gender-matched healthy controls (HCs), who underwent DA D2/3 receptor [18F]fallypride PET imaging. Frontal binding potential (BPND) was used as the main outcome measure., Results: BPND was significantly lower in adults with 22q11DS compared with HCs in the prefrontal cortex and the anterior cingulate gyrus. After Bonferroni correction significance remained for the anterior cingulate gyrus. There were no between-group differences in BPND in the orbitofrontal cortex and anterior cingulate cortex., Conclusions: This study is the first to demonstrate lower frontal D2/3 receptor binding in adults with 22q11DS. It suggests that a 22q11.2 deletion affects frontal dopaminergic neurotransmission.

Objectives: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities., Methods: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected., Results: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95 th and 99 th percentile and 62% for fetuses with NT≥99 th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively., Conclusion: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement., (© 2019 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: The aim of the study was to assess genotype-phenotype correlation of prenatally diagnosed fetal DGS and dup22q11 syndrome by fetal molecular genetic analysis, fetal ultrasound, and/or MRI., Methods: In this retrospective consecutive case series, pregnant women were screened for fetal anomalies during a period of 10 years. Fetal genotype was assessed in 72 cases upon the occurrence of five prenatal fetal phenotypic features: cardiac anomalies, hypo/aplastic thymus, craniofacial malformations, urinary abnormalities, or IUGR; genotype-phenotype correlation was tested to potentially improve prenatal diagnosis of fetal DGS and dup22q11 syndrome., Results: Fetal genotypes of deletions or duplications in proximal clusters of LCR22s (A-B) were associated with fetal cardiac anomalies in combination with hypo/aplastic thymus and craniofacial malformations, suggesting a correlation with deleted HIRA. TOF associated with aplastic thymus in combination with renal defects indicated a relevant correlation with TBX1 deletion. Deletions in central LCR22s (B-D) with the loss of CRKL supposed a trend of genotype-phenotype correlation with fetal urinary abnormalities., Conclusion: Genotype-phenotype correlation might improve prenatal diagnosis of fetal DGS and dup22q11 syndrome. Hence, prenatal screening and counseling is highly enhanced by a combination of fetal molecular genetic analysis, fetal ultrasound, and/or MRI. The implications of these findings remain to be explored., (© 2019 John Wiley & Sons, Ltd.)

22q11.2 deletion syndrome (DS) is considered to be the most robust genetic model of psychosis. In the last decade, there has been increased interest in the brain abnormalities associated with these genetic changes. Most imaging findings in this population come from small samples. This increases the risk of reporting spurious effects that reflect the idiosyncrasies of each study. Thus, the current work is aimed at identifying whether there are spatially consistent structural and functional brain abnormalities in individuals with 22q11.2 DS through (i) a comprehensive label-based systematic review and (ii) a coordinate-based meta-analysis of magnetic resonance imaging studies. The systematic review identified the frontal middle gyri, posterior cingulum, right cuneus and bilateral precuneus as the most affected regions. The meta-analysis revealed consistent abnormalities in the bilateral inferior parietal lobe, right precuneus, right superior temporal gyrus and posterior cingulate cortex. This study provides an important starting point for future research as it sheds light on possible genetically determined psychosis susceptibility regions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Our goal is to correlate the findings on flexion and extension radiographs with dynamic magnetic resonance imaging (MRI), and the clinical history, in a nonrandomly selected cohort of patients with 22q11.2 deletion syndrome (22q)., Methods: All patients with the 22q who had a dynamic MRI from January 2004 to March 2015 were included. We analyzed multiple radiographic measurements on both the dynamic plain films and the MRIs, and correlated these findings with a review of each patient's medical record., Results: Multiple congenital anomalies were identified as noted in previous studies, and 61% of the patients had a failure of fusion of the anterior (n=2, 9%), posterior (n=2, 9%), or anterior and posterior arches (n=10, 43%). Quantitative measurements were impossible to report with certainty because of the upper cervical anomalies, and no cases of instability were identified using a qualitative assessment. We identified spinal cord encroachment (30%) and impingement (18%); however, none of the patients had any signal change in their spinal cord. None of these findings could be definitively correlated with any clinical symptoms. A single patient was diagnosed with a Chiari I malformation, while another had cerebellar ectopia., Conclusions: Although the upper cervical anomalies are extremely common in 22q, we did not identify cases of instability on dynamic plain radiographs and MRI. Although our findings do not support routine screening with flexion and extension MRI, this study may be required in patients with neurological symptoms and/or findings or abnormalities on dynamic plain radiographs., Level of Evidence: Level III.

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)